Culinary Herbs and Spices: A Global Guide [1 ed.] 1839161566, 9781839161568

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Culinary Herbs and Spices A Global Guide

Culinary Herbs and Spices A Global Guide

By Elizabeth I. Opara London Metropolitan University, UK E-mail: [email protected] and Magali Chohan St Mary's University, UK E-mail: [email protected]

Print ISBN: 978-1-83916-156-8 PDF ISBN: 978-1-83916-444-6 EPUB ISBN: 978-1-83916-325-8 A catalogue record for this book is available from the British Library © Elizabeth I. Opara and Magali Chohan 2021 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Whilst this material has been produced with all due care, The Royal Society of Chemistry cannot be held responsible or liable for its accuracy and completeness, nor for any consequences arising from any errors or the use of the information contained in this publication. The publication of advertisements does not constitute any endorsement by The Royal Society of Chemistry or Authors of any products advertised. The views and opinions advanced by contributors do not necessarily reflect those of The Royal Society of Chemistry which shall not be liable for any resulting loss or damage arising as a result of reliance upon this material. The Royal Society of Chemistry is a charity, registered in England and Wales, Number 207890, and a company incorporated in England by Royal Charter (Registered No. RC000524), registered office: Burlington House, Piccadilly, London W1J 0BA, UK, Telephone: +44 (0) 207 4378 6556. For further information see our web site at www.rsc.org Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK

Preface It was in 2005 that I was asked by a student if I would be interested in supervising their undergraduate research project. The student's name was Magali Chohan, my co-author, who had just completed year 2 of the Nutrition degree at Kingston University. She talked of her eagerness to carry out a project on culinary herbs and spices, an eagerness that stemmed from her use of them in the preparation of food. She went on to talk about the research that had been done which focused on their polyphenol content and antioxidant properties but thought it strange that no one had investigated the impact of cooking on these properties. My research at that time concerned medicinal plants so, along with the fact that I was the Course Director for Kingston's Nutrition programme, I was the obvious choice. I must admit that at the time my interest in culinary herbs and spices did not extend beyond that of most people. When I used rosemary, black pepper, ginger, basil, coriander (leaves or seeds), oregano, sage and/or thyme to prepare lamb, chicken, rice, vegetables, stews and soups I did give not give them much thought beyond ensuring that they enhanced the flavour of the foods I prepared. That meeting fifteen years ago was the start of a not always easy journey – one that continues to this day – to understand the significance of these foods beyond their flavour enhancing properties with Magali's undergraduate research project spawning other research projects both undergraduate and postgraduate and a number of research publications. Despite our work and the work of other researchers on establishing the significance of culinary herbs and spices in the context of health and disease, writing a book about them was never on my wish list. Yet, when I was contacted by the Royal Society of Chemistry to write a proposal for a book, I jumped at the opportunity to produce a body of work that communicates and reflects the global nature of the research that has and is being done on these foods. I knew I could not do justice to these foods on my own and so asked my long time research collaborator and friend Magali if she would like to get involved; in fact, it was she that put the list of thirty together and came up with the title of the book. The task was far greater than we had anticipated, as the literature concerning the bioactive properties and purported health benefits for many of culinary herbs and spices we discuss, particularly those used in the Indian subcontinent and the Middle East, is vast. However, we found writing this book extremely educational. I thought I knew a lot about culinary herbs and spices before the book – I even dared consider myself an expert – but over the time it took to write this book, I learnt so much more about these foods and the work that has been done to understand more fully what role they might play in the maintenance of health, disease prevention and management. The experience of writing this book was not only one of learning; midway

through writing it the pandemic hit and with it came a number of personal and professional challenges. I am, therefore, very happy, proud, and relieved, that Magali and I completed what we set out to do – write a global guide on foods that have done more than simply hold our interest for over fifteen years. Dr Elizabeth Opara For as long as I can recall I have been passionate about aromatic plants, probably stemming from a childhood spent in rural France, surrounded by a wide variety of plants with memorable scents. I remember twigs of thyme were picked to add flavour to soups as well as to prepare infusions to treat a cold. This interest led me to study part-time courses in Aromatherapy, Herbal Medicine and Nutritional Medicine when I arrived in the UK. These courses enabled me to learn enough English and grasp sufficient foundation in science to obtain a place at university as a mature student with three young children in tow, thanks to the then course director for Nutrition at Kingston University, London, Dr Elizabeth Opara, who was willing to offer me a chance at obtaining an education, for which I am eternally grateful. Dr Opara had an interest in medicinal plants, so I decided to pitch a specific research project idea concerning the impact of food processing and cooking on the antioxidant properties of a selection of culinary herbs and spices, rather than select one of the undergraduate research topics offered that year. This project idea was not only warmly welcomed and approved but was eventually awarded a first-class grade and successfully published. This then led to the development of my PhD thesis, and my career as an academic, from which further publications and research projects emerged over the past fifteen years. When Dr Opara was contacted by the Royal Society of Chemistry to write a proposal for a book, she invited me to lunch to discuss the project and offer that I get involved, and I did not hesitate to agree. I now realise that I had a very naïve idea of what this would entail, and it became especially challenging through the Covid-19 pandemic, with juggling professional and personal commitments alongside the research for the book. Overall the main difficulty for my sections was in sourcing literature in English (or French) concerning the historical and folk uses of some of the plants outside Western culture, which made me aware of my Eurocentric perspective. However, I am delighted to have contributed to completing this work with my ongoing mentor, Dr Opara, and share with the reader the incredible journey of this selection of culinary herbs and spices, the role these have played in various cultures all over the globe and how they still inspire ongoing high-quality research today. Dr Magali Chohan

Glossary

3-hydroxy-3-methylglutaryl coenzyme A (3-HMGCoA) reductase Aberrant crypt foci (ACF)

Acetylation Acetylcholinesterase

Acaricides Adenocarcinoma

Adipocytes Adipose tissue Adrenergic Advanced protein oxidation products Aerial parts of the plant Agonist Alkylating agents Allocation concealment

Alpha-amylase Alpha-glucosidase Amyloid β plaques (or amyloid plaques)

Analgesia Analgesic Anaphylactic shock

key regulatory enzyme in cholesterol synthesis.

abnormal tube-like glands (lesions) that form on the epithelial cells that line the colon and rectum. They may progress to colorectal cancer. the introduction of an acetyl group into a chemical compound. an enzyme which hydrolyses (breaks down) the neurotransmitter acetylcholine and plays a role in the pathogenesis of Alzheimer's disease. pesticides that are used to kill ticks and mites. cancer that begins in mucus producing glandular cells. Examples include types of breast, colorectal, lung, pancreatic and prostate cancer. fat cells. connective tissue rich in adipocytes. working on or mimicking the action of adrenaline (epinephrine) and noradrenaline (norepinephrine). biomarkers of oxidative modification of protein which are used as a marker of oxidative stress. the parts of the plant above the soil – stem, leaves, flower, fruit, seed. compound that binds and activates a receptor to elicit a biological response. agents which bind covalently to DNA resulting in DNA strand breaks. They are carcinogenic. used in the randomization of participants into groups for clinical trials. The concealment hides the method of sorting the participants to minimise bias. an enzyme which breaks down starch and glycogen. an enzyme which breaks down starch and disaccharides to glucose. aggregates of proteins that form between nerve cells (neurons). Evidence points to their formation, initially in regions of the brain that are involved with cognitive functions including memory, contributing to the development of Alzheimer's disease. pain relief. medication used to relieve pain. a severe allergic reaction, which results in a marked drop in blood pressure and narrowing of airways leading to difficulty breathing.

Androgenic Androgens Androgen dependent prostate cancer Androgen independent prostate cancer Angina Angiogenesis Angiotensin Angiotensin-1-converting enzyme (ACE) Antagonist Anti-mutagenic Anti-proliferative Antinociceptive Antioxidant activity

Antioxidant capacity

Antioxidant content Antioxidant status Anti-platelet aggregation Anxiolytic Aorta Apolipoprotein Apoptosis Assay

referring to male hormones, for example testosterone. steroid hormones that regulate the development maintenance and function of male characteristics and reproductive activity. prostate cancer dependent on or sensitive to androgens. prostate cancer not dependent on or sensitive to androgens. chest pain caused by reduced blood flow to the heart. formation of new blood vessels. a hormone that gives rise to vasoconstriction and increased blood pressure. an enzyme which plays a key role in the regulation of blood pressure. a compound that blocks the action of a receptor, its ligands, or agonists by binding to it. agents/compounds that inhibit the action of mutagens. agents/compounds that inhibit cell proliferation. the blocking of the detection of pain by sensory neurons (nerve cells). the blocking, limitation, or prevention of the oxidation of molecules, for example proteins, lipids and DNA by reactive oxygen species. The term antioxidant activity is sometimes used interchangeable with the term antioxidant capacity. the capacity of a substance to act as an antioxidant, normally the scavenging of free radicals, compared to that of a standard. The term antioxidant capacity is sometimes used interchangeable with the term antioxidant activity. the amount of antioxidant in food. the overall antioxidant state of the body. inhibition of platelet aggregation. an anti-anxiety, calming agent. the aorta is the main artery that carries blood away from the heart to the rest of the body.

a protein that binds to a lipid to form a lipoprotein. programmed death of damaged/cancerous cells. a laboratory-based method used to measure the presence of a compound or activity. Arterial blood pressure blood pressure. Arterial thrombosis a blood clot that forms in an artery. Such a clot can obstruct blood flow to the brain or heart, and can narrow an artery or arteries going to the heart leading to angina. Atherogenic index used as a marker of abnormal lipid levels and an indicator of risk of developing cardiovascular disease. Atherogenesis/atherosclerosis a build-up of lipids, specifically triglyceride (fat) and cholesterol in and on the walls of arterial blood vessels. (This build up forms into plaques which restrict blood form. If the plaques rupture, they can lead to the formation of blood clots). Autophagy meaning the ‘eating of self’, it is a cellular process in which cells degrade and destroy old and damaged proteins, other substances and organelles. The breakdown products are recycled to support cellular functions during periods of stress and starvation. Bactericidal an action which results in killing bacteria. Before the Common Era another and now more commonly used term for before the (BCE) Christian Era.

Beta-adrenergic Biofilm Blinding

Body mass index

Bradycardia Cancer stem cells Candidiasis Carcinogen Carcinogenesis

Cardiac hypertrophy Cardio-depressant Cardiotonic

Cardiotoxicity Cardiovascular disease

Carrageenan

Catalase (CAT) Cell cycle Cell cycle arrest Cell differentiation Cell migration

Central nervous system

Cerebral infarction Cerebral ischaemia

an action mediated by beta-adrenoreceptors resulting in the relaxation of the muscle of airways and easier breathing. a collection of one or more microorganisms that adhere to one another and grow on different surfaces. a process used in the design of experimental studies in which participants and/or investigators are unaware of the allocation of the participants to a treatment/treatments and the control/placebo. When only the participants or the investigators are unaware of the allocation it is called single blinding. When neither the participants and the investigators are aware of the allocation it is called double blinding. an index derived from the height and the weight of a person. It is an indicator of body fatness and is defined as the body mass divided by the square of the body height. It is expressed in units of kg m−2. the slowing down of heart rate. a subpopulation of cells present in tumours which are able to initiate and sustain tumour growth in vivo. a fungal infection caused by the species of Candida. The infection commonly affects the vagina and skin. a compound that promotes the cancer process (carcinogenesis). the cancer process which consists of three stages: stage 1 initiation (gene mutation/s), stage 2 promotion (increase in the proliferation of cells carrying the gene mutation/s), and stage 3 progression (irreversible genetic changes in the affected cells (now malignant cells)) with the malignant cells acquiring more aggressive characteristics over time. abnormal enlargement or thickening of the heart muscle. an agent that depresses heart function and lowers blood pressure. an effect in which the efficiency and contraction of heart muscle is improved which leads to increased blood flow throughout the body. damage to the heart caused by harmful chemicals. a group of diseases affecting the heart and blood vessels. Angina, coronary heart disease (CHD), myocardial infarction (heart attack) and stroke are examples of cardiovascular disease. a polysaccharide extracted from red edible seaweed used in the food industry as a thickening and stabilizing agent; kappa (κ)carrageenan is a class of carrageenan. an enzyme that catalyses the breakdown of hydrogen peroxide to oxygen and water. a 4-stage process of the growth and division of cells. a stopping point in the cell cycle. a process by which a cell changes into a more specialized cell type. the movement of cells in a particular direction to specific locations. Cell migration plays a key role in wound healing and the immune response. the central nervous system is made up of the brain and spinal cord with the brain playing a central role in the control of most bodily functions including. stroke. insufficient blood flow to the brain due to a blockage in an artery. It is a type of stroke.

Chemopreventive Chitosan

an agent that stops the development of cancer. a polysaccharide made from the shell of crustaceans.

Cholesterol ester Cholinergic compounds

an ester of cholesterol and a dietary lipid. compounds/agents that mimic and modulate the neurotransmitter acetylcholine. a study or experiment in which the effect of a treatment on human health outcomes is investigated. a study in which participants receive a sequence of treatments. For example, participants are given either the treatment or the control for a given period of time after which they go through a washout period and then those previously given the treatment are given the control and those previously given the control, are given the treatment for the same given period of time. cross-reactivity between allergens occurs when an antibody raised against a specific allergen has a high affinity for a different allergen due to structural similarities between the two allergens. a protein that is a key regulator of the cell cycle. Over expression (overproduction) of this protein has been linked to the development and progression of cancer. an enzyme involved in the synthesis of prostaglandin. It is a key pro-inflammatory mediator and is overexpressed in certain cancers including colorectal cancer. a family of enzymes located in liver cells, which are involved in the metabolism of drugs and other foreign substances commonly referred to as xenobiotics. These enzymes are involved in the activation of pro-carcinogens (a compound or agent that becomes carcinogenic once it has been metabolised). a large group of protein or peptides that are produced by immune cells. Cytokines mediate and regulate immune responses, inflammation and the formation of blood cells. inhibition of cell growth and proliferation. an action that results in cell damage or cell death. removal of compounds responsible for the bitter sensation/taste. a method used to extract herbal or plant material by boiling. dendritic cells are cells involved in the immune response; they present antigens, substances that trigger an immune response to T cells, which are a type of immune cell. enzymes are involved in the deactivation and/or removal of procarcinogens and carcinogens. pressure in the arteries when the heart rests between beats. It is the bottom number of a blood pressure reading. a region of DNA covalently bound to a chemical which is potentially carcinogenic. The formation of DNA adducts can initiate carcinogenesis. DNA damage. a compound or agent that mimics or modulates the neurotransmitter dopamine. a specified amount of an agent or drug prescribed to be taken a set number of times a day/week for a specified period of time. In some cases the dosage also takes into consideration body weight and age. a specified amount of an agent or drug taken at one time. the level of a response to drug, chemical or food in relation to

Clinical trial Crossover trial

Cross-reactivity

Cyclin D1

Cyclo-oxygenase 2 (COX-2)

Cytochrome P450 enzymes

Cytokine

Cytostatic Cytotoxic Debitterized Decoction Dendritic cells

Detoxification enzymes Diastolic blood pressure DNA adduct

DNA lesions Dopaminergic Dosage

Dose Dose-dependent

Double blind placebo randomized controlled trial

Dry mouth

Dysmenorrhea (primary)

Dyslipidemia ED50 Emulsifier

Endothelial cells Endothelial function/endothelial vascular function Endothelin-1 Epididymal fat Epigenetics Epithelial

Erythema Expression Ex vivo

Ferric reducing antioxidant power (FRAP) Fibrinogen

Fibrinolysis Fibrinolytic effect

Fibromyalgia Flatus Flow mediated dilation Follicular stimulating hormone (FSH)

the amount/dose used. a study designed so that participants are randomly assigned a treatment or placebo; neither the participants nor the investigators are aware of who has been allocated the treatment or the placebo. on its own dry mouth is not a serious condition; however, it can be a sign of a number of conditions including autoimmune diseases, diabetes, thrush (fungal infection in the mouth), stroke and Alzheimer's disease. a condition in which abdominal cramps occur just before or during menstruation which are not caused by another female reproductive disorder, for example endometriosis – a painful condition in which tissue similar to the lining of the uterus (the womb) called the endometrium are found outside the womb, for example in the ovaries or fallopian tubes. abnormal, normally high lipid levels. The dose at which a biological effect occurs in 50% of the test sample to which an agent was administered. an agent that allows for the mixing of two liquids that are immiscible (they do not mix) in a suspension commonly referred to as an emulsion. cells that line the interior side of blood vessels. the function of the endothelium, which is the lining of the inside of heart and blood vessels. a key regulator of blood pressure as it is a potent vasoconstrictor. fat in rodents attached to the testis/testicle. changes to gene expression that do not involve changes to the gene sequence. thin layer of tissue that lines the skin, the respiratory and digestive tracts and other hollow organs including the urinary bladder, fallopian tubes and ureters. redness of skin. the synthesis/production of protein or when genetic information is used in the synthesis of a protein. experiment or investigation of tissue or cells taken from an organism (human or animal) carried out in an external environment. an assay used to determine the antioxidant capacity of a compound, plant or food. a glycoprotein utilized in the production of blood clots, it is a substrate of thrombin, which is a protease enzyme, and is converted to the protein fibrin. the breakdown of the protein fibrin in blood clots. fibrin is a clotting protein and fibrinolytic agents/medicines/substances are used to treat conditions caused by arterial thrombosis (blood clots that obstruct the flow of blood to major organs such as myocardial infarction and stroke). a chronic condition associated with pain. gas from the stomach or intestine. Sometimes referred to as intestinal gas. a marker of improved arterial endothelial function and thus decreased risk of cardiovascular disease. a hormone which stimulates the production of ovarian follicles (small fluid filled sacs in the ovaries which have the potential

to release an egg for fertilisation). produced from the breakdown of triglyceride/triacylglycerol/fat. Free radicals unstable molecules that can cause damage to cells, DNA, lipids and protein. They are unstable as they have one or more unpaired electrons in their outer shell. Fructose 1,6 bisphosphatase an enzyme involved in gluconeogenesis (the synthesis of glucose from non-carbohydrates) Fungicidal destroying or inhibiting the growth of fungi. Gamma amino butyric acid an inhibitory neurotransmitter which decreases activity of the (GABA) central nervous system. Gastric lesions damage to the stomach, which include ulcers, enlargement due to tissue growth as the result of increased cell proliferation, inflammation of the lining (mucosa) of the stomach. Gastric motility movement of food along the gastro-intestinal tract. Gastric mucosa lining of stomach. Genotoxicity damaging to DNA. Gingivitis inflammation of the gums, which if left untreated can lead to gum disease. Glucagon a hormone produced by alpha cells of the pancreas. It is involved in the regulation of glucose and triglyceride metabolism by increasing the levels of glucose and fatty acids in the blood. Glucokinase an enzyme involved in glycolysis (the breakdown of glucose) in the liver. Gluconeogenesis the synthesis of glucose from non-carbohydrates. Glucose 6 phosphatase an enzyme found mainly in the kidney and liver which is involved in gluconeogenesis. Glucose homeostasis the maintenance of glucose levels/concentration within a narrow range. Glucose oxidation the conversion of glucose to carbon dioxide. This process results in the release of energy in the form of adenosine triphosphate (ATP). Glucose tolerance the ability to dispose (metabolise) of a glucose load (for example a glucose drink or white bread). Glucose transporter type 4 insulin dependent glucose transporter found in adipose tissue, (GLUT 4) skeletal and cardiac muscle. Glucuronidase an enzyme that breaks down complex carbohydrates for example starch. Glutathione peroxidase (GPx) an enzyme that catalyzes the conversion of hydrogen peroxide to oxygen and water. Glutathione S-transferase a phase 2 enzyme involved in the detoxification of procarcinogens and carcinogens. Glutamatergic compounds compounds/agents that mimic and modulate the amino acid neurotransmitter glutamate respectively. Glycaemic control maintenance of normal blood glucose levels – see cinnamon chapter. Glycated haemoglobin glucose bound to haemoglobin. It is a biomarker of diabetes and (HbA1c) can lead to the vascular complications that result from this disease. Glycogen a glucose polysaccharide found in the liver and skeletal muscle. It is the main storage form of glucose in the human body. Glycoprotein a protein bound to a carbohydrate. Glycoside a molecule in which a carbohydrate is bound to a non carbohydrate compound, for example a flavonoid, via a glycosidic bond. Free fatty acids

Gram-negative

Gram-positive

Granuloma Haematocrit Hepatic fatty acid synthase Hepatic steatosis Heterogeneity High density lipoprotein cholesterol

Hip circumference

Hippocampus

Histamine Histone Homeostasis Hormone sensitive lipase Hydroalcoholic extract Hypercholesterolemia Hyperglycaemia Hyperlipidemia Hyperlipidemic Hypertension Hypoglycaemia Hypothermia Immunoglobulin E (IgE) Inducible nitric oxide synthase (iNOS) Infantile colic

Interleukin 1 Interleukin 1 beta (β)

bacteria that have a cell wall made up of a thin layer of peptidoglycans (polymers of carbohydrates and amino acids). When undergoing a technique called Gram staining they stain pink/red. bacteria that have a cell wall made up of a thick layer of peptidoglycans (polymers of carbohydrates and amino acids). When undergoing a technique called Gram staining they stain purple/violet. a granuloma forms as a result of infection or inflammation; it is a collection of macrophages. the ratio of the volume of red blood cells to the total volume of blood, platelet and red blood cell number. an enzyme that catalyses the synthesis of long chain fatty acids in the liver. accumulation of triglyceride (fat) in liver, which results in liver enlargement and dysfunction. variability in study design and/or outcomes. cholesterol removed from blood by high density lipoproteins and carried back to the liver. It is also referred to as ‘good’ cholesterol as elevated levels are associated with a decrease risk of cardiovascular disease. the distance around the largest parts of one's hips. It is used with the waist circumference to determine the waist-hip ratio, which is used for determining body fat distribution and as an indicator/marker of cardiovascular disease risk. a region of the brain involved in the formation of new memories. It is also involved in/associated with learning and emotions. an allergic response mediator. a protein that binds to DNA. Histones through this binding are essential for the packaging of DNA into chromosomes. the state of steady internal conditions maintained via tight regulatory processes. an enzyme that breaks down triglyceride (fat) to fatty acids in adipose tissue. culinary herb or spice extracted in a water and ethanol solvent mix. elevated cholesterol levels. high blood glucose. high blood lipid. low blood lipid. high blood pressure. low blood glucose. dangerously low body temperature due to the body losing heat faster that it can produce heat. a class of antibodies involved in the generation of allergic reactions known as type 1 reactions. an enzyme that produces nitric oxide from arginine. It is a key inflammatory mediator. a condition in which an infant has repeated episodes of excessive crying. The causes are not clear but a number of conditions have been put forward including food allergies, food intolerance, gastrointestinal inflammation and poor feeding technique. a cytokine that plays a key role in regulating and mediating immune and inflammatory responses. a cytokine and a form of interleukin 1. It is a key mediator of

Interleukin 6

Interleukin 8 Intestinal mucosa

Intraperitoneal (i.p.)

Ischaemia Isoenzyme Isoprostanes

In vitro

In vivo Ketonuria Larvicidal LD50 Leukocytosis Lipid peroxidation Lipids

Lipolysis Lipogenesis Lipoprotein

Lipoxygenases

Low density lipoprotein cholesterol

Luteinising hormone (LH)

Malondialdehyde (MDA) Medium chain fatty acids Meridians

the inflammatory response. a cytokine and key mediator of immune responses. It plays a key role in activating host defenses shortly after an injury or an infection occurs and is a pro-inflammatory cytokine. a pro-inflammatory cytokine. the innermost lining of the intestinal tract. It is involved in absorption and consists of epithelial cells. It also acts as a barrier against infectious agents. within or administered via the peritoneum. The peritoneum is a thin, transparent membrane which lines the abdominal cavity and encloses abdominal organs within this cavity. restriction of blood flow to tissue leading to a lack of oxygen resulting in tissue damage or tissue death – see basil chapter. enzymes with different structural forms but the same enzyme activity. products formed from the peroxidation of essential fatty acids by free radicals – they are used as a marker of oxidative stress. meaning ‘in glass’ and describes studies/experiments on microorganisms, cells and tissues outside their normal environment, for example in a test tube, petri dish, plate or flask. studies carried out using whole and living organisms, for example animals or humans. a condition in which ketone bodies are present in urine. action against the immature form of a parasite. lethal dose for 50% of the test sample (group) used. a marked increase in the number of whole blood cells. oxidative degradation of lipids by free radicals – it is a marker of oxidative stress. molecules that contain hydrogen, carbon and oxygen and tend to be insoluble in water. Lipids of concern with regards to diet and health include cholesterol and triglycerides (fat). breakdown of triglyceride. synthesis of triglyceride. complex particles made up of proteins and lipids which transport lipids including triglycerides (fat) and cholesterol. There are four types – low density lipoprotein (see below), high density lipoprotein (see above), very low density lipoprotein (see below) and chylomicrons, which transport dietary triglyceride (fat). enzymes involved in the regulation of the inflammatory response via the synthesis of leukotrienes, which are proinflammatory mediators. They are also involved in the synthesis of anti-inflammatory mediators. cholesterol transported by low density lipoproteins from the liver to other tissue. Also referred to as ‘bad cholesterol’ as elevated levels are associated with increased risk of cardiovascular disease. a hormone which triggers the ovulation and the development of the corpus luteum (which are cells in the ovaries that produce progesterone during early pregnancy). a reactive aldehyde and a marker of oxidative stress. fatty acids with between 6 and 12 carbon atoms. paths through which ‘qi’ life-energy flows. Meridians are used in traditional Chinese medicines.

Mesenteric fat Meta-analysis Metabolic syndrome (MetS)

Metal-chelating property

Metal-chelator

fat attached to the intestines. a statistical analysis of combined results/data from multiple studies identified by a systematic review. a combination of diabetes, high blood pressure (hypertension), elevated lipid (triglyceride (fat) and/or cholesterol levels) – hyperlipidemia – excess fat around the waist, and high blood glucose levels (hyperglycaemia); it can increase the risk of cardiovascular disease (coronary heart disease, stroke). the ability to bind to metals and to form stable complexes that are water soluble. This property is used to treat excessively high levels of iron, lead and also copper.

an agent able to bind to metals to form stable complexes that are water soluble. Metastases/Metastatic the spreading of cancer beyond its original site to other parts of the body. Microencapsulation a technique by which the active ingredients are packaged within a second material for shielding the active ingredient from the surrounding environment. Mid upper arm circumference the circumference of the upper arm (the non-dominant arm). It is used to assess nutritional status. Monocyte white blood cells/immune cells which differentiate (develop) into macrophages or dendritic cells. Motor activity movement. Mucin a glycoprotein produced by epithelial cells. Mucus consists of mucins. Mucous membrane a membrane that lines cavities in the body and covers the surface of internal organs including the gastrointestinal tract and its organs. Mutagen an agent that causes mutations. Mutagenesis the changing of DNA that results in mutations. Mutagenic causes a mutation. Myocardial injury damage to heart muscle resulting in for example myocardial infarction (heart attack). Narrative review a comprehensive and objective analysis of research on a topic using peer reviewed literature. It is also referred to as a literature review. Neuroblastoma cancer that develops in immature nerve cells. Neurofibrillary tangle the aggregation of tau proteins which are abundant in neurons formation (nerve cells) in the central nervous system. This formation is a feature/characteristic of Alzheimer's disease. Neuropathy damage or dysfunction of nerves which result in numbness, tingling, pain and muscle weakness in the affected areas. Neutrophils a type of white blood/immune cell. Nitric oxide a free radical, pro-inflammatory mediator and lowers blood pressure by stimulation vasodilation. Nitrosative the ability to introduce nitric oxide (NO) into organic compounds. Nitrosative stress, as with oxidative stress, gives rise to cell damage and is said to be involved in the development of chronic disease via the action of reactive nitrogen species, which are formed due to very high levels of NO. No observed adverse effect the highest dose at which no toxic or adverse effect is observed. level (NOAEL) Non-alcoholic fatty liver a group of conditions caused by the accumulation of fat in the disease (NAFLD) liver. Non-peer review work that is not evaluated by individuals who are expert in an

Nonsteroidal antiinflammatory drug (NSAID) Normotensive Nuclear factor κB (NFκB) (full name – nuclear factor kappa-light-chain-enhancer of activated B cells) Oedema Oestradiol (also estradiol)

Oestrogen/estrogen Oestrogen/estrogen receptor negative breast cancer Oestrogen/estrogen receptor positive breast cancer Open label

Opioid Osteoclasts Oxidative stress Pancreatic beta (β) cells Parasympathetic nervous system (PNS)

Pathogenic Peer review Percentage body fat Peripheral nervous system

Periodontitis Peritoneal

Phagocytic activity Phagocytic cells Phagocytosis Phase 1 enzymes

Phase 2 detoxification Phase 2 enzymes

appropriate field of research. a class of drugs that are not steroids which are used to decrease pain, inflammation, fever and blood clots. normal blood pressure. a protein that regulates immune and inflammatory responses via activating the expression of genes involved in these responses. fluid retention. is an oestrogen steroid and the main oestrogen in women. The other oestrogen hormones are estrone (made after menopause) and estriol (the main oestrogen/estrogen during pregnancy). a class of female steroid hormones. breast cancer that does not have any oestrogen/estrogen receptors. It tends to grow faster than oestrogen positive breast cancer. breast cancer that has oestrogen receptors. This type of breast cancer uses of oestrogen to grow. not a blinded study; the participants and investigators know what treatment they have been given/what intervention they have received. pain relieving drugs. bone cells that break down bone tissue – a process that is required for normal bone formation and remodelling. imbalance between antioxidants and reactive oxygen species in the body. The latter are in excess. cells in the pancreas that synthesize and release insulin. part of the autonomic nervous system the PNS decreases respiration, heart rate and blood pressure and increases digestion, the production of saliva and mucus and urine secretion, and by doing so conserves energy. causes disease. work that is evaluated by individuals who are expert in an appropriate field of research. the percentage of total body mass that is fat. the peripheral nervous system extends beyond the brain and spinal cord and forms a communication network between the central nervous system and the rest of the body. gum disease. pertaining to the peritoneum – a membrane that lines the abdominal cavity and covers the surface of abdominal organs including the liver and intestines. the engulfing/ingestion of bacteria, harmful foreign particles and dead and dying cells. immune cells that use the process of phagocytosis. engulfing of bacteria, debris and dead cells by immune cells. enzymes involved in drug metabolism. Phase 1 enzymes also activate pro-carcinogens. The cytochrome P450 enzymes are phase 1 enzymes. a process which involves the removal of carcinogens and procarcinogens. enzymes involved in drug metabolism. Many but not all phase 2 enzymes are involved in the detoxification of carcinogens or procarcinogen. The glutathione S-transferases are phase 2 enzymes.

Placebo Plaques of β-amyloid fibrils Platelet aggregation Platelets Polycystic ovary syndrome (PCOS)

Postprandial PPM Pre-adipocytes Precursor Pre-diabetic

Preprandial Pro-inflammatory Prolactin Prostacyclins Prostaglandins

Protein glycation

Proteinuria Pro-thrombotic Provitamin A

Quorum sensing

Radical scavenging Randomization Randomized crossover trial Randomized triple blind placebo controlled clinical trial Reactive oxygen species

an intervention or treatment that has no therapeutic value. these characterize Alzheimer's disease and are neurotoxic as they destroy connections between neurons. this process – the clumping together of platelets plays an important role in the development of arterial thrombosis. small blood cells that form clots via a process called aggregation. an endocrine disorder that gives rise to a number of conditions in women of reproductive/child bearing age including hyperandrogenism (excess androgen (male hormone) levels), irregular menstrual cycles and/or polycystic ovaries (ovaries that form small fluid filled sacs, also called follicles, which may fail to release eggs). the period following the consumption of food or a meal. parts per million, for example 1 mg in 1 Litre. cells that develop/differentiate into fat cells. a compound from which another compound is formed via a chemical reaction. a subject who has a higher than normal blood glucose which is not high enough for their condition to be diagnosed as type 2 diabetes. However, they have an increased risk therefore of developing type 2 diabetes. The preferred term is intermediate hyperglycaemia to avoid any stigma linked to the word diabetes. before the consumption of food or a meal. promotes inflammation. a hormone required for breast growth and development and breast milk production. members of the prostaglandin family. family of lipids produced at the site of tissue damage or infection. They are key mediators/regulators of inflammation/tissue injury – see basil chapter. the binding of glucose to a protein. Protein glycation is a biomarker of diabetes and can lead to the vascular complications that result from this disease. An example of a glycated protein is glycated haemoglobin (HbA1c). excess protein in urine. promotes thrombosis/blood clotting. carotenoids, such as beta-carotene and alpha carotene, that are converted to vitamin A. Provitamin A is found in plant foods. Please note: not all carotenoids can be converted to vitamin A. a process in which bacteria release chemicals that act as signalling molecules via which bacteria are able to sense the number of bacteria and as a consequence behaviour. In the case of pathogenic bacteria this behaviour is virulence, which is the severity of the infection. scavenging of free radicals by compounds such as antioxidants. subjects are randomly assigned to different groups. Randomization reduces the risk of bias in experiments. a study in which participants are randomly assigned to receive a sequence of treatments. a randomized experiment in which the participants are randomly assigned to an intervention/treatment which is unknown to the participants, those who give the intervention/treatment and those who assess the outcomes. unstable/highly reactive oxygen containing molecules, which

can cause cell damage/cell death by interacting/reacting with proteins, lipids and DNA. Reactive nitrogen species highly reactive molecules derived from nitric oxide which can cause cell damage/cell death by interacting/reacting with proteins, lipids and DNA. Receptor a protein or glycoprotein that initiates a biological/biochemical/chemical response by binding to molecules commonly preferred to as ligands or messengers. Reduced glutathione (GSH) reduced form of glutathione, which is a tripeptide (a small protein). The reduced form of glutathione is an antioxidant. Reducing power the ability of a chemical to reduce (give electron to) another compound. It is used by some as a measure of antioxidant capacity. Reperfusion-induced cerebral restoration of blood flow to previously ischaemic (see above for damage ischaemia) tissue resulting in extensive/increased tissue damage. Reporting bias only favourable results are reported leading to inappropriate conclusions. Research bias an error introduced into a research study which can result in false or misleading conclusions. Retrospective cohort study a study in which investigators look back at/analyse already obtained data obtained from a cohort to determine an association between an exposure and an outcome. Saponin bitter tasting compound normally derived from plants. Selection bias introduction of bias into the selection of participants resulting in randomization not being properly achieved. The end result is results/outcomes that do not represent the population the investigator intended to investigate. Serotonergic an effect that results in the mimicking or release of the neurotransmitter serotonin. Single centred study a study in which participants/subjects from a hospital, clinic, region or country are used. Split mouth study design a study design popular in oral health research in which each of two treatments are randomly assigned to either the right or left side of the dentition (teeth). Squamous relates to thin flattened cells that make up a layer of epithelium. Sub-mucosa a layer of connective tissue that supports/sits under the mucosa. Substrate a molecule or compound that undergoes a chemical reaction under the action of an enzyme or other catalyst resulting in a product. Supercritical fluid any substance with properties between a gas and a liquid. Supercritical fluid extraction extraction using a supercritical fluid. Sympathetic nervous system part of the autonomic nervous system, the SNS readies the body (SNS) for the fight or flight response by increasing heart rate and respiration and therefore increases energy expenditure. Superoxide dismutase (SOD) an enzyme that catalyses the conversion of the free radical superoxide to hydrogen peroxide and oxygen. Superoxide radical a free radical. Synergy

Systematic review

Systolic blood pressure

occurs when the biological effect of two agents or compounds exceed that of the sum of the biological effects of the individual agents or compounds. a type of literature review in which the collection of data (obtained from peer reviewed research papers) and the analysis and critical appraisal of the data are carried out using a systematic approach. pressure blood exerts against the arterial wall when the heart

T cell Tachycardia Thiobarbituric acid reactive species (TBARS) Tincture Total antioxidant power/capacity Toxigenic fungi Triphala Triglyceride Tumorigenesis Tumorigenic Tumour multiplicity Tumour necrosis factor alpha (TNF-α) Uropathogen Vascular permeability

Vascular relaxation Vasodilatory Vasoprotective Very low density lipoprotein cholesterol

Waist-hip ratio

Waist circumference

beats. It is the top number of a blood pressure reading. a type of lymphocyte, which is an immune/white blood cell. term for when the heart rate is over 100 beats per minute. a marker of oxidative stress. an extract prepared/dissolved with/in ethanol. used to assess antioxidant status. fungi that produce toxins for example mycotoxins. also known as the three fruits is a polyherbal Ayurvedic formulation. a dietary lipid, also known as fat or triacylglycerol. tumour formation. forming or tending to form tumours. the mean number of tumours per organism. a pro-inflammatory cytokine. a pathogen that causes urinary tract infection. the capacity of the blood vessel wall to allow small molecules and cells in and out of the vessel. Vascular permeability increases due to inflammation. relaxation of smooth muscle in blood vessels. opening/dilation of blood vessels. ability to protect blood vessels from certain conditions. cholesterol transported by very low density lipoproteins, which are made in the liver. Although it carries cholesterol from the liver to other tissues, it mainly transports triglyceride (fat) in the body. the ratio of the waist circumference to the hip circumference. It is used for determining body fat distribution and as an indicator/marker of cardiovascular disease risk. the circumference of one's abdomen at the level of the umbilicus (belly button). It is a good measure of visceral fat and so on its own it can be used as a marker of high blood lipid levels, high blood pressure and type 2 diabetes. It can also be used to determine one's waist hip ratio, which can be used as an indicator/marker of cardiovascular disease risk.

Contents Chapter 1 An Introduction to Culinary Herbs and Spices: A Global Guide References Chapter 2 Allspice – Jamaican Pepper, Pimenta, Newspice (Pimenta dioica, Pimenta officinalis Lindl) 2.1 Names 2.2 Taxonomy 2.3 Origin, Description and Adulteration 2.4 Historical and Current Uses 2.5 Chemistry, Nutrition and Food Science 2.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 2.6.1 Antioxidant Properties 2.6.2 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 2.6.3 Chemopreventive/Anti-cancer Properties 2.6.4 Anti-platelet, Hypotensive and Antinociceptive/Analgesic Properties 2.6.5 Potential Use in Managing Menopausal Symptoms 2.6.6 Antimicrobial Properties 2.7 Safety and Adverse Effects References Chapter 3 Basil – Sweet Basil, Common Basil, Thai Basil, Tropical Basil (Ocimum basilicum) 3.1 Names 3.2 Taxonomy 3.3 Origin, Description and Adulteration 3.4 Historical and Current Uses 3.5 Chemistry, Nutrition and Food Science 3.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 3.6.1 Antioxidant Properties 3.6.2 Anti-inflammatory and Analgesic Properties 3.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

3.6.4 Cardiovascular Stimulatory and Cardioprotective Properties 3.6.5 Chemopreventive/Anti-cancer Properties 3.6.6 Hepatoprotective Properties 3.6.7 Anti-ulcerative Properties 3.6.8 Anxiolytic (Calming), Sedative, Hypnotic, Anti-convulsant, Anti-depressant-like, Memory Retaining/Enhancing Properties 3.6.9 Antimicrobial Properties 3.6.10 Anti-parasitic Activity 3.6.11 Effect on the Respiratory System 3.6.12 Effect on Wound Healing 3.6.13 Effect on Fertility 3.7 Safety and Adverse Effects

References Chapter 4 Bay Leaf (Laurus nobilis) 4.1 Names 4.2 Taxonomy 4.3 Origin, Description and Adulteration 4.4 Historical and Current Uses 4.5 Chemistry, Nutrition and Food Science 4.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 4.6.1 Antioxidant Properties 4.6.2 Anti-inflammatory Properties 4.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 4.6.4 Chemopreventive/Anti-cancer Properties 4.6.5 Hepatoprotective Properties 4.6.6 Anti-ulcer Properties 4.6.7 Anti-convulsant Properties 4.6.8 Antimicrobial Properties 4.6.9 Alcohol Lowering Properties 4.7 Safety and Adverse Effects References Chapter 5 Black Pepper (Piper nigrum L) 5.1 Names 5.2 Taxonomy 5.3 Origin, Description and Adulteration 5.4 Historical and Current Uses 5.5 Chemistry, Nutrition and Food Science 5.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 5.6.1 Antioxidant Properties 5.6.2 Anti-inflammatory Properties 5.6.3 Glucose Lowering, Anti-diabetic, Lipid Lowering Properties and Effect on Appetite

5.6.4 Chemopreventive/anti-cancer Properties 5.6.5 Neuroprotective Properties 5.6.6 Antinociceptive/Analgesic and Anti-

convulsant Properties 5.6.7 Digestive Properties and Gastrointestinal Stimulant 5.6.8 Prebiotic Potential 5.6.9 Antimicrobial Properties 5.7 Safety and Adverse Effects References Chapter 6 Caraway (Carum carvi) 6.1 Names 6.2 Taxonomy 6.3 Origin, Description and Adulteration 6.4 Historical and Current Uses 6.5 Chemistry, Nutrition and Food Science 6.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 6.6.1 Antioxidant Properties 6.6.2 Anti-inflammatory Properties 6.6.3 Glucose-lowering, Anti-diabetic and Lipid Lowering Properties 6.6.4 Chemopreventive/Anti-cancer Properties 6.6.5 Hepato- and Nephro-protective Properties 6.6.6 Anti-convulsant and Anti-epileptic Properties 6.6.7 Diuretic Properties 6.6.8 Effect on Reproductive Organs 6.6.9 Impact on Drug Bioavailability 6.6.10 Therapeutic Potential of Caraway in the Management of Obesity, Functional Dyspepsia and Irritable Bowel Syndrome 6.6.11 Antimicrobial Properties 6.7 Safety and Adverse Effects References Chapter 7 Cardamom – Small Cardamom, Green Cardamom, True Cardamom, Ceylon Cardamom, Malabar Cardamom (Elettaria cardamomum) 7.1 Names 7.2 Taxonomy 7.3 Origin, Description and Adulteration 7.4 Historical and Current Uses 7.5 Chemistry, Nutrition and Food Science 7.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 7.6.1 Antioxidant Properties 7.6.2 Anti-inflammatory Properties

7.6.3 Glucose Lowering, Anti-diabetic, Lipid Lowering and Other Cardioprotective Properties 7.6.4 Chemopreventive/Anti-cancer Properties 7.6.5 Hepatoprotective Properties 7.6.6 Gastroprotective Activity 7.6.7 Gut Modulatory and Anti-nausea Properties 7.6.8 Neuroprotective Properties and Impact on Behaviour, Learning, Memory and Development 7.6.9 Anticonvulsant Properties 7.6.10 Anti-microbial Activity 7.7 Safety and Adverse Effects

References Chapter 8 Chives (Allium schoenoprasum) 8.1 Names 8.2 Taxonomy 8.3 Origin, Description and Adulteration 8.4 Historical and Current Uses 8.5 Chemistry, Nutrition and Food Science 8.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 8.6.1 Antioxidant Properties 8.6.2 Anti-inflammatory Properties 8.6.3 Lipid Lowering Properties 8.6.4 Anti-hypertensive Properties 8.6.5 Anti-platelet Activity 8.6.6 Chemopreventive/Anti-cancer Properties 8.6.7 Anti-microbial Activity 8.6.8 Anti-parasitic Activity 8.7 Safety and Adverse Effects References Chapter 9 Cinnamon: Cinnamomum verum (syn Cinnamomum zeylanicum), Cinnamomum cassia (syn Cinnamomum aromaticum), Cinnamomum burmanni, Cinnamomum loureiroi 9.1 Names 9.2 Taxonomy 9.3 Origin, Description and Adulteration 9.4 Historical and Current Uses 9.5 Chemistry, Nutrition and Food Science 9.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 9.6.1 Antioxidant Properties 9.6.2 Anti-inflammatory Properties 9.6.3 Antinociceptive/Analgesic and Wound Healing Properties 9.6.4 Glucose Lowering and Anti-diabetic Properties 9.6.5 Lipid Lowering Properties

9.6.6 Anti-obesity Properties 9.6.7 Efficacy in the Treatment of Non-

insulin/Non Lipidaemic Symptoms of Polycystic Ovarian Syndrome (PCOS) 9.6.8 Anti-hypertensive Properties 9.6.9 Neuroprotective Properties 9.6.10 Chemopreventive/Anti-cancer Properties 9.6.11 Anti-microbial Properties 9.6.12 Prebiotic Potential 9.6.13 Anti-parasitic Properties 9.7 Safety and Adverse Effects References Chapter 10 Clove (Syzygium aromaticum, Eugenia aomaticum, Eugenia caryophyllata) 10.1 Names 10.2 Taxonomy 10.3 Origin, Description and Adulteration 10.4 Historical and Current Uses 10.5 Chemistry, Nutrition and Food Science 10.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 10.6.1 Antioxidant Properties 10.6.2 Anti-inflammatory Properties 10.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 10.6.4 Chemopreventive/Anti-cancer Properties 10.6.5 Hepatoprotective Properties 10.6.6 Gastroprotective Properties 10.6.7 Analgesic, Wound Healing, Anticonvulsive, Anxiolytic, Anti-allergic and Aphrodisiac Properties 10.6.8 Anti-microbial Properties 10.6.9 Anti-parasitic Activity 10.7 Safety and Adverse Effects References Chapter 11 Coriander or Cilantro Coriander/Chinese Parsley (Coriandrum sativum) 11.1 Names 11.2 Taxonomy 11.3 Origin, Description and Adulteration 11.4 Historical and Current Uses 11.5 Chemistry, Nutrition and Food Science 11.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 11.6.1 Antioxidant Properties 11.6.1 Anti-inflammatory Properties 11.6.2 Glucose Lowering, Anti-diabetic and Lipid

Lowering Properties 11.6.3 Hypotensive Properties 11.6.4 Hepato- and Renal Protective Properties 11.6.5 Chemopreventive/Anti-cancer Properties 11.6.6 Neurological and Neuroprotective Properties 11.6.7 Gut Modulatory Properties 11.6.8 Detoxification Properties 11.6.9 Anti-microbial Properties 11.6.10 Anti-parasitic Activity 11.7 Safety and Adverse Effects References Chapter 12 Cumin (Cuminum cyminum) 12.1 Names 12.2 Taxonomy 12.3 Origin, Description and Adulteration 12.4 Historical and Current Uses 12.5 Chemistry, Nutrition and Food Science 12.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 12.6.1 Antioxidant Properties 12.6.2 Anti-inflammatory and Immunomodulatory Properties 12.6.3 Antinociceptive/Analgesic Properties 12.6.4 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 12.6.5 Cardioprotective/Hypotensive Properties 12.6.6 Chemopreventive/Anti-cancer Properties 12.6.7 Hepatoprotective Properties 12.6.8 Gastrointestinal-protective Properties 12.6.9 Neurological and Neuroprotective Properties 12.6.10 Memory Enhancing and Antioxidant Properties 12.6.11 Anti-epileptic Properties 12.6.12 Effect on Opioid Tolerance and Dependence 12.6.13 Fertility Inhibitory and Promoting Properties 12.6.14 Anti-osteoporotic Properties 12.6.15 Anti-microbial Properties 12.6.16 Antiparasitic Properties 12.7 Safety and Adverse Effects References Chapter 13 Dill (Anethum graveolens, Anethum foeniculum, Peucedanum graveolens, Anethum sowa) 13.1 Names

13.2 Taxonomy 13.3 Origin, Description and Adulteration 13.4 Historical and Current Uses 13.5 Chemistry, Nutrition and Food Science 13.6 Bioactive Properties, Purported Health Benefits and

Therapeutic Potential: Current and Emerging Research 13.6.1 Antioxidant Properties 13.6.2 Anti-inflammatory and Analgesic Properties 13.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 13.6.4 Hepatoprotective Properties 13.6.5 Chemopreventive/Anti-cancer Properties 13.6.6 Neuroprotective/Memory Enhancing Properties 13.6.7 Anxiolytic/Calming Properties 13.6.8 Anti-epileptic Effect 13.6.9 Antispasmodic and Contractile Properties 13.6.10 Fertility 13.6.11 Impact on Skin/Dermal Properties 13.6.12 Anti-microbial Properties 13.7 Safety and Adverse Effects References Chapter 14 Fennel (Foeniculum vulgare) 14.1 Names 14.2 Taxonomy 14.3 Origin, Description and Adulteration 14.4 Historical and Current Uses 14.5 Chemistry, Nutrition and Food Science 14.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 14.6.1 Antioxidant Properties 14.6.2 Anti-inflammatory and Analgesic Properties 14.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 14.6.4 Cardioprotective Properties 14.6.5 Hepatoprotective Properties 14.6.6 Chemopreventive/Anti-cancer Properties 14.6.7 Effect on Fertility and Lactation and Use in the Management of Polycystic Ovarian Syndrome and Menstrual Disorders and Menopause 14.6.8 Potential Use in the Treatment/Management of Gastrointestinal Disorders 14.6.9 Anti-microbial Properties 14.6.10 Other Bioactive Properties 17.7 Safety and Adverse Effects References

Chapter 15 Fenugreek (Trigonella foenum-graecum) 15.1 Names 15.2 Taxonomy 15.3 Origin, Description and Adulteration 15.4 Historical and Current Uses 15.5 Chemistry, Nutrition and Food Science 15.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 15.6.1 Antioxidant Properties 15.6.2 Anti-inflammatory and Analgesic Properties 15.6.3 Glucose Lowering, Anti-diabetic, Lipid Lowering Properties 15.6.4 Neuroprotective/Neurological Properties 15.6.5 Hepato-/Renal/Gastro- and Pancreatic Protective Properties 15.6.6 Chemopreventive/Anti-cancer Properties 15.6.7 Effect on Fertility and Lactation, Weight Management and Use in the Management of Menopause 15.6.8 Impact on Exercise Performance 15.6.9 Anti-microbial Properties 15.6.10 Larvicidal Properties 15.7 Safety and Adverse Effects References Chapter 16 Ginger (Zingiber officinale) 16.1 Names 16.2 Taxonomy 16.3 Origin, Description and Adulteration 16.4 Historical and Current Uses 16.5 Chemistry, Nutrition and Food Science 16.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 16.6.1 Antioxidant and Anti-inflammatory Properties 16.6.2 Glucose Lowering, Anti-diabetic, Lipid Lowering and Weight Management Properties 16.6.3 Chemopreventive/Anti-cancer Properties 16.6.4 Anti-nausea/Antiemetic Properties 16.6.5 Nociceptive/Analgesic Properties 16.6.6 Anti-microbial Activity 16.6.7 Prebiotic Potential 16.7 Safety and Adverse Effects References Chapter 17 Lemon Grass (Cymbopogon citratus/Cymbopogon flexuosus) 17.1 Names 17.2 Taxonomy 17.3 Origin, Description and Adulteration

17.4 Historical and Current Uses 17.5 Chemistry, Nutrition and Food Science 17.6 Bioactive Properties, Purported Health Benefits and

Therapeutic Potential: Current and Emerging Research 17.6.1 Antioxidant Properties 17.6.2 Anti-inflammatory Properties 17.6.3 Chemopreventive/Anti-cancer Properties 17.6.4 Anxiolytic (Calming), Antinociceptive/Analgesic and Sedative Properties and Effect on Cognitive Function and Mood 17.6.5 Hypotensive Effect 17.6.6 Neuroprotective Effect 17.6.7 Anti-microbial Activity 17.6.8 Anti-malarial Activity 17.7 Safety and Adverse Effects References Chapter 18 Mint – Mentha piperita (Peppermint), Mentha spicata (Spearmint), Mentha aquatica (Water Mint), Mentha arvensis (Corn, Field, Wild Mint, Japanese Mint, Marsh Mint) 18.1 Names 18.2 Taxonomy 18.3 Origin, Description and Adulteration 18.4 Historical and Current Uses 18.5 Chemistry, Nutrition and Food Science 18.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 18.6.1 Antioxidant Properties 18.6.2 Anti-inflammatory and Analgesic Properties 18.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 18.6.4 Cardioprotective Properties 18.6.5 Neuroprotective Properties 18.6.6 Other Neurological Properties 18.6.7 Management of Gastrointestinal Symptoms 18.6.8 Hepatoprotective Properties 18.6.9 Chemopreventive/Anti-cancer Properties 18.6.10 Anti-allergic Properties 18.6.11 Anti-microbial Properties 18.6.12 Larvicidal/Anti-parasitic Properties 18.7 Safety and Adverse Effects 18.7.1 Peppermint 18.7.2 Spearmint References Chapter 19 Nutmeg (Myristica fragrans) 19.1 Names 19.2 Taxonomy

19.3 Origin, Description and Adulteration 19.4 Historical and Current Uses 19.5 Chemistry, Nutrition and Food Science 19.6 Bioactive Properties, Purported Health Benefits and

Therapeutic Potential: Current and Emerging Research 19.6.1 Antioxidant Properties 19.6.2 Anti-inflammatory and Analgesic Properties 19.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 19.6.4 Antithrombotic Properties 19.6.5 Hepatoprotective Properties 19.6.6 Chemopreventive/Anti-cancer Properties 19.6.7 Antidepressant and Anti-convulsant Properties 19.6.8 Anti-microbial Properties 19.6.9 Anti-parasitic Properties 19.7 Safety and Adverse Effects References Chapter 20 Oregano – Oregano/Mediterranean Oregano (Origanum vulgare) and Mexican Oregano (Lippia graveolens, Lippia palmeri, Hedeoma patens, Poliomintha longiflora) (Also Referred to as Rosemary Mint) 20.1 Names 20.2 Taxonomy 20.3 Origin, Description and Adulteration 20.4 Historical and Current Uses 20.5 Chemistry, Nutrition and Food Science 20.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 20.6.1 Antioxidant Properties 20.6.2 Anti-inflammatory Properties 20.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 20.6.4 Antiplatelet Activity 20.6.5 Chemopreventive/Anti-cancer Properties 20.6.6 Nephroprotective Properties 20.6.7 Antimicrobial Properties 20.6.8 Anti-parasitic Activity 20.6.9 Prebiotic Potential 20.7 Safety and Adverse Effects References Chapter 21 Paprika (Capsicum annuum or Capsicum tetragonum) 21.1 Names 21.2 Taxonomy 21.3 Origin, Description and Adulteration 21.4 Historical and Current Uses 21.5 Chemistry, Nutrition and Food Science

21.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 21.6.1 Antioxidant and Anti-inflammatory Properties 21.6.2 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 21.6.3 Anti-microbial Properties 21.7 Safety and Adverse Effects References

Chapter 22 Parsley (Petroselinum crispum/Petroselinum Hortense/Petroselinum sativum) 22.1 Names 22.2 Taxonomy 22.3 Origin, Description and Adulteration 22.4 Historical and Current Uses 22.5 Chemistry, Nutrition and Food Science 22.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 22.6.1 Antioxidant Properties 22.6.2 Analgesic and Anti-inflammatory Properties 22.6.3 Glucose Lowering and Anti-diabetic Properties 22.6.4 Anti-platelet Properties 22.6.5 Anti-hypertensive Properties 22.6.6 Hepatoprotective Properties 22.6.7 Renal Protective Properties 22.6.8 Gastroprotective and Antispasmolytic Properties 22.6.9 Chemopreventive/Anti-cancer Properties 22.6.10 Effect on Fertility 22.6.11 Anti-microbial Properties 22.6.12 Potential Use in the Treatment of Melasma 22.7 Safety and Adverse Effects References Chapter 23 Rosemary (Rosmarinus officinalis syn, Salvia rosmarinus) 23.1 Names 23.2 Taxonomy 23.3 Origin, Description and Adulteration 23.4 Historical and Current Uses 23.5 Chemistry, Nutrition and Food Science 23.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 23.6.1 Antioxidant Properties 23.6.2 Anti-inflammatory Properties 23.6.3 Chemopreventive/Anti-cancer Properties 23.6.4 Glucose Lowering, Anti-diabetic and Lipid

Lowering Properties 23.6.5 Antinociceptive/Analgesic Properties 23.6.6 Anxiolytic (Anti-anxiety/Calming) Properties 23.6.7 Anti-hypotensive Properties 23.6.8 Anti-microbial Properties 23.7 Safety and Adverse Effects References Chapter 24 Saffron (Crocus sativus var. kashmiriana) 24.1 Names 24.2 Taxonomy 24.3 Origin, Description and Adulteration 24.4 Historical and Current Uses 24.5 Chemistry, Nutrition and Food Science 24.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 24.6.1 Antioxidant Properties 24.6.2 Anti-inflammatory Properties 24.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 24.6.4 Potential Use in the Management of Obesity 24.6.5 Preventive and Therapeutic Potential in the Development and Management of Cardiovascular Disease 24.6.6 Chemopreventive/anti-cancer Properties 24.6.7 Prevention and Therapeutic Potential in the Development and Management of Neurodegenerative Disorders and Other Neurological Conditions 24.6.8 Potential Use in the Treatment of Ocular Disorders 24.6.9 Potential Use in the Treatment of Sexual and Menstrual Disorders and Management of the Menopause 24.7 Safety and Adverse Effects References Chapter 25 Sage/Common Sage (Salvia officinalis) 25.1 Names 25.2 Taxonomy 25.3 Origin, Description and Adulteration 25.4 Historical and Current Uses 25.5 Chemistry, Nutrition and Food Science 25.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 25.6.1 Antioxidant Properties 25.6.2 Anti-inflammatory Properties 25.6.3 Antinociceptive/Analgesic Properties 25.6.4 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

25.6.5 Chemopreventive/Anti-cancer Properties 25.6.6 Anti-microbial Properties 25.6.7 Cognitive and Memory

Enhancing/Neuroprotective Properties 25.6.8 Anti-menopausal Properties 25.6.9 Anti-diarrheal and Anti-spasmodic Properties 25.7 Safety and Adverse Effects References Chapter 26 Star Anise/Chinese Anise (Illicium Verum) 26.1 Names 26.2 Taxonomy 26.3 Origin, Description and Adulteration 26.4 Historical and Current Uses 26.5 Chemistry, Nutrition and Food Science 26.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 26.6.1 Antioxidant Properties 26.6.2 Weight Management Potential 26.6.3 Chemopreventive/Anti-cancer Properties 26.6.4 Analgesic and Sedative Properties 26.6.5 Anti-microbial Activity 26.7 Safety and Adverse Effects References Chapter 27 Sumac (Rhus Coriaria L., Rhus glabra L., Rhus typhina L.) 27.1 Names 27.2 Taxonomy 27.3 Origin, Description and Adulteration 27.4 Historical and Current Uses 27.5 Chemistry, Nutrition and Food Science 27.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 27.6.1 Antioxidant Properties 27.6.2 Anti-inflammatory and Analgesic Properties 27.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 27.6.4 Cardioprotective Properties 27.6.5 Potential Use in the Management of Obesity 27.6.6 Chemopreventive/Anti-cancer Properties 27.6.7 Anti-microbial Properties 27.7 Safety and Adverse Effects References Chapter 28 Sweet Marjoram (Origanum majorana/marjorama hortensis) 28.1 Names

28.2 Taxonomy 28.3 Origin, Description and Adulteration 28.4 Historical and Current Uses 28.5 Chemistry, Nutrition and Food Science 28.6 Bioactive Properties, Purported Health Benefits and

Therapeutic Potential: Current and Emerging Research 28.6.1 Antioxidant Properties 28.6.2 Anti-inflammatory Activity 28.6.3 Antiplatelet Activity and Cardioprotective Activity 28.6.4 Chemopreventive/Anti-cancer Properties 28.6.5 Anti-ulcer Activity 28.6.6 Hepatoprotective Activity 28.6.7 Anti-microbial Properties 28.6.8 Anti-acetylcholinesterase Inhibitory Activity 28.6.9 Effect on Hormonal and Metabolic Profile 28.6.10 Other Reported Purported Beneficial Health and Therapeutic Effects of Sweet Marjoram 28.7 Safety and Adverse Effects References Chapter 29 Tarragon (Artemisia dracunculus) 29.1 Names 29.2 Taxonomy 29.3 Origin, Description and Adulteration 29.4 Historical and Current Uses 29.5 Chemistry, Nutrition and Food Science 29.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 29.6.1 Antioxidant Properties 29.6.2 Anti-inflammatory and Analgesic Properties 29.6.3 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 29.6.4 Antiplatelet Properties 29.6.5 Gastro- and Hepato-protective Properties 29.6.6 Chemopreventive/Anti-cancer Properties 29.6.7 Neurological and Neuroprotective Properties 29.6.8 Anti-microbial Properties 29.6.9 Anti-parasitic Activity 29.7 Safety and Adverse Effects References Chapter 30 Thyme (Thymus vulgaris) 30.1 Names 30.2 Taxonomy 30.3 Origin, Description and Adulteration

30.4 Historical and Current Uses 30.5 Chemistry, Nutrition and Food Science 30.6 Bioactive Properties, Purported Health Benefits and

Therapeutic Potential: Current and Emerging Research 30.6.1 Antioxidant Properties 30.6.2 Anti-inflammatory Properties 30.6.3 Antinociceptive/Analgesic Properties 30.6.4 Chemopreventive/Anti-cancer Properties 30.6.5 Hepatoprotective Effects 30.6.6 Antimicrobial Properties 30.6.7 Anti-parasitic Properties 30.7 Safety and Adverse Effects References Chapter 31 Turmeric (Curcuma longa, Curcuma domestica) 31.1 Names 31.2 Taxonomy 31.3 Origin, Description and Adulteration 31.4 Historical and Current Uses 31.5 Chemistry, Nutrition and Food Science 31.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 31.6.1 Antioxidant Properties 31.6.2 Anti-inflammatory Properties 31.6.3 Chemopreventive/Anti-cancer Properties 31.6.4 Glucose Lowering, Anti-diabetic and Lipid Lowering Properties 31.6.5 Treatment and Management of Digestive Disorders 31.6.6 Neurological and Neuroprotective Properties 31.6.7 Use in the Treatment of Kidney Disease 31.6.8 Use in the Treatment of Skin Conditions 31.6.9 Ongoing Clinical Trials 31.6.10 Anti-microbial Properties 31.6.11 Larvicidal Activity 31.7 Safety and Adverse Effects References Subject Index

CHAPTER 1

An Introduction to Culinary Herbs and Spices: A Global Guide There is no globally established or agreed definition for culinary herbs and spices. In some literature. Herbs and spices are separate and distinct foods and their definition is based on the part of the plant of origin from which they are sourced. In other literature, the words ‘herb’ and ‘spice’ are used interchangeably because there are similarities between them. For the purposes of this book, the following definitions are used in acknowledgement of the key differences between the foods: “Herbs are obtained from the leaves of herbaceous (non-woody) plants.” “Spices are obtained from roots, flowers, fruits, seeds or bark. They (spices) are native to warm tropical climates and can be woody or herbaceous plants”.1

When one talks about culinary herbs and spices, it is likely that the conversation focuses on their diverse range of distinct and strong aromas – from the sharp pinelike with a hint of lemon of rosemary to the earthy mild pungency of black pepper; what they look like – the solid and sturdy root that is ginger and the feathery, almost ethereal, appearance of dill; the forms in which they are purchased – fresh and dried; or their use in meats, curries, casseroles, stews, soups, desserts, and cakes to enhance flavour. These foods are unique in a culinary context because, as stated above, they possess a range of aromas, which are due to the abundance of certain chemical compounds in them – many of which are volatile2 – and as a consequence they are used as flavour enhancers. However, unlike other foods in one's diet, they are used and consumed in relatively small amounts; a factor that for many years led to the underestimation of their nutritional contribution.3,5 Furthermore, the levels of habitual use and thus consumption are dependent on a range of factors3,4,6,7 that include personal choice, appetite, the type of food or dish to be flavoured and how it (the food or dish) is to be prepared, the number of recipes, in which the amounts of culinary herbs and spices added to a food or dish vary, and also the portion size. Thus, the amount used and consumed can vary considerably from day to day for one person, between individuals, and between recipes for the same meal or dish. Predictably, due their culinary use, which forms an important part of their history of use, the amounts consumed from region to region also vary, with estimated intake levels ranging from 0.5 g per day for Europeans to 1.3–1.9 g per day for Australians and New Zealanders to 1.8 g per day in parts of Africa. Moderate intakes are reported for the Middle East and Eastern Asia (2.6 g per person and 3.1 g per person, respectively) and in India, South Africa and Latin America the average intake is reported to be approximately 4.4 g per day.8,9 However, these foods are so much more than their culinary properties. History – which is not limited to that of Western countries, introduced to culinary herbs and

spices relatively late,10,12 but also encompasses the pasts of African, Asian, Central and South American countries – suggests that their earliest use by hunter and gatherers to wrap meat led to the accidental discovery that culinary herbs and spices enhanced the taste of food.10,13 Their history also reveals that their use was, and is, steeped in folklore and that they were used for their health promoting effects by ancient civilizations long before modern day science's focus on these foods for their bioactive properties. For example, the use of culinary herbs and spices to ease digestion and treat digestive disorders dates back to the time of Hippocrates in Ancient Greece and the first and second century in the practice of Ayurvedic medicine in India.10,13 The history of culinary herbs and spices is a global one, with records of their use in other ancient civilizations, including those of China, Egypt, Rome and Arabia (the pre-Islamic era, as early as 5000 Before the Common Era (BCE) in Mesopotamia (now southern Iraq) in which the use of culinary herbs and spices was influenced by the ancient Greek physician Galen and also the practice of the ancient Romans).10,13 The international trade of these foods, which is said to date back thousands of years (4500–1900 BCE) to trade between Mesopotamia and Ethiopia, resulted in establishing and influencing the use of culinary herbs and spices in Africa, Asia and Europe.10,13 Relatively recent research has now added to the long history of these foods. The last two decades have revealed an array of properties conferred via secondary compounds that are bioactive phytochemicals – many of which are alkaloids, phenolic acids, flavonoids and terpenoids and possess, amongst others, antioxidant, anti-microbial, anti-inflammatory, anti-diabetic and anti-cancer activities. Based on a growing amount of evidence, many of these culinary herbs and spices are purported to be of benefit in the maintenance of health and the prevention of chronic non-communicable diseases including type 2 diabetes, obesity, metabolic syndrome neurodegenerative diseases, including Alzheimer's disease, cancer, cardiovascular disease, and chronic inflammation, which now gives their daily/habitual/routine use a whole new meaning.5,14 Commentaries and information about these foods now extend beyond their culinary use. Not only have they led to position papers on, and research about, their use as alternatives to fat, salt and sugar to flavour food and to encourage the consumption of vegetables, but also they have led to discussions in scientific literature about the levels of consumption that might confer benefit – an area that is extremely challenging due to their subjective use – and their potential uses due to their bioactive constituents.14,16 There is a significant amount of literature (16 800 000 results from a Google search of culinary herbs and spices carried out in October 2019) ranging from peerreviewed literature on their chemical constituents, bioactive properties and health benefits to their culinary, dietary and medicinal uses, adverse effects, safety and adulteration –- the latter of which is a global issue with some countries reporting significant levels of foreign material such as Sudan I, II, III and IV and lead chromate pigment in commercially available culinary herbs and spice.17,19 The aim of the authors of this book is to bring together these key elements and more, by focussing on the thirty culinary herbs and spices listed, with both their common and botanical/scientific names, in the Table 1.1 below; the common names, where possible, are in both English and non-English languages so as to reflect the global use of these foods. The inclusion of some of the non-English names also highlights two facts: (1) that there are regional and dialectic differences in the names within

countries; and (2) the languages are mainly European and Asian with some that are African. When it comes to Indigenous groups in Australia, New Zealand, and the Americas, although there is a paucity of information, their use for medicinal purposes is acknowledged in the literature.20 The authors acknowledge that more culinary herbs and spices than the thirty of focus in this book are used around the world. However, these thirty were consistently among the lists of the most common culinary herbs and spices provided by online resources, including Gernot Katzer's excellent Geographic Spice Index,21,22 which provides information on culinary herbs and spices worldwide and categorises them based on regions – Central and Northern Europe, the Mediterranean, West and Central Asia, South Asia, South East Asia, East Asia, Africa, America, and Australia. Other resources that included the thirty of focus here in their list of common culinary herbs and spices include the Seasoning and Spice Association, the European Spice Association, global seasonings and spice market data, and academic literature from around the world.23,26 Table 1.1

Common, local and scientific names of the culinary herbs and spices

Common and local namesa

Botanical/Scientific namesa

Allspice, Jamaican pepper, Pimenta, Newspice Arabic – bhar hub wa na'im and Bahar Halu Finnish – Maustepippuri, Hindi – Kebab Chini French – Piment Spanish – Pimienta de Jamaica Yiddish – English pevirts and Englisher fefer Basil, Sweet Basil, Common Basil, Thai Basil, Tropical Basil Albanian – Bozilok I mermë and Borziloku Bengali – Tulsi French – Basilic Italian – Basilico Malay – Kemangi, Duan selaseh jantan Bay leaf Armenian – Tapni Derev, Dabni-I Terew, Dapni Dutch and French – Laurier German – Lorbeer Japanese – Gekkeiju, Roreru Black pepper Bengali – Golmoris French – Poivre noir Hausa – Masoro German - PfefferKorean – Huchu, Pepeo, Pepo Spanish – Pimienta negra Caraway Albanian – Qimnoni Burmese – Ziya French – Cumin des pres Spanish – Alcaravea Norwegian – Karve Cardamom, Small Cardamom, Green Cardamom, True Cardamom Armenian – Shooshmir, Shushmir and Andritak French – Cardamome Hindi – Choti Tamil – Elakkai Tibetan – Sug smel and Sugmel

Pimenta dioica, Pimenta officinalis

Ocimum basilicum

Laurus nobilis

Piper nigrum

Carum carvi

Elettaria cardamomum

Chives French – Civette Gaelic – Cebolete; Spanish – Cebollino Spanish – Cebollin Vietnamese – Hanh tam, Hanh trang Cinnamon (Ceylon Cinnamon, True Cinnamon) Basqu – Kanela, Kanelondo; Mongolian – Shantsaj French – Cannelle Spanish – Canela Tigrinya (spoken in Ethiopia and Eritrea) – Qerfe Urdu – Dar chini and Dal chini Other Species: Cinnamon (Chinese Cinnamon, Chinese Cassia), Cinnamon (Indonesian Cinnamon), Cinnamon (Saigon Cinnamon) Cloves Bulgarian – Karamfil Chinese (Cantonese) – Ding Heung French – Clous de girofle Spanish – Clavos de olor Welsh – Clawlys and Clof Coriander, Cilantro Coriander, Chinese parsley Catalan – Celiàdria and Coriandre English – Chinese parsley (herb) and Indian parsley (herb) French – Coriandre Spanish – Cilantro Tagalog (spoken in the Philippines) – Kulantro, Unsuey, Wansuey and Uan-soi (herb) Cumin Coptic – Tapen and Thapen Hebrew – Kamon, Kammon and Kamoon French – Cumin Spanish – Comino Tulu (spoken in Southwestern India) – Jirige Dill Croatian – Kopar and Mirodija Korean – Tir and Inondu French – Aneth Spanish – Eneldo Russian – Ukrop Fennel Czech – Fenykl, Fenýkl obecný, Vlašský kopr, Sladký kopr and Řimský kopr Gujarati – Varyyali French – Fenouil Spanish – Hinojo Swahili – Shamari Xhosa – Imbambosib Fenugreek Albanian – Kopër Greqie, Trëndetina yzerlike, Trëndetine, Yzerlik Farsi – Shanbalile French – Fenugrec Spanish – Fenogreco Swahili – Uwatu Ginger Fante (spoken in Ghana) – Akakdur, Tsintsimir and Tsintsimin Ga-Dangme (spoken in Ghana and Togo) – Kakaotshofa, Odzahui

Allium schoenoprasum

Cinnamomum verum (syn Cinnamomum zeylanicum)

Other Species: Cinnamomum cassia (syn Cinnamomum aromaticum), Cinnamomum burmanni, Cinnamomum loureiroi Syzygium aromaticum, Eugenia aomaticum, Eugenia caryophyllata

Coriandrum sativum

Cuminum cyminum

Anethum graveolens, Anethum foeniculum, Peucedanum graveolens, Anethum sowa

Foeniculum vulgare

Trigonella foenum-graecum

Zingiber officinale

Hausa – Chittar and Afu French – Gingembre Spanish – Jengibre Lemon grass Danish – Citrengras, Sereh and Kamelhewe Ga-Dangme – Ti-ba Icelandic – Sitrónugras French – Verveine des Indes Thai – Takrai, Krai Marjoram (sweet majoram) Belarusian – Majaran Hindi – Mirzam josh and Kuthara French – Marjolaine Spanish – Mejorana Turkish – Mercanköşk, Merzengûş, Kekik otu and Kekikotu Mint (peppermint) Arabic – Eqama, Nana, Nana al-fulfuli French – Menthe anglaise, menthe poivrée, Sentebon Lao – Bai Hom Lap, Bai kankam, Phak hom lap, Phak kan kam and Saranae Spanish – Menta Mint (spearmint) Mint (water mint) Nutmeg Bulgarian – Indijsko orehche Japanese – Natumegu French – Noix de muscade Spanish – Nuez moscada Oregano English – Wild Marjoram and Oregano French – Oregan Maltese – Riegnu Italian – Origano Thai – Orikano Mexican oregano Mexican oregano/small oregano Mexican oregano/rosemary mint Paprika Albanian – Specë and Speci French – Paprika Hausa – Tattase Nepali – Bhede Khursani Spanish – Pimenton Parsley Croatian (and Serbian) – Peršin and Peršun French – Persil Polish – Pietruszka zwyczajina Spanish – Parejil Triginya – Persamelo Rosemary Dutch – Rozemarijin French – Romarin Latvian – Rozmarīns Spanish – Romera Triginya – Rozmeri Xhosa – Roselinerb Saffron Armenian – Kerkoom and Kerkum French – Safran

Cymbopogon citratus, Cymbopogon flexuosus

Origanum majorana/Majorana hortensis

Mentha piperita

Mentha spicata Mentha aquatica Myristica fragrans

Origanum vulgare

Lippia graveolens, Lippia palmeri, Hedeoma patens, Poliomintha longiflora Capsicum annuum, Capsicum tetragonum

Petroselinum crispum, Petroselinum Hortense, Petroselinum sativum

Rosmarinus officinalis

Crocus sativus

Swahili – Zafarani Urdu – Zafaron and Kisar Sage, Common Sage French – Sauge Portuguese – Chá-da-Europa and Salva-mansa Spanish – Salvia Punjabi – Sathi Star anise, Chinese Anise Estonian – Harilik tähtaniisipuu and Tähtaniis French – Anis étoilé Indonesian – Bunga lawang, Adas cina, Pe ka, Pekak, Kembang lawing Spanish – Anis estrellado Swedish – Stjärnanis Sumac Coptic – Alithriten French – Sumac Lithuanian – Žagrenis Spanish – Zumaque Telugu (spoken in the south-east of India) – Karkkararingi Tarragon Chinese – Long Hao; Xia Ye Qing Hao Spanish – Dragoncilla; estragon French – Dragon; estragon Germany – Estragon Italy – Dragone; estragone Thyme Albanian – Timus Chinese (Mandarin) – Bai li xiang Chinese (Cantonese) – Baak leih heung French – Thym Spanish – Tomillo Tigrinya – Tesna Xhosa – Umakhunkulab Turmeric Bodo (spoken in Northeast India, Nepal and Bengal) – Halde French – Safran des Indes Hungarian – Kurkuma, Sárga gyömbérgyökér Spanish – cúrcuma Swahili – Manjano

Salvia officinalis

Illicium verum

Rhus coriaria, Rhus glabra, Rhus typhina

Artemisia dracunculus

Thymus vulgaris

Curcuma longa, Curcuma domestica

aSources of some common and botanical names: ref. 21 and 22. bSource of local names: ref. 26. The authors have listed only a selection of local names, which are

extensive.

The book is organised so that each culinary herb and spice has its own chapter, beginning with the chapter on allspice and ending with the chapter on turmeric. Each chapter begins with the names of the culinary herb or spice as listed in Table 1.1. A brief taxonomy and description of each culinary herb or spice are provided, as well as a list of varieties (both edible and inedible) and information concerning adulteration. The history of the culinary herb or spice, its region/s of origin and its journey from region to region via the spice trade are explored, as is the development of cultivars as a result of these journeys. Each chapter then delves into the historical uses of each culinary herb or spice and how they influenced and/or were influenced by cultural, religious and traditional beliefs and practices, and also their culinary

and medicinal uses of the past and present. (The authors acknowledge that in many cases there is little distinction between these beliefs, practices and uses as they overlap, interact, and/or influence one another. For example, a medicinal use could stem from a traditional belief that is also a religious one.) The major nutritional and phytochemical constituents of each culinary herb or spice are provided, and the culinary and bioactive properties of each are explained in the context of their (the constituents') chemistry. The next section of each chapter is focused on their bioactive properties, purported health benefits and therapeutic potential based on current and emerging research. This section attempts to review and, where possible, assess the potential of each culinary herb and spice to be used as a functional food, specifically their capacity to protect against the development of, and use in the treatment of, chronic non-communicable diseases and other diseases/conditions. However, in a number of cases the assessment is limited by the paucity and/or quality of some of the research carried out. For this section, every attempt has been made to focus on work that has come from clinical trials. However, the findings from in vitro and animal studies, which in many cases have formed the basis for much of the clinical work, have also been included. The final section of each chapter is on safety and adverse effects. The aim of the book is to provide an in-depth guide for a diverse set of readers on thirty common culinary herbs and spices. The challenge throughout has been to ensure that the book appeals to students, academics and those who work with and have a general interest in these foods. We hope we have found the right balance.

References 1. Herbs vs. Spices, Horticulture and Home Pest News, Iowa State University, Extension and Outreach, https://hortnews.extension.iastate.edu/2003/8-222003/herbsnspices.html, accessed 12 November 2020. 2. Chemical Compounds in Herbs & Spices, https://www.compoundchem.com/2014/03/13/chemical-compounds-in-herbsspices/, accessed 12 November 2020. 3. M. H. Carlsen, R. Blomhoff and L. F. Andersen, Nutr. J., 2011, 10, 50. 4. J. Pérez-Jiménez, L. Fezeu, M. Touvier, N. Arnault, C. Manach, S. Hercberg, P. Galan and A. Scalbert, Am. J. Clin. Nutr., 2011, 93, 1220-1228. 5. E. I. Opara and M. Chohan, Int. J. Mol. Sci., 2014, 15, 19183-19202. 6. I. Baker, M. Chohan and E. I. Opara, Plant Foods Hum. Nutr., 2013, 68, 364369. 7. N. Pellegrini, S. Salvatore, S. Valtueña, G. Bedogni, M. Porrini, V. Pala, D. Del Rio, S. Sieri, C. Miglio, V. Krogh, I. Zavaroni and F. Brighenti, J. Nutr., 2007, 137, 93-98. 8. World Health Organization, GEMS/Food Regional Diets: Regional Per Capita Consumption of Raw and Semi-processed Agricultural Commodities Prepared by the Global Environment Monitoring System/Food Contamination Monitoring and Assessment Programme (GEMS/Food), World Health Organization, Rev. edn, 2003, Available from https://apps.who.int/iris/handle/10665/42833. 9. R. Vázquez-Fresno, A. R. R. Rosana, T. Sajed, T. Onookome-Okome, N. A. Wishart and D. S. Wishart, Genes Nutr., 2019, 14, 18. 10. McCormick Science Institute, History of Spices,

https://www.mccormickscienceinstitute.com/resources/history-of-spices, accessed 12 November 2020. 11. A. Gilboa and D. Namdar, Radiocarbon, 2015, 57, 265-283. 12. S. G. Haw, J. Anc. Hist. Archaeol., 2017, 4, 5-18. 13. L. C. Tapsell, I. Hemphill, L. Cobiac, D. R. Sullivan, M. Fenech, C. S. Patch, S. Roodenrys, J. B. Keogh, P. M. Clifton, P. G. Williams, V. A. Fazio and K. E. Inge, Med. J. Aust., 2006, 185, S1-S24. 14. E. I. Opara, J. Sci. Food Agric., 2019, 99, 4511-4517. 15. J. O. Hill, Nutr. Today, 2014, 49, S12. 16. R. C. Post, Nutr. Today, 2014, 49, S22. 17. P. Galvin-King, S. A. Haughey and C. T. Elliott, Food Control, 2018, 88, 8597. 18. J. E. Forsyth, S. Nurunnahar, S. S. Islam, M. Baker, D. Yeasmin, M. S. Islam, M. Rahman, S. Fendorf, N. M. Ardoin, P. J. Winch and S. P. Luby, Environ. Res., 2019, 179, 108722. 19. Food and Drink Federation, https://www.fdf.org.uk/herbs-spicesguidance.aspx, accessed 13 November 2020. 20. M. Gossell-Williams, O. Simon and M. E. West, West Indian Med. J., 2006, 55, 217-218. 21. G.Katzer, Welcome to Gernot Katzer's Spice Pages, http://gernot-katzers-spicepages.com/engl/index.html, accessed 12 November 2020. 22. G.Katzer, Geographic Spice Index, http://gernot-katzers-spicepages.com/engl/spice_geo.html#top_of_index, accessed 12 November 2020. 23. The Seasoning and Spice Association, SSA: Culinary Herbs and Spices, http://www.seasoningandspice.org.uk/ssa/background_culinary-herbsspices.aspx, accessed 12 November 2020. 24. European Spice Association, ESA: List of Culinary Herbs and Spices, https://www.esa-spices.org/download/esa-list-of-culinary-herbs-and-spices.pdf, accessed 12 November 2020. 25. Grandview Research, Global Seasonings & Spices Market Size Report, 2020– 2027, https://www.grandviewresearch.com/industry-analysis/seasoningsspices-market, accessed 12 November 2020. 26. A. M. Asowata-Ayodele, A. J. Afolayan and G. A. Otunola, S. Afr. J. Bot., 2016, 104, 69-75.

CHAPTER 2

Allspice – Jamaican Pepper, Pimenta, Newspice (Pimenta dioica, Pimenta officinalis Lindl) 2.1

Names

English: Allspice Arabic: Bhar hub wa na'im and Bahar Halu Finnish: Maustepippuri Hindi: Kebab chini French: Piment Chinese: Duo xiang guo Spanish: Pimienta de Jamaica Yiddish: English pevirts and Englisher fefer

2.2

Taxonomy

Order: Myrtales Family: Myrtaceae Genus: Pimenta Species: Pimenta dioica and Pimenta officinalis L.

2.3

Origin, Description and Adulteration

The Myrtaceae family comprises about 140 genera and over 3000 species of tropical and subtropical origins. The genus, Pimenta, is made up of several species of aromatic trees in tropical America. The small Pimenta dioica tree is native to Jamaica. Allspice (Pimenta dioica) L., syn. Pimenta officinalis (Berg) L. is very common in Jamaica, in the West Indies, Mediterranean areas and Asia. It is also known as pimenta, pimento, clove pepper and Jamaica pepper. In Africa, specifically Egypt, it is called fulful afrangi.1 Another plant, relative to P. dioica, called Pimenta racemosa, is also used to make allspice and is more prominent in Central and South America. Japanese allspice (Chimonanthus praecox), which is native to eastern Asia, is used as an ornamental plant in England and the United States. Wild allspice or spicebush (Lindera benzoin), which is native to eastern North America, is often used as a substitute for true allspice. Pimenta dioica measures up to 8–10 metres high with smooth, peeling bark,

oblong leaves and prominent veins. The flowers are small and white, the fruit is green and ripens to dark brown and contains two kidney shaped seeds. The plant grows best in wet limestone forests. No known pests or specific diseases affecting the plant are reported in the literature, and P. dioica is documented as “very invasive” in certain parts of the world such as Maui.2 Allspice has been adulterated with several plants, such as powdered clove stem or Myrtus tobasco berry, known as ‘pimienta de tobasco’. In the US, Lindera benzoin (wild allspice) is used as a substitute for allspice.3 A mixture of pimento leaf oil and clove stem and leaf oils can serve as a relatively inexpensive substitute for berry oil. Pimento berry oil is sometimes adulterated with the leaf oil or clove stem oil as well as eugenol, which is cheaper.

2.4

Historical and Current Uses

Allspice was found by the crew of the Italian explorer Christopher Columbus during his voyage to Jamaica in 1494.4 These early explorers first mistook allspice for a type of pepper, which they sought after, and so named it allspice pimenta, which led to its Western botanical name. The first recorded importation of allspice to Europe was from 1601. Myrtus pimenta is mentioned in the Apicius Roman cookbook as an ingredient of fine spiced wine – containing wine, honey and many other hot spices. Allspice was also used in nut custard and fruit compotes. Kromeskis was a dish containing a mixture of grown wheat mixed with wine, pepper and broth with crushed berries, nuts and more pepper, shaped into small rolls, fried and served with wine and gravy.5 Allspice possesses a flavour of combined clove, cinnamon, nutmeg and a hint of juniper berry and peppercorn. Allspice can be used powdered or as whole berries. Some spice mixtures are labelled as “allspice”, yet they are not allspice but rather blends of spices used to mimic the flavour of allspice. Allspice is added to festive mincemeat and eggnog. It is also present in baked goods, such as spiced apple pie, pumpkin pies, banana bread spice cake, bread pudding and gingerbread.6 Allspice is a major component of Jamaican pickling spice, which contains a dozen other spices. It is also used in traditional Caribbean cuisine for the preparation of savoury and sweet dishes, vegetables, soups and desserts. Examples include Jamaican beef patties and jerk chicken kabobs.7 In the UK, allspice is added to stews, sauces and pickled vegetables. It is an essential component of the staple Palestinian slow cooked chicken Musakhan. A liqueur called allspice Dram, or pimento Dram, is made in the Caribbean by soaking the berries in rum, and is the basis of many exotic alcoholic cocktails such as Jalisco Pear, the Wildest Redhead and the Ancient Mariner, to name but a few. Furthermore, allspice essential oil has been used as a natural agent to substitute for synthetic pesticides and fungicide.8,9 The United States Department of Agriculture (USDA)10 granted allspice a Generally Recognized as Safe (GRAS) certification when used as food, however in excess of amounts naturally found in food, safety and efficacy are uncertain (see section on Safety and Adverse Effects). Allspice was incorporated into the British Pharmacopoeia of 1898 (specifically pimento oil and pimento water). The oil was

later deleted in 1914. In Caribbean traditional folk medicine, P. dioica has a long history of use including the use of its hot tea for colds, menstrual cramps and dyspepsia.11,12 Several plant parts have been used for aches and pains, and in Caribbean folk medicine, decoctions of P. racemosa are also used as anti-inflammatory and analgesic and hypotensive agents.3 In Costa Rica, P. dioica is used to treat dyspepsia and diabetes, and in Guatemala crushed berries are applied to bruises, aching muscles and sore joints.11,12 In Cuban medicine, herbal mixtures including allspice are prescribed for indigestion. Allspice also features in Ayurvedic Indian traditional medicine, with its likely origins from European colonization, to help relieve respiratory congestion and toothache. In Europe, there were anecdotal uses of allspice extract for treating dyspepsia.4 In modern herbal medicine, allspice essential oil is added to aromatherapy massage oils and baths to promote circulation and to relieve pain from muscle strains. It has also been used to relieve headaches, and to overcome fatigue and low mood, due to its comforting aroma.4 Although it does not feature in the Online Encyclopaedia of Traditional Chinese Medicine (TCM), allspice has been used in TCM for treatment of the meridians of the small intestines, spleen, stomach and large intestine.13 Considered warming and hot, allspice aids digestion, and is used to help improve blood circulation.14

2.5

Chemistry, Nutrition and Food Science

There is no information on the constituents of allspice in Phenol Explorer,15 however studies have shown that it contains biologically active constituents, such as phenolic acids, flavonoids, catechins and galloyl-glucosides, as well as terpenoids, alkaloids, and other polyphenols.16 Allspice berries contain volatile oils (1%–4%) of which 60%–80% is eugenol and 40% to 45% is eugenol methyl ether. Allspice leaf oil consists of eugenol (96%) (similar to clove leaf oil). The pharmacological activity of the essential oil is most likely due to the presence of eugenol.17 Essential oils of allspice are extracted by steam distillation of the dried fruit or the leaf, although several new methods have been investigated (hydrodistillation and supercritical carbon dioxide) to qualify and quantify the allspice oil and compare the effects of the extraction methods on the quality of the oil.18,20 The nutritional composition of allspice (see Table 2.1) has been obtained from the United States database. With regards to the nutritional quality of allspice, it is generally considered to be poor in the energy yielding nutrients (carbohydrate, protein and fat). However, it is relatively rich in fibre, magnesium and potassium. These values have to be considered in context, specifically with regards to the proportion of the spice used in the diet, where only a pinch or two of dried allspice is likely used.21 Table 2.1

Nutrition composition of dried allspice21

Allspice (100 g) – US data

Dried

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg

263 72.12 21.6 8.69 6.09 8.46 —a 661 0.553 —a 7.06 135 2.943 113 1044 2.7 77 1.01 27 0.101 0.063 2.86 0.21 39.2 36

a—: Not assessed or not present.

Allspice was tested as a synthetic acaricides' replacement for tick control in the meat (rearing) industry with effective results.22,23 It has antioxidant and antimicrobial activities and has been used to preserve meat and dairy products. Innovation research investigated the release rates and antimicrobial activity of microencapsulated P. dioica essential oil in a chitosan and chitosan–κ-carrageenan microsphere complex.22,24 According to Dima et al., allspice warrants further investigation, as improved functionality in meat products showed promising results with antimicrobial activity against Candida utilis, Bacillus cereus and Bacillus subtilis.

2.6

2.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

Primarily due to its phenolic constituents, including eugenol, quercetin and gallic acid, allspice (berries and essential oil) possesses quite a high antioxidant capacity compared to other culinary herbs and spices.4,16,25,31 Commercially available dried allspice ranked 2nd out of 38 dried and commercially available culinary herbs and spices for antioxidant capacity in vitro.31 However, values for antioxidant capacity vary due to the nature of the spice preparation and the assay used. The antioxidant

property of allspice has been linked to inhibition of reactive oxygen species (ROS) mediated DNA damage in Escherichia coli (E. coli).26 However, there is a paucity of in vivo studies, which are limited to the use of animal models. In the single in vivo (animal) study identified concerning the antioxidant property of allspice, Shyamal et al. 32 reported that powdered aqueous extract of leaves decreased oxidative stress, based on inhibition of lipid peroxidation, and improved antioxidant status, based on increased reduced glutathione and increased activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, in rats fed a high fat diet.

2.6.2

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

There is some limited evidence supporting the glucose lowering, anti-diabetic and lipid lowering properties of allspice. However, these are limited to in vitro and/or animal studies. Aqueous extracts of allspice proved to be a potent stimulator of insulin-dependent glucose oxidation by rat adipocytes (fat cells) in vitro. This activity is believed to be due to the spice's polyphenolic constituents,33 which are also suggested to be responsible for its anti-glycation effects in vitro.34 Protein glycation is a biomarker of diabetes and can lead to the vascular complications that result from this disease. Out of the culinary herbs and spices investigated, allspice, along with clove and cinnamon, were reported to be the most active inhibitors of fructose mediated protein glycation. The in vitro system of glycation used depended on the generation of ROS so the antioxidant properties of allspice's phenolic compounds, including eugenol, might be responsible for the effects observed especially as hyperglycaemia (high blood glucose) can induce oxidative stress.35,36 Concerning its lipid lowering properties, allspice may be of benefit in the management of hyperlipidemia (elevated lipid levels) as it was reported to lower serum cholesterol and triglyceride levels in hyperlipidemic rats.32 These effects were associated with improved antioxidant status.

2.6.3

Chemopreventive/Anti-cancer Properties

There is a small amount of evidence concerning the chemopreventive/anti-cancer properties of allspice. Shamaladevi et al. 37 reported that aqueous extracts of Pimenta berries displayed cytotoxic (killed the cells) and/or antiproliferative (inhibited cell division/cell growth) effects on a number of prostate cancer cell lines in vitro, including LNCaP, DU145, PC3 and CW22RV1, as well as primary prostate cancer and tumour cell lines LAPC-4 and EOO6AA, respectively, and an androgen repressed prostate cancer cell line, ARCaP, which is tumorigenic and highly metastatic.38 The reported lower level of cytotoxicity on immortalized prostate epithelial cells (RWPE-1) and normal lung fibroblast cells indicates a cancer cell specific effect, although regarding the latter the lower level of cytotoxicity occurred only in non-proliferating (quiescent) cells. Furthermore, aqueous extract of Pimenta berries inhibited the growth of human breast cancer cells (MCF-7, SKBR3, MDA-MB231, T47D and BT474) in vitro.39

Animal studies provide evidence of Pimenta extract's ability to inhibit tumour (subcutaneous, breast cancer (MB231) and prostate (LNCaP) tumours) growth in vivo.37 Research to elucidate the mechanism of action has revealed that the plant – either leaf or berries – induces cell cycle arrest in a dose-dependent manner in prostate cancer cells, and induces apoptosis and autophagy, in both breast and prostate cancer cells in vitro. Furthermore, aqueous allspice extract is reported to inhibit the growth of androgen receptor dependent prostate cancer cells via an epigenetic mechanism, specifically the inhibition of histone acetylation.40 Regarding the bioactive compounds of this spice, evidence suggests that the spice's phenolic constituents are responsible, with research identifying the compound eugenol-5-Oβ-(6′-galloylglucopyranoside), also known as Ericifolin, as a novel anti-tumour compound isolated from allspice.1,4 This compound, however, to date appears to be only effective against prostate cancer cells; it is not cytotoxic against breast cancer cells, specifically MCF-7 or MB231 cells, and does not induce apoptosis, thus indicating that allspice's anti-cancer effect involves other bioactive compounds.1,37,39,40

2.6.4

Anti-platelet, Hypotensive and Antinociceptive/Analgesic Properties

The anti-platelet aggregation effect of allspice was reported by Okazaki et al. 41 Methanol extracts of dried powdered allspice inhibited the aggregation of human platelets in vitro by 71%. In fact this spice had the most potent effect with sweet marjoram slightly behind with a percentage inhibition of 69%. Platelet aggregation plays an important role in the development of arterial thrombosis. However, the significance of allspice, in vivo, particularly in those at risk of blood clots, remains to be established. Studies on the ability of the Pimenta plant to lower blood pressure are based on its traditional use in South America to use extracts of its leaves to treat hypertension (high blood pressure).4,42 Suárez et al. 42 reported that extracts of Pimento leaf, both total aqueous and ethanol extracts, decreased arterial blood pressure in vivo (in rats). The effect of the aqueous extract was dose-dependent, and the leaf fraction (identified in the study as the final aqueous extract – that is what remained following extraction with hexane, ethyl acetate and n-butanol) was the most potent compared to the total aqueous and ethanol extracts. Dosages of the aqueous extract that were lower than 100 mg kg−1 body weight had no significant effect on heart rate but at 100 mg kg−1 body weight, bradycardia (the slowing down of heart rate) and death resulted (with the aqueous extract); for the ethanol extract at this dosage the heart rate was lowered significantly. The findings of this study suggested that the extracts had a vasodilatory effect. Finally, both the aqueous and ethanol extracts at dosages greater than 100 mg kg−1 of body weight (specifically 250 and 500 mg kg−1 of body weight) caused loss of motor activity, slight analgesia and diminution of the animals' alarm response – all of which were indicative of depression of the central nervous system (CNS). In a similar study, this time using normotensive and hypertensive rats, administration of the aqueous and ethanol extracts resulted in

depression of the CNS as well as analgesic effects and hypothermia. The effect was dose-dependent and again the final aqueous extract was the most potent. However, there was no change in blood pressure or heart rate when it was given orally for 14 days to both the normotensive and hypertensive rats.43 Later work by the same authors confirmed that the hypotensive effect of aqueous extracts of the leaves occurs following short term (of up to 1 hour) administration.44

2.6.5

Potential Use in Managing Menopausal Symptoms

In a study on the health related quality of life of women in the US, the use of herbal remedies, including allspice, to treat menopausal symptoms was identified.45 This work led researchers to investigate whether or not these remedies possessed properties that could explain their use. Doyle et al.46 identified that a number of the herbal remedies, which were plant extracts, including allspice (a methanol extract of the dried plant) elicited oestrogenic activity, via binding to oestrogen receptors, altered the expression of oestrogenic responsive genes in human breast cancer cells (MCF-7 cells) and acted as partial oestrogen agonists (by binding and activating the oestrogen receptor to elicit a biological response) and/or antagonists (by blocking the action of oestrogen and oestrogen agonists). Although these effects were demonstrated in vitro, they do provide an explanation for the use of allspice to treat menopausal symptoms. However, the authors of this study also expressed concerns about the safety of allspice and the other oestrogenic herbal remedies investigated with regards the development of oestrogenic sensitive cancers including breast, ovarian and womb cancers, and thus highlighted the need for further studies in vitro and in vivo to investigate the safety and efficacy of these remedies.

2.6.6

Antimicrobial Properties

Studies dating back to the early part of the 20th century have reported on the antimicrobial effects, both against bacteria and fungi pathogenic to humans, of allspice47,48 with evidence indicating that eugenol, found mainly in the essential oil fraction of this spice, is responsible primarily for its anti-bacterial, and also its antifungal activities.47,48

2.6.6.1 Anti-bacterial Activity Work has focussed on allspice's anti-bacterial properties particularly with regards to its essential oil fraction. The essential oil of allspice is reported to inhibit the growth of pathogenic gram-negative bacteria including Escherichia coli O157:H7 strain and Salmonella enterica, and the pathogenic gram-positive bacteria Listeria monocytogenes.49,52 One study reported that the essential oil of allspice was a more effective anti-bacterial agent (in this case acting against E. coli UTI89 – a uropathogen (a pathogen that causes urinary tract infection)) than a number of antibiotics – including levoflaxcin, cefdinir, fosfomycin, nitrofurantoin and a combination of trimethoprim and sulfamethoxazole.53 Dried and coarsely ground preparations of allspice also possess anti-bacterial activity. Bagamboula et al. reported the inhibitory effect of these preparations against strains of the pathogenic

gram-positive bacteria Shingella, which infects the digestive system.54 However, this effect was dependent on the growth medium used. Extract of allspice was also reported to not be effective against Listeria monocytogenes in contrast to its essential oil, which appears to be far more potent.49,52,55,56 This differential effect is likely due to the difference in the profile of allspice's bioactive constituents between the essential oil and the plant extract.

2.6.6.2 Anti-fungal Activity Research from the 1980s reported on the potent inhibitory effect of allspice (commercial powdered spice) on the growth of toxigenic (produces toxins called mycotoxins) fungi including strains of Aspergillus and Penicillium.55,56

2.7

Safety and Adverse Effects

With the exception of the study by Suárez et al.42 who reported that aqueous extracts of Pimento leaves at 100 mg kg−1 of body weight can result in bradycardia and death in animals (rats), there is little in peer reviewed literature concerning the safety of this spice. This paucity of information is likely due primarily to a lack of in vivo and clinical studies on the safety and efficacy of allspice. Non-peer reviewed online resources state that allspice is not considered toxic and that it is safe for consumption by pregnant and breast-feeding women when consumed at amounts used in the preparation of food, but it should not be consumed in excessive amounts.57,58 They also state that allspice can cause mucosal irritation (pain or inflammation of the gastro-intestinal tract) and might slow down clotting (the latter is likely based on the anti-platelet aggregation study summarised above) so it should not be used/consumed prior to surgery to avoid any chance of it increasing bleeding. However, no clinical evidence is available to support these safety concerns. No information is available concerning any interactions with other herbs/spices/remedies or drugs, or contraindications. It is advised that allspice not be consumed in high amounts due to its constituent eugenol, also known as clove oil, which is toxic in large amounts and can also affect the CNS.57,59

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https://www.gutenberg.org/files/29728/29728-h/29728-h.htm, accessed 16 November 2020. 6. Good Housekeeping, Spiced Apple Pie, https://www.goodhousekeeping.com/recipefinder/spiced-apple-pie-recipeghk1110, accessed 16 November 2020. 7. https://www.bonappetit.com/ingredient/allspice, accessed 16 November 2020. 8. S.-M. Seo, J. Kim, S.-G. Lee, C.-H. Shin, S.-C. Shin and I.-K. Park, J. Agric. Food Chem., 2009, 57, 6596-6602. 9. I.-K. Park, J. Kim, S.-G. Lee and S.-C. Shin, J. Nematol., 2007, 39, 275-279. 10. US Food and Drug Administration, USFDA, https://www.fda.gov/food/foodadditives-petitions/food-additive-status-list, accessed 21 November 2020. 11. N. Nakatani, BioFactors, 2000, 13, 141-146. 12. E. N. Onwasigwe, M. Verghese, R. Sunkara, L. Shackelford and L. T. Walker, Food Sci. Nutr., 2017, 08, 778. 13. H.-Y. Xu, Y.-Q. Zhang, Z.-M. Liu, T. Chen, C.-Y. Lv, S.-H. Tang, X.-B. Zhang, W. Zhang, Z.-Y. Li, R.-R. Zhou, H.-J. Yang, X.-J. Wang and L.-Q. Huang, Nucleic Acids Res., 2019, 47, D976-D982. 14. White Rabbit Institute of Healing, Allspice, https://www.whiterabbitinstituteofhealing.com/herbs/allspice/, accessed 16 November 2020. 15. V. Neveu, J. Perez-Jiménez, F. Vos, V. Crespy, L. du Chaffaut, L. Mennen, C. Knox, R. Eisner, J. Cruz, D. Wishart and A. Scalbert, Database, 2010, 2010, bap024. 16. H. Kikuzaki, A. Sato, Y. Mayahara and N. Nakatani, J. Nat. Prod., 2000, 63, 749-752. 17. J. A.Duke and J. A.Duke, Handbook of Medicinal Herbs, CRC Press, Boca Raton, FL, 2nd edn, 2002. 18. E. Lemberkovics, Á. Kéry, A. Kakasy, E. Szöke and B. Simái, Acta Hortic., 2003, , 49-56. 19. T. Stewart, H. I. Lowe and C. Watson, Am. J. Essent. Oil. Nat. Prod., 2016, 4, 27-30. 20. Y. Y. Andrade-Avila, J. Cruz-Olivares, C. Pérez-Alonso, C. H. Ortiz-Estrada and M. D. C. Chaparro-Mercado, J. Chem., 2017, 2017(2), 6471684. 21. J.Bodner-Montville, J. K. C.Ahuja, L. A.Ingwersen, E. S.Haggerty, C. W.Enns and B. P.Perloff, USDA Food and Nutrient Database for Dietary Studies: Released on the web, https://pubag.nal.usda.gov/catalog/7356, accessed 21 November 2020. 22. M. Martinez-Velazquez, G. A. Castillo-Herrera, R. Rosario-Cruz, J. M. FloresFernandez, J. Lopez-Ramirez, R. Hernandez-Gutierrez and E. D. C. LugoCervantes, Parasitol. Res., 2011, 108, 481-487. 23. M. Zabka, R. Pavela and L. Slezakova, Ind. Crops Prod., 2009, 30, 250-253. 24. C. Dima, M. Cotârlet, P. Alexe and S. Dima, Innov. Food Sci. Emerg. Technol., 2014, 22, 203-211. 25. H. Kikuzaki, S. Hara, Y. Kawai and N. Nakatani, Phytochemistry, 1999, 52, 1307-1312. 26. A. Ramos, A. Visozo, J. Piloto, A. García, C. A. Rodríguez and R. Rivero, J. Ethnopharmacol., 2003, 87, 241-246. 27. Y. S. Yun, Y. Nakajima, E. Iseda and A. Kunugi, J. Food Hyg. Soc., 2003, 44, 59-62. 28. R. Blomhoff, Tidsskr. Nor. Legeforen., 2004, 124, 1643-1645.

29. Y. Miyajima, H. Kikuzaki, M. Hisamoto and N. Nakatani, BioFactors, 2004, 22, 301-303. 30. M. Khatun, S. Eguchi, T. Yamaguchi, H. Takamura and T. Matoba, Food Sci. Technol., 2006, 12, 178-185. 31. S. Dragland, H. Senoo, K. Wake, K. Holte and R. Blomhoff, J. Nutr., 2003, 133, 1286-1290. 32. M. Shyamala, J. J. Paramundayil, M. R. Venukumar and M. S. Latha, Indian J. Physiol. Pharmacol., 2005, 49, 363-368. 33. C. L. Broadhurst, M. M. Polansky and R. A. Anderson, J. Agric. Food Chem., 2000, 48, 849-852. 34. R. P. Dearlove, P. Greenspan, D. K. Hartle, R. B. Swanson and J. L. Hargrove, J. Med. Food, 2008, 11, 275-281. 35. T. V. Fiorentino, A. Prioletta, P. Zuo and F. Folli, Curr. Pharm. Des., 2013, 19, 5695-5703. 36. P. V. Dludla, E. Joubert, C. J. F. Muller, J. Louw and R. Johnson, Nutr. Metab., 2017, 14, 45. 37. N. Shamaladevi, D. A. Lyn, K. A. Shaaban, L. Zhang, S. Villate, J. Rohr and B. L. Lokeshwar, Carcinogenesis, 2013, 34, 1822-1832. 38. H. Y. E. Zhau, S.-M. Chang, B.-Q. Chen, Y. Wang, H. Zhang, C. Kao, Q. A. Sang, S. J. Pathak and L. W. K. Chung, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 15152-15157. 39. L. Zhang, N. Shamaladevi, G. K. Jayaprakasha, B. S. Patil and B. L. Lokeshwar, OncoTarget, 2015, 6, 16379-16395. 40. Y.-H. Lee, S. W. Hong, W. Jun, H. Y. Cho, H.-C. Kim, M. G. Jung, J. Wong, H.-I. Kim, C.-H. Kim and H.-G. Yoon, Biosci., Biotechnol., Biochem., 2007, 71, 2712-2719. 41. K. Okazaki, S. Nakayama, K. Kawazoe and Y. Takaishi, Phytother. Res., 1998, 12, 603-605. 42. A. Suárez, G. Ulate and J. F. Ciccio, J. Ethnopharmacol., 1997, 55, 107-111. 43. A. Suárez Urhan, G. Ulate Montero and J. F. Ciccio, Rev. Biol. Trop., 1997, 44–45, 39-45. 44. A. Suárez, G. Ulate and J. Ciccio, J. Ethnopharmacol., 1997, 55, 107-111. 45. N. E. Avis, M. Ory, K. A. Matthews, M. Schocken, J. Bromberger and A. Colvin, Med. Care, 2003, 41, 1262-1276. 46. B. J. Doyle, J. Frasor, L. E. Bellows, T. D. Locklear, A. Perez, J. GomezLaurito and G. B. Mahady, Menopause, 2009, 16, 748-755. 47. F. M. Bachmann, J. Ind. Eng. Chem., 1918, 10, 121-123. 48. F. M. Bachmann, J. Ind. Eng. Chem., 1916, 8, 620. 49. M. Friedman, P. R. Henika and R. E. Mandrell, J. Food Prot., 2002, 65, 15451560. 50. W.-X. Du, C. W. Olsen, R. J. Avena-Bustillos, T. H. McHugh, C. E. Levin and M. Friedman, J. Food Sci., 2009, 74, M372-M378. 51. W.-X. Du, C. W. Olsen, R. J. Avena-Bustillos, T. H. McHugh, C. E. Levin, R. Mandrell and M. Friedman, Food Sci., 2009, 74, M390-M397. 52. D. H. Gilling, S. Ravishankar and K. R. Bright, J. Environ. Sci. Health, Part A: Toxic/Hazard. Subst. Environ. Eng., 2019, 54, 608-616. 53. S. Xiao, P. Cui, W. Shi and Y. Zhang, Discovery Med., 2019, 28, 179-188. 54. C. F. Bagamboula, M. Uyttendaele and J. Debevere, J. Food Prot., 2003, 66, 668-673. 55. H. Hitokoto, S. Morozumi, T. Wauke, S. Sakai and H. Kurata, Appl. Environ.

Microbiol., 1980, 39, 818-822. 56. M. A. Azzouz and L. B. Bullerman, J. Food Prot., 1982, 45, 1298-1301. 57. Drugs.com, Allspice Uses, Benefits & Dosage – Drugs.com Herbal Database, https://www.drugs.com/npp/allspice.html, accessed 10 February 2020. 58. WebMD, Allspice, https://www.webmd.com/vitamins/ai/ingredientmono81/allspice, accessed 10 February 2020. 59. PubChem, Eugenol, https://pubchem.ncbi.nlm.nih.gov/compound/3314, accessed 10 February 2020.

CHAPTER 3

Basil – Sweet Basil, Common Basil, Thai Basil, Tropical Basil (Ocimum basilicum) 3.1

Names

English: Basil Albanian: Bozilok I mermë and Borziloku Bengali: Tulsi Chinese: Luo Le French: Basilic Italian: Basilico Malay: Kemangi, Duan selaseh jantan Basil, the name, is thought to originate from an abbreviated form of the Greek Basilikon phuton, translating as “royal herb”, or derives from the Greek okimon, “smell” and basilikon, “royal”.1,2

3.2

Taxonomy

Order: Lamiales Family: Lamiaceae Genus: Ocimum Species: Ocinum basilicum L.3

3.3

Origin, Description and Adulteration

Basil is native to Asia but cultivated all over the world, with an estimated 65 to 150 Ocimum species4,5 mentioned in the literature, reclassified into a total of 64 species.6 The most commercially significant basils are sweet basil (O. basilicum), which includes French basil, with aromatic bright green leaves which is also used as an ornamental plant. American cultivars of basil include ‘Genovese’, ‘Mammoth’, and ‘Napoletano’. Egyptian basil, also called African basil or clove basil (O. gratissimum L), which owes its name to its camphorous, clove-like aroma, is popular in Nigeria. Holy basil (O. tenuiflorum, syn. O. sanctum) also called tulasi or tulsi (Hindi) is popular in India, and is more pungent than sweet basil due to higher levels of caryophyllene and methyl eugenol.7

Sweet basil is an aromatic evergreen annual or perennial shrub that has opposite, linear to broadly-ovate (oval shaped) leaves and small tubular white or pinkish flowers in whorls (spirals) forming a spike with bright green, elliptic leaves. The small flowers, which are approximately 1 cm in length, bloom in late summer. These are edible with a sweet, clover-like flavour, which can be added to tomato dishes as well as oils, salad dressings and soups.8 Sweet basil grows 0.1 to 0.5 metres in height and the same in width, it is better suited in a light, well-drained, fertile soil in a sheltered position in full sun. It is best grown containerised, and can be a short-lived winter sub-shrub if placed under glass. Sweet basil suffers from a number of pests such as leafhoppers and aphids (both small sap-sucking insects). Slugs and snails may also be a problem and it can be affected by the fungal disease powdery mildew.9 Overall, the quality of sweet basil is defined by the presence of adulterant weeds, colour, and aroma.10 Common adulterants in basil include Holy basil (O. sanctum) and Vitex negundo, which is used instead of pure sweet basil. DNA barcoding is a promising tool in the identification of plant species and herbal medicines, including sweet basil and other herbs and spice.11

3.4

Historical and Current Uses

Basil species from Iran, India and other tropical regions of Asia, have been cultivated for over 5000 years. In India Holy basil is referred to as “The Queen of Herbs”, often grown around temples in devotion to the gods Krishna and Vishnu. Hindus are laid to rest with a basil leaf on their chest as a passport to Paradise. It was brought to ancient Greece by Alexander the Great (356–323 BCE), arrived in England from India in the mid-1500s and reached the US in the early 1600s.5 Sweet basil was grown in medieval gardens and is mentioned in the work of English herbalists Culpeper (1616–1645), Gerard (1545–1612), and Parkinson (1567–1650). Ancient Roman and Greek physicians Galen (129–216 CE) and Dioscorides (50–70 CE) thought it should not be taken internally. Gerard praised sweet basil as a remedy for melancholy but concurred with Dioscorides who warned too much basil “dulleth the sight and is of a hard digestion”. Pliny the Elder (23/24–79 CE), the Roman scholar, prescribed its use to lower blood pressure and to cleanse the blood of excess sugar and cholesterol. In Italy it is a symbol of love, in France it is the herb of the royals. In the Middle Ages in Western Europe, it was considered the devil's herb but used in potions and drunk to offer protection against witches. In Victorian times, it was recognised as a sign of good wishes and Jews believed they drew strength from basil during fasting. African legends link basil to protection against scorpions.2,4,6,12,13 In the Apicius Roman cookbook, basil (O. basilicum) is mentioned in one recipe, used to flavour green peas, similar to “Petits Pois à la Française”, where young peas are cooked in broth, served with shredded bacon, lettuce, parsley, onions fresh mint, pepper, salt.14 Rosalind Northcote mentioned basil in The Book of Herbs (1903),15 sweet basil (O. basilicum) and bush basil (O. minimum), as emblems of love and health. She quotes a passage of Parkinson's Earthly Paradise, (1619): “The ordinary basil is in a

manner wholly spent to make sweete, or washing waters, among other sweet herbes, yet sometimes it is put into nosegays (a small bouquet of flowers).” She then comments that “Basil is too much neglected nowadays”. She also mentions that sweet basil has the flavour resembling that of cloves, which was in demand by French cooks, species are not always specified used to flavour soups and salads, and that basil was grown in Louis XIV's gardens. Today, recipes with sweet basil are found in a range of Western and Asian dishes, and include pesto recipes, salsa/sauces, dressings and basil flavoured hummus. It is added fresh to salads, soups and pasta dishes. An essential component of stir fries, basil fried rice, potato salads, sweet potato fries, bruschetta and pizza. It is also added to breads/cornbread, shortcakes, as well as sorbets and ice creams.16 Several cocktails also contain fresh sweet basil leaves. These include gin basil smash, Mojitos, Martini and Moscow Mule. The United States Department of Agriculture (USDA) granted sweet basil, Generally Recognized as Safe (GRAS) certification, when used as food, and granted sweet basil essential oil GRAS certification when used as a food additive.17 Sweet basil does not feature on the list of Commission E monographs or the extended versions of monographs as an approved herb. It features under the list of unapproved herbs as the effectiveness for use is not sufficiently evidenced. It is used to relieve fullness and flatulence, to stimulate appetite and digestion, and as a diuretic (increase urination). The herb contains about 0.5% essential oil of which estragole makes up 85%, which after metabolic activation, showed a mutagenic (leading to a carcinogenic) effect in animal studies (see section on Safety and Adverse Effects). Its use as an aroma or flavour in preparations, for up to 5 percent, is permitted.18 Holy basil or tulsi, is used as an adaptogenic and stress-relieving remedy in India and to help with asthma, diabetes and ageing in Ayurvedic medicine.18 Sweet basil is not mentioned in the online encyclopedia of traditional Chinese medicine,19 but an online source suggests it is associated with the lung, spleen and stomach meridians. It is used to promote blood circulation after birth and to treat kidney problems and stomach disorders. It is reported to be useful in anxiety, depression, insomnia and exhaustion, as well as adrenal insufficiency, fainting, coma and epilepsy. It is also used to treat colds, low back pain, nausea, vomiting, poor appetite, indigestion, bloating and intestinal worms.20

3.5

Chemistry, Nutrition and Food Science

Phenol Explorer21 shows that dried basil contains phenolic acids; vanillic acid and rosmarinic acid. The aroma of basil is mainly due to 1,8-cineole, linalool, methyl chavicol, and eugenol. Monoterpenes, sesquiterpenes and phenylpropanoids are also present but vary greatly. Liquorice flavour in basil is due to high levels of methyl chavicol. African basil species contain high levels of camphor. The cinnamon-like scent is due to methyl cinnamate, whilst the lemon-like scent is due to citral. In Holy basil higher levels of caryophyllene and methyl eugenol render the scent more pungent.7 UK data indicate that basil (species non specified) is nutrient poor, however dried

basil may make important dietary contributions towards dietary intakes of iron, phosphorus, potassium, and provitamin A. Phytosterol levels are 1.06 mg g−1 (see Table 3.1),22 therefore it may make a significant contribution to the 2 g per day of dietary phytosterol recommended for the prevention of cardiovascular diseases if consumed regularly. Table 3.1

Nutrition composition of fresh and dried basil.22 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0

Basil (100g) – UK data

Fresh

Dried

Energy/kcal Carbohydrates/g Dietary Fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

40 5.1 Na 0.8 (Na) 0.5 88 14 250 Na Na 5.5 11 Na 37 300 Na 9 0.7 660 0.08 0.31 1.1 Na 26 Na Na —b Na

251 43.2 Na 4 (Na) 2.3 6.4 106 2110 1.37 Na 42 420 3.2 490 3430 Na 34 5.8 940 0.15 0.32 6.9 Na 0 0 Na —b Na

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. Dry basil leaves have much less aroma than fresh leaves, and freeze-drying is considered the best method for flavour preservation.4,5,23 Dehydration of basil impacts its sensory and nutritional quality, with changes dependent on the method and temperature used for drying. The content of all the minerals analyzed in oven-dried basil was higher than that of sun-dried basil, suggesting oven drying was a better method to preserve nutrients.

Trakoontivakorn, Tangkanakul and Nakahara,12 investigated the impact of five different cooking methods, blanching, boiling, steaming, sautéing and high temperature (121 °C) cooking, on four Basil Ocimum species: O. americanum, O. tenuiflorum, syn. O. sanctum, O. basilicum and O. gratissimum. The antioxidant capacity, total phenolic content and phytochemicals were assessed. Results showed that cooking with blanching and boiling resulted in a greater reduction in both antioxidant capacity and phenolic content (with evidence of rosmarinic acid leaching out established via HPLC chromatography). Sautéing and steaming increased the antioxidant capacity matching an increase in phenolic content (particularly rosmarinic acid, the most abundant constituent).12 Sweet basil's constituents have been shown to have antimicrobial activities, but these are not traditionally used as food preservatives – although a review carried out in 2003 suggested that they have the potential to be used in this way (for food preservation); the lack of evidence warrants further research. Extracts of Holy basil have been investigated for their preservative effects on meat with positive results. Various concentrations of dried Holy basil powder and ethanolic extracts were tested on slowing oxidative rancidity in cooked ground pork, during 14 days of refrigerated storage (5 °C). Measures of oxidation including thiobarbituric acid-reactive substances (TBARS), peroxide value (POV), conjugated diene and hexanal content were evaluated. Results showed that dried Holy basil powder and its ethanolic extract significantly inhibited the formation of TBARS, POV, conjugated dienes and hexanal. Dried Holy basil powder was the most effective at retarding oxidation in meat.24 Gluten free baking poses challenges for the food industry, and novel approaches seek to improve baking volume loss in the absence of gluten. Sweet basil seed gum is a polysaccharide extracted from basil seeds with good functional properties (viscosity, foaming, emulsifying, gelling, solubility, and overall texture improvement) resulted in an increase in baking volume increase in gluten free rice cake.25

3.6

3.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

The antioxidant properties of sweet basil are well established in vitro and also in vivo and are due primarily to its polyphenolic constituents. Studies demonstrate that both the aerial parts and the essential oil of this herb possess antioxidant capacity in vitro, although values vary based on the nature of the preparation and the assay used, and/or the ability to decrease oxidative stress and improve antioxidant status in vivo.26,36 It is suggested in some studies that the antioxidant properties of this herb may be linked to its reported glucose lowering, anti-diabetic, cardioprotective, chemopreventive/anti-cancer and hepatoprotective properties, which are discussed below.

3.6.2

Anti-inflammatory and Analgesic Properties

Research indicates that sweet basil possesses anti-inflammatory properties, likely due to its polyphenolic constituents including its phenolic acids and flavonoids,35 although this area of work is limited to a very small number of in vitro and in vivo (animal) studies, so the significance of this property in humans has yet to be established. Benedec et al. 38 reported that a tincture (ethanol extract) of sweet basil inhibited total white blood cell counts, with its effect on the monocyte (a class of white/immune cells that develop into macrophages and dendritic cells) population being particularly potent in vivo (when administered to an animal model of inflammation), and it also significantly inhibited the activity of phagocytic cells (white/immune cells that carry out the process of phagocytosis, which is the engulfing of bacteria, debris and dead cells). These effects were comparable to those of the non-steroidal anti-inflammatory drug diclofenac. In fact, compared to this drug the sweet basil tincture was more potent. The tincture also inhibited the synthesis of nitric oxide, which is a pro-inflammatory mediator, however this effect was less than that of diclofenac. Ethanol extracts of sweet basil, and also petroleum ether, chloroform, ethyl acetate and butanol fractions of the extract, decreased stimulated and basal prostaglandin E2 (PGE-2), another pro-inflammatory mediator, and PGE-2 production by murine (mice) macrophages in vitro following 30 min and 24 h exposure, with the ethyl acetate and butanol fractions producing the most significant reductions in PGE-2.39 Furthermore, sweet basil essential oil, and its constituent estragole, are reported to decrease oedema (fluid retention), vascular permeability (the capacity of the blood vessel wall to allow small molecules and cells in and out of the vessel – it increases due to inflammation) and/or white blood cell infiltration in both acute and chronic animal models of inflammation.40 These anti-inflammatory effects are in contrast to research that reported that extracts (both aqueous and ethanol) of sweet basil leaves increased antibody responses, delayed (type 4) hypersensitivity (a type of allergic reaction) and phagocyte activity generated in mice.41 The authors of this study suggested that the flavonoids in sweet basil may be responsible for the outcomes reported.42 The pain relief properties of sweet basil have been demonstrated in vivo (animal studies) using extracts (methanol) of its leaves, and also its essential oils. In their review on biological and pharmacological properties of sweet basil, Ch et al. 43 summarised a study by Choudhury et al. 44 in which sweet basil leaf extract elicited analgesic effects in mice. Essential oil of sweet basil is also reported to provide pain relief in mice including in a model of fibromyalgia, a chronic condition associated with pain,45 both on its own and when complexed with beta-cyclodextrin, with the complex having a greater effect.46 (Beta-cyclodextrin is used to improve the solubility and bioavailability of drugs with low water solubility.47) Findings of the study suggest a mechanism of action involving interaction with opioid receptors as well as the inhibition of the synthesis of mediators of pain including the prostaglandins and prostacyclins.

3.6.3

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

The glucose lowering action and anti-diabetic potential of sweet basil is based on the demonstration of activities that influence blood glucose levels. Extracts (ammonium hydroxide) of commercially available sweet basil have been shown to increase insulin dependent glucose oxidation in rodent adipocytes in vitro.48 Dearlove et al. 49 reported that ethanol extracts of commercially available dried sweet basil inhibited protein glycation, again in vitro (protein glycation is a biomarker of diabetes and can lead to the vascular complications that result from this disease). El-Beshbishy and Bahashwan50 reported that aqueous extracts of sweet basil inhibited the activity of carbohydrate digestion enzymes, namely sucrase, maltase and alpha-amylase, also in vitro; this action was dose-dependent and the effect was particularly potent for maltase activity. In this study, based on the significant positive correlation between the percentage of radical scavenging and the percentage inhibition of the carbohydrate digestion enzymes, the authors concluded that sweet basil may be of use in the control of diabetes due to both its antioxidant capacity and sucrase, maltase and alpha-amylase inhibiting properties. Hyperglycaemia can induce oxidative stress,51,52 so speculating that sweet basil's antioxidant properties may be of significance in the management of diabetes, possibly via conferring some degree of protection on the liver, is tempting particularly as Ugwu et al. 53 reported that, in addition to normalising the levels of the liver function enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and also normalising serum albumin, urea and creatinine levels, in a rat model of chemically induced diabetes, aqueous, methanol and petroleum extracts of sweet basil decreased lipid peroxidation. They also improved antioxidant status via increases in the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). These effects were found to be comparable to the drug glibenclamide, which is used to treat type 2 diabetes (T2D). Extracts of aerial parts of sweet basil significantly reduced fasting blood glucose, slightly improved oral glucose tolerance and caused a decrease in liver glycogen that was dose-dependent in vivo (in an animal study). The inhibitory effect of the extract on carbohydrate digestion enzymes, hepatic alpha-glucosidase and alpha amylase, reinforced the suggestion that sweet basil may act as an anti-diabetic via its inhibitory action on these enzymes54 (previously demonstrated in vitro as described above). In that study, the extract also decreased lipid levels, specifically cholesterol and triglyceride, to a far greater extent than metformin, which is a standard drug used to treat T2D. Additional work on the hyperlipidemic action of sweet basil is reviewed below in this section. The anti-diabetic property of this herb may also be via its action on the GLUT 4 glucose transporters,55 which are found in skeletal muscle and adipose tissue and, via insulin stimulation, translocate from intracellular membranes to the plasma membrane of skeletal muscle cells and adipocytes (and are therefore insulin dependent).56 Extracts of sweet basil (methanol, hexane and dichloromethane) increased the translocation of GLUT4 transporters to the plasma membrane of muscle cells in vitro, in the presence and absence of insulin, following 20 h of exposure.55 The authors concluded that the ability of the herb to increase translocation in the presence and absence of insulin suggests that it might possess an effect that is either like insulin or sensitizes the transporters to insulin stimulation. The constituents of sweet basil believed to contribute to its glucose lowering effects are its polyphenols, namely eugenol, p-

coumaric acid, chicoric acid and caffeic acid.57 It is clear that further studies are required to determine how sweet basil elicits the effects summarised above, and clinical trials are required to establish if the outcomes reported in vitro and in animal studies are of significance in the prevention and treatment of diabetes. The lipid lowering activity of sweet basil has been demonstrated in a study by Amrani et al.,58 who reported that intragastric administration of aqueous extracts of the aerial part of the plant significantly reduced total cholesterol, triglyceride and low density lipoprotein cholesterol (LDL-C) in the plasma of hyperlipidemic rats compared to hyperlipdemic rats who were not given the sweet basil extract. High density lipoprotein cholesterol (HDL-C) was not significantly different. The lipid lowering effect of the sweet basil extract was comparable to that of the lipid lowering drug fenofibrate. The basis for this study was the use of sweet basil, prescribed by herbalists, for subjects with high blood lipid levels in East Morocco, and the findings clearly indicate that sweet basil may be of potential benefit in conferring some degree of protection in those at risk of developing conditions caused by high blood lipid levels such as atherosclerosis, which is the build up of lipids, specifically triglyceride and cholesterol in and on the walls of arterial blood vessels. This build up forms into plaques which restrict blood form. If the plaques burst they can lead to the formation of blood clots and metabolic syndrome. A more recent study by Irondi et al. 59 might provide some insight into the antihyperlipidemic effect of sweet basil, as they reported that polyphenolic extracts of the herbs, leaves inhibited the lipid digestion enzyme, pancreatic lipase in vitro. However, despite the promising results reported by Amrani et al. 58 no further work in this area is currently available.

3.6.4

Cardiovascular Stimulatory and Cardioprotective Properties

Evidence suggests that sweet basil, specifically extracts of the aerial part of the plant, may stimulate and confer protection on cardiovascular function via mechanisms beyond its lipid lowering activity. In an animal study, Muralidharan and Dhananjayan60 reported that aqueous and ethanol extracts exhibited cardiotonic activity (an effect in which the efficiency and contraction of heart muscle is improved which leads to increased blood flow throughout the body). With regards its ability to confer protection, Okazaki et al. 61 reported that sweet basil (methanol extract of dried powdered herb) was a potent inhibitor of human platelet aggregation in vitro. Platelet aggregation plays in the development of arterial thrombosis. An animal study further supported the antiplatelet/antithrombotic properties of sweet basil: Amrani et al. 58 reported that aqueous extracts of sweet basil significantly inhibited platelet aggregation and thrombin-induced platelet activation. Ethanol extracts of sweet basil increased the release of 6-keto– prostaglandin F1alpha (6-keto-PGF1α) – a potent vasodilator (a compound that dilates blood vessels) – from human umbilical vein endothelial cells in vitro following short-term exposure; this effect was dose-dependent.39 However, after 24 h exposure its release was decreased. Different fractions of the ethanol extract (petroleum ether, chloroform, ethyl acetate and butanol) elicited differing responses, with the chloroform and butanol fractions increasing 6-keto-PGF1α and

the other fractions tending to decrease 6-keto-PGF1α release after 24 h exposure. In the same study the extract also increased 6-keto-PGF1α but decreased thromboxane 2 (a pro-thrombotic factor which stimulates platelet activation and aggregation) in vivo in rat models of peripheral arterial occlusive disease (blockage or narrowing of the arteries).39 Sweet basil's reported fibrinolytic effect (fibrin is a clotting protein and fibrinolytic medicines are used to treat conditions caused by arterial thrombosis, such as myocardial infarction and stroke) may also contribute to its cardioprotective properties. Kuerban et al. found that ethanol extracts of the herb increased the levels of fibrin degradation products in a dose-dependent manner following administration for 21 days to mice. Further evidence of sweet basil's cardioprotective potential comes from a study in which its extracts (hydroalcoholic) provided significant protection against chemically induced myocardial infarction, with the extract decreasing levels of serum and myocardium (heart muscle) malondialdehyde – a marker of oxidative stress, thus suggesting that sweet basil's cardioprotective and antioxidant properties are linked.62 Evidence of this suggested link is also provided by work carried out by Bora et al. 63 who reported that ethyl acetate extracts of sweet basil leaves protected against cerebral infarction (stroke), using animal models of ischaemia (restriction of blood flow to tissue leading to a lack of oxygen resulting in tissue damage or tissue death) and reperfusion-induced cerebral damage (restoration of blood flow to previously ischaemic tissue resulting in extensive/increased tissue damage). As indicated by a reduction in the extent of damaged brain tissue, significantly decreased lipid peroxidation, and normalised reduced glutathione (GSH) – a marker of antioxidant status. Evidence suggests that sweet basil may also confer cardiovascular protection via hypotensive (blood pressure lowering) activity. Extracts (aqueous and polyphenolic) of the herb's leaves are reported to inhibit angiotension-1-converting enzyme (ACE), which plays a key role in the regulation of blood pressure,64 in vitro.59,65 A study by Umar et al. provides evidence of sweet basil's hypotensive effects in vivo with the aqueous extract decreasing the diastolic and systolic blood pressure of hypertensive rats (these decreases were comparable to those caused by captopril, an ACE inhibitor used to treat hypertension). Alongside the decrease in blood pressure, cardiac hypertrophy (abnormal enlargement or thickening of the heart muscle) was reduced, angiotensin (a hormone that gives rise to vasoconstriction and increased blood pressure66) was also decreased (although captopril was more effective), and endothelin-1 (another key regulator of blood pressure67 as it is a potent vasoconstrictor) was decreased to a greater extent by sweet basil.

3.6.5

Chemopreventive/Anti-cancer Properties

As stated above, sweet basil's chemopreventive/anti-cancer properties have been linked to its antioxidant properties/polyphenolic constituents. Niture et al. 32 demonstrated that aqueous and ethanol extracts of ground and powdered dried leaves of sweet basil, increased the amount and activity of O-6-methylguanineDNA-methyltransferase in human cancer cells and human peripheral blood mononuclear cells in vitro. This enzyme plays a role in removing DNA lesions

induced via exposure to alkylating agents. This stimulatory action was associated with an increase in expression of the phase 2 detoxification enzyme glutathione Stransferase P1, which is known to be activated by antioxidants.68 (Phase 2 detoxification is a process which involves the removal of carcinogens and procarcinogens.69,70) Additional work by Dasgupta et al.,34 this time in vivo, supports the antioxidant properties of sweet basil contributing to its chemopreventive/anti-cancer effect. They reported that hydroalcoholic extracts of sweet basil leaves reduced lipid peroxidation and increased markers of antioxidant status, including the antioxidant enzymes CAT, SOD, glutathione peroxidase (GPx), glutathione reductase (GR), and also GSH. Along with these improvements in antioxidant status, the extracts inhibited significantly the phase 1 enzyme cytochrome p450, which is required for the activation of certain carcinogens, and increased glutathione S-transferase and DT-diaphorase (another phase 2 enzyme reported to be involved in cancer chemoprevention via the removal of carcinogens and procarcinogens71), and reduced the tumour burden and tumour number in murine models of chemically induced tumours. The chemopreventive effect of sweet basil, specifically methanol extracts of the dried plant, also appears to operate via its ability to inhibit the production of DNA adducts in HepG2 human liver cancer cells in vitro, possibly through the inhibition of sulfotransferases, which are involved in the bioactivation of procarcinogens.72 The chemopreventive activity of sweet basil has also been demonstrated by Saha et al.,73 who reported that when extracts (methanol) of dried and powdered leaves were given to mice exposed to benzene, which in mice can cause alterations in cell cycle progression (cell growth and division) resulting in uncontrolled cell division as well as give rise to an inflammatory response and oxidative stress, sweet basil altered the expression of key protein regulators of cell cycle progression which translated into inhibition of the deregulation of the cell cycle by benzene.74 In addition, the sweet basil extract reduced haematological abnormalities. The inhibitory effect of extracts of sweet basil leaves on the growth and cell cycle of cancer cells (human laryngeal epidermoid carcinoma (HEP-2) cells, human cervical cancer cells (HeLa), human breast cancer cells (MCF-7), human colorectal cancer cells (HT29), and human pancreatic cancer cells (MIAPaCa-2)) in vitro has been reported, along with their pro-apoptotic effects (apoptosis is the programmed death of damaged or cancer cells).75,76 In addition to studies described above concerning the chemopreventive/anticancer effects of sweet basil leaves, the essential oil of this herb is also reported to inhibit the proliferation of human cancer cells, namely human mouth epidermal carcinoma, HELa and human laryngeal epithelial carcinoma cell lines.77,78 Evidence suggests that the inhibitory effect of sweet basil on cancer cell growth in vitro may be due in part to eugenol, which is able to inhibit the growth of a number of cancer cells, some via apoptosis, and animal models of cancer,79,81 and also ursolic acid, which was reported to be the most potent constituent in the action of fractionated methanolic extracts of the aerial parts of sweet basil against MCF-7 cells in vitro,82 and linalool in its essential oil, again against MCF-7 cells.83 Finally, beyond its action against cancer cell growth and proliferation in vitro, sweet basil may also inhibit metastases (the spreading of a cancer beyond its original site to other parts of the body). Hydroalcoholic extracts of sweet basil

decreased significantly tumour volume, and increased average body weight and the survival rate in vivo (using mice). Sweet basil also demonstrated radioprotective activity by influencing radiation induced chromosomal damage, and also increased GR and glutathione S-transferase activity. The latter results reinforce the possible antioxidant mediated chemopreventive/anti-cancer activity of this herb.84

3.6.6

Hepatoprotective Properties

The section above on the glucose lowering/anti-diabetic effects of sweet basil already touched on the hepatoprotective potential of this herb. Sweet basil's hepatoprotective properties have also been investigated in studies using animal models of hepatic damage. A study by Meera et al. 30 reported that extracts (ethanol) of powdered sweet basil protected against chemically induced liver damage in rats as indicated by the normalization of the liver function enzymes ALT and AST. This effect, which was comparable to that of silymarin, an extract of milk thistle which is purported to be a potential treatment for liver toxicity although its efficacy has yet to be fully established,85,86 was associated with normalization of antioxidant enzymes including CAT, SOD and GPx. Furthermore, in vitro, the extract inhibited lipid peroxidation, as well as the scavenging activity of the superoxide free radical and nitric oxide. Despite these findings suggesting a link between the antioxidant properties of sweet basil and its reported hepatoprotective activity, more work, including clinical trials is required to establish the healthpromoting and therapeutic potential of sweet basil's hepatoprotective properties.

3.6.7

Anti-ulcerative Properties

Extracts (aqueous and ethanol) of a powdered form of the whole sweet basil plant, given orally to rat models of chemically induced gastric and duodenal ulcers, suppressed ulceration (based on ulcer score, ulcer area, ulcer index and ulcer number). The ethanol extract was not as potent as the aqueous extract, which based on the ulcer score, had an effect that was comparable to that of ranitidine – also known as Zantac (a drug used to treat peptic ulcers via its inhibition of gastric acid reduction, although it was recalled in North America in 2019 due to detection of low levels N-nitrosodimethylamine (NDMA) an environmental contaminant which is also classified as a probable carcinogen based primarily on animal studies87). The difference in potency is very likely due to the different constituent profiles that result from using different extraction solvents, although the constituents responsible for the effects reported were not identified. The authors concluded that sweet basil had a protective effect against gastric and duodenal ulceration which might be due to its inhibition of gastric secretion, protection of cells of the gastric mucosa, and/or its anti-microbial activity. They talked specifically about Helicobacter pylori, which can infect the stomach and cause stomach cancer; methanolic extracts of sweet basil inhibit the growth of this bacteria.88 The suggested anti-gastric secretion activity of sweet basil to explain its anti-ulcerative activity is supported by earlier studies by Akhtar and Munir,89 and Singh.90 The former study reported that extracts (aqueous and methanol) of powdered green aerial parts of the plant, given to rat models of, aspirin induced, gastric ulceration, significantly inhibited gastric ulceration (based

on the ulcer index) (powdered sweet basil was only significantly effective at the highest dosage used which was 2 g kg−1 of body weight). Pepsin – a gastric enzyme involved in protein digestion – levels were also decreased, which was indicative of decreased gastric secretions, however acid secretion was not affected. Singh90 reported that oil extracted from sweet basil seeds impeded the development of ulcers in chemically and stress induced ulcer animal models in a dose-dependent manner. Along with this effect, Singh reported that gastric secretion and acidity were also decreased. Rashidian et al. 91 fed sweet basil essential oil to rats and reported that when administered orally prior to chemical induction of colitis (inflammatory bowel disease), the ulcer severity, area and index were significantly reduced. This anti-ulcerative effect occurred alongside amelioration of colitis as indicated by significant decreases in neutrophil (a type of white blood cell) infiltration, oedema and the severity and extent of damage to the colon, indicating that sweet basil's anti-inflammatory activity might contribute to its ulcerative activity. A double blind placebo randomized controlled clinical trial on the effect of sweet basil on functional dyspepsia (a condition that causes gastric pain, abdominal bloating and problems finishing meals that is recurrent) by Rafieian-kopaei and Hosseini-asl,92 reported that sweet basil taken in the form of 30 drops of hydroalcoholic extract (equivalent to 1.5 g of leaf powder) daily, 30 minutes before lunch and dinner for 4 weeks, lessened the severity of symptoms of this condition.

3.6.8

Anxiolytic (Calming), Sedative, Hypnotic, Anticonvulsant, Anti-depressant-like, Memory Retaining/Enhancing Properties

Based on the traditional use of other species of basil (Ocimum gratissimum (clove or African sweet basil) and Ocimum sanctum (Holy sweet basil)) to treat disorders of the central nervous system and their anti-depressant activity,93,96 the motor, sedative, anti-convulsant and anti-depressant-like activities of sweet basil have been investigated. Ismail97 reported that the essential oil of the aerial part of sweet basil induced motor impairment as well as anti-convulsant and sedative activity in vivo in mice, with the latter two activities shown to be dose-dependent. These effects were elicited at dosages ranging from ≥0.2–1.2 mL kg−1 of body weight, administered intraperitoneally (i.p.), for the anti-convulsant activity, although the lowest dosage depended on the convulsant used – it was least effective when strychnine was used as a convulsant, and 0.4–1.2 mL kg−1 of body weight for the sedative activity. In comparison to the drug diazepam, a sedative drug, sweet basil essential oil was not as potent a sedative. A later study by Oliveira et al. 95 confirmed the sedative and anti-convulsant effects of sweet basil in vivo (again using mice), using the essential oil extracted from its leaves. In this study, the effective dosages for the sedative effect were comparable to that of diazepam. Although neither study identified the mechanism of action, based on the literature, a central gamma amino butyric acid (GABA) receptor mediated activity involving constituents of sweet basil essential oil, namely linalool, 1-8-cineole and eugenol has been put forward. Gamma amino butyric acid (GABA) is an inhibitory neurotransmitter which decreases activity of the nervous system. However, a study by Rabbani et al.,98 in which sweet basil

essential oil, and to a lesser extent hydroalcoholic extracts of sweet basil, administered to rats, elicited both sedative and anxiolytic effects, argued, based on the type of responses observed, that a GABA mediated mechanism was unlikely. Finally, Askari et al. 99 reported that hydroalcoholic extracts of sweet basil leaves were found to be an effective sedative, as their effect was comparable to that of diazepam. In humans, essential oil of sweet basil (100 fold dilution) has been reported to have a calming effect when inhaled following a mental performance test.100 The anti-depressant-like activity of the essential oil and hydroalcoholic extracts of sweet basil have also been reported, again using animal models. Ayuob et al. 101 reported that in stressed induced mice the essential oil, administered via inhalation, improved significantly alterations in behaviour to levels similar to those caused by the anti-depressant drug fluoxetine. Hydroalcoholic extracts of sweet basil seeds produced this anti-depressant-like activity in these rat models of stress. The authors suggested that this effect might be related to sweet basil's antioxidant properties, as markers of antioxidant status, specifically SOD, CAT, GPx, GR and ascorbic acid (vitamin C), increased and the level of lipid peroxidation decreased. Concerning the memory enhancing/retention properties of sweet basil, the study by Bora et al. 63 summarised above (see section on Cardiovascular Stimulatory and Cardioprotective Properties) reported that ethyl acetate extracts of sweet basil leaves improved motor skills and reduced short term memory impairment in animal models of ischaemia and reperfusion-induced cerebral damage. Sarahroodi et al.,102 using hydroalcoholic extracts reported that they improved memory retention in mice, and although they provided no evidence of a direct link, attributed this effect to the antioxidants in sweet basil based in part on the findings of Bora et al. 63 described above. Finally, Zahra et al. 103 reported that extracts of sweet basil leaf improved short term memory as well as motor coordination and object recognition in mice. In summary, these studies provide some evidence that sweet basil could be used as a natural alternative to drugs used to treat anxiety, depression and conditions in which motor coordination and/or memory are adversely affected. However, as the authors conclude, further studies are required to establish sweet basil's clinical efficacy.

3.6.9

Antimicrobial Properties

Review articles have summarised the many studies that have reported the in vitro anti-microbial activity of the aerial parts and essential oil of sweet basil, with the linalool and estragole constituents of the latter suggested to be of the greatest significance, specifically with regards to its anti-bacterial and anti-fungal activity.43,104,105

3.6.9.1 Anti-bacterial Activity Extracts of basil (methanol) and its essential oil inhibit the growth of bacteria pathogenic to humans including plaque forming and cariogenic bacteria. These include gram-negative pathogenic bacteria Pseudomonas aeruginosa, species of

Shigella, Salmonella typhimurium, Klebsiella pneumonia, Streptococcus mutans, and/or Pasteurella multocida,106,108 as well as gram-positive pathogenic bacteria including Listeria monocytogenes and Staphylococcus aureus.104 The essential oil also inhibits the growth of Bacillus subtilis, which is generally non-pathogenic but has been found to be infectious in those that are immunocompromised.109,111 The mechanism of action might involve degradation of the bacterial cell wall followed by bacterial lysis due to the action of basil's phenolic acids.107

3.6.9.2 Anti-fungal Activity Methanol extracts and the essential oil of sweet basil also inhibit the growth of a range of pathogenic and toxigenic (toxin producing) fungi including species of Aspergillus and Penicillium, and also Candida albicans.35,112 Furthermore, the essential oils of sweet basil have been shown to be more potent than the antibiotics ampicillin and ketoconazole and bifonazole, which are anti-fungal agents.113

3.6.9.3 Other Anti-microbial Activity Sweet basil (crude aqueous, ethanol and/or methanol extracts) is also reported to act against mycobacterium, namely Mycobacterium tuberculosis, Mycobacterium bovis, and viruses including H37Rv, the herpes virus-1, and/or HIV-1.114,116

3.6.10

Anti-parasitic Activity

The essential oil and crude petroleum ether leaf extracts of sweet basil also possess larvicidal activity against carriers (vectors) of the malaria parasite, West Nile virus, dengue virus and/or Japanese encephalitis virus,117 with the leaf extract shown to be more potent against mosquito larvae (Anopheles stephensi) when combined with imidacloprid – an insecticide. Its anti-parasitic action covers the parasites Blastocystis hominis, Giardia duodenalis, Entamoeba histolytica, Giardia lamblia, which give rise to gastrointestinal symptoms, and Trichomonas vaginalis, which infects the vagina, urethra and penis foreskin, and it is documented to act against drug resistant strains of the malaria parasite Plasmodium falciparum.118 This activity might be due to its polyphenolic constituents.115,116,118,126

3.6.11

Effect on the Respiratory System

Sweet basil is traditionally used to treat respiratory diseases as well as sore throats, coughs and hiccoughs globally,37,127,128 and it is this traditional use that formed the basis of studies by Boskabady et al. 129 and Janbaz et al. 130 with both studies reporting that extracts possess relaxant, broncho-dilatory and/or vasodilatory effects in vitro using tracheal muscle. The mechanisms of action suggested include the blocking of histamine H1 receptors and beta-adrenergic and non-adrenergic/noncholinergic mediated actions.

3.6.12

Effect on Wound Healing

Many of the bioactive properties of sweet basil, summarised and discussed above, formed the basis of the study by Solanki et al. 131 in which ethanol extract of sweet basil, applied within an ointment (5% w/w) to an animal model of wound excision, improved/increased wound healing activity, specifically wound closure and wound contraction, compared to control animals and those treated with povidone iodine ointment, which is an antiseptic used to treat wound infections, minor cuts, grazes and burns.

3.6.13

Effect on Fertility

Sweet basil's antioxidant properties, alongside its hepato- and cardio-protective effects in animals in vivo, provided, in part, the basis for the investigation of its effect against cadmium induced testicular toxicity (cadmium is a heavy metal that causes oxidative stress, which is reported to be a common feature of testicular dyfunction132,133). Aqueous extracts of sweet basil leaves resulted in improvements to the histological damage to the testis caused by cadmium in rats.134 In contrast to the findings above, sweet basil appears to decrease female fertility. It is reported to possess contraceptive properties.135 In addition, extracts of sweet basil leaves (hydroalcoholic) adversely affected ovulation and decreased the weight of the ovaries and uteruses of female rats.

3.7

Safety and Adverse Effects

There is a paucity of literature on the safety of sweet basil in humans; the placebo controlled clinical trial by Rafieian-kopaei and Hosseini-asl90 did not report on adverse effects. In animal studies, sweet basil is reported to have a medium to high lethal dose for 50% of the test sample used (LD50).53,135,136 For example, Bilal et al. reported that hydroalcoholic extracts of sweet basil leaves at 364 and 624 mg kg −1 of body weight can adversely affect female rat fertility. Rasekh et al. 136 reported that sweet basil had a LD50 of greater than 5 mg kg−1 of body weight (in male and female rats) with the dosages resulting in no adverse effects, and that a dosage of 2 g kg−1 of body weight was neither toxic nor lethal. However, they did report a reduction in the haematocrit (the ratio of the volume of red blood cells to the total volume of blood, platelet and red blood cell number) at 500 mg kg−1 of body weight of hydroalcoholic extracts of the aerial parts of sweet basil. Although, as pointed out by Sestili et al.,37 the amount used by Rasekh et al. 136 to cause the haematological changes far exceeds what one is expected to consume as part of one's diet. The essential oil of sweet basil is also reported to have a medium to high LD50 value (approximately 500 mg kg−1 of body weight to greater than 2 g kg−1 of body weight) in rats, with no mortality occurring at a dosage of 1.5 g kg−1 of body weight.46,137 In non peer reviewed online resources, it is stated that sweet basil is likely to be

safe when taken in amounts normally consumed with food, and possibly safe when taken short term as a medicine by adults. When taken long term in amounts larger than those normally consumed with food (i.e. taken as a medicine) both the aerial parts and its essential oil may possibly not be safe (for adults, children, during pregnancy and breastfeeding) as they contain estragole, which is reported to cause liver cancer in experimental animals.138,140 Sestili et al. 37 highlighted that concerns regarding the safety of sweet basil, both the plant and its essential oil, are focussed on the amounts of estragole and a derivative of eugenol, methyl eugenol, as both pure compounds possess carcinogenic and genotoxic properties. However, as stressed by these authors, it is their metabolites that are responsible for these activities; the parent compounds are not very reactive. Thus, the conversion of the parent compounds when part of a complex food matrix such as sweet basil is less likely. In fact, as highlighted in the anti-cancer section above, methanol extracts of sweet basil appear to inhibit DNA adduct formation in human liver cancer cells via the inhibition of the bioactivation of procarcinogens.72 Sestili et al. 37 also point out that the levels of methyl eugenol and estragole vary based on the cultivars of sweet basil. Additional information online warns against the use of sweet basil prior to surgery and in combination with low blood pressure and anticoagulant/antiplatelet drugs, due to its anti-clotting and hypotensive properties.138 These warnings may possibly be based on these activities being reported in peer reviewed literature (see section on Cardiovascular Stimulatory and Cardioprotective Properties).

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CHAPTER 4

Bay Leaf (Laurus nobilis) 4.1

Names

English: Bay leaf, sweet bay, bay Laurel Armenian: Tapni derev, Dabni-I terew, Dapni Chinese: Yue gui shu ye Dutch and French: Laurier German: Lorbeer Japanese: Gekkeiju, roreru The name Laurus nobilis comes from the Latin laurus, which means to praise, and Nobilis, which means noble.

4.2

Taxonomy

Order: Laurales Family: Lauraceae Genus: Laurus Species: Laurus nobilis

4.3

Origin, Description and Adulteration

Bay tree is native to the Mediterranean region and Asia minor. It is an evergreen shrub that flowers in the spring, and grows up to 7.5 m (23 ft). It enjoys full sun or partial shade, is generally hardy to −5 °C (23 °F) but it can withstand lower temperatures when sheltered and in the ground. The bark can be described as smooth and olive-green sometimes with a reddish hue, and the leaves can be described as luxurious, coriaceous (having the texture of leather), alternate (single at each node and borne along the stem), narrowly oblong-lanceolate (shaped like a lance head) with a short stalk. Bay leaf produces small four lobed flowers and ovoid (oval shaped) green fruits that turn black when ripe.1 Bay leaf2 can be mistaken, mis-sold or adulterated with a variety of leaves from other species, including Cinnamomum tamala, Litsea glaucescens, Pimenta racemosa, Syzygium polyanthum and Umbellularia californica.

4.4

Historical and Current Uses

Bay leaf was used by the Ancient Greeks and by many Mediterranean, Asian and American cultures to flavour foods. During the first millennium BCE, bay leaf was

Apollo's sacred plant. Apollo was the Greek God of light and truth, who killed, cured, and taught men, through his son Asclepius, the art of medicine. Bay leaves were burned to purify the air, and bring calm to a room. In Delphi (an ancient and religious sanctuary dedicated to Apollo) a priest was said to interpret the Phyta's (priestess') “frenzied utterances” possibly induced by chewing bay leaves.3 In the Greek's annual athletic games (to honour Apollo), winners were crowned with a wreath made of bay leaves as a symbol of victory. The academic accomplishment word “baccalaureate” stems from the giving of the bay leaf crowns to signify success.4 In Chinese folk tradition and Taoism, the symbolism of bay leaf reflects the healing and strength qualities seen in Mediterranean cultures. Wu Gang, a flawed character, and figure in traditional Chinese folklore, was given as a punishment the impossible task of cutting down a self-healing bay laurel tree that was located on the moon, with the lesson about not giving up still celebrated during the autumnal Moon Festival.5 The Apicius Roman cookbook6 mentions bay/laurel leaves as one of the ingredients for the famous “laser flavour”. Silphium was a plant, now extinct, with a powerful sulfurous smell, the root (called laser root) was used in foods and medicine and “laser flavour” was a broth used to prepare or accompany dishes, made with laser root, pepper, parsley, dried mint, honey, vinegar and broth (there were variations of this recipe with bay leaves). Bay leaf was used for sauces such as the green sauce for fowl, and also sausages, roasts, boiled lobster (with cumin sauce) and many seafood dishes, as well as beets. Bay leaves were used in a mixture to keep meat fresh (it is still popular today for pickling raw meats) mixed with honey, whole pepper, cloves, onions, root vegetables, sugar and wine, which the French and Germans call Marinade and Sauerbraten-Einlage, respectively. Bay leaves were also macerated in oils and wines. The Book of Herbs by Northcote (1903)7 dedicates a large chapter to bay leaf, which includes many citations from previous manuscripts, highlighting the spiritual importance of the plant. Providing a quintessential classic flavour in French, Chinese and Indian cuisine, bay leaves are also used in Thai and Arabic dishes, where the leaves are either used whole or as a garnish. Bay leaves marry well with beef, chicken, game, lamb, fish, seafoods, lentils, rice, tomatoes, and beans. Popular dishes include spicy black bean soup and fish curry. Bay leaf is an essential component of the French Cassoulet, and roast pigeon with butter bean, and the American chicken Jambalaya. It is also added to pasta dishes as a garnish. Lu Wei is a popular Chinese slow cooking method in brine which uses bay leaf, cardamom and cinnamon to flavour the dish. Bay leaf is used in alcoholic drinks such as The Bay Leaf Gin Sour, Marmalade and Bay Gin or The Old Battle Axe cocktail, which contains Mezcal, pineapple rum, pepper, bay leaf syrup and lemon juice.8,9 Bay leaf is Generally Recognized as Safe (GRAS)10 when used as food in the United States (herb) and the essential oil GRAS as a food additive. Bay leaf does not feature on the list of Commission E monographs or extended versions of the monographs as an approved herb, nor does it feature on the unapproved list of herbs. It is best to avoid taking bay leaf before receiving anaesthesia, and it has been the subject of much research for various ailments (see section on Safety and Adverse Effects).

Grieve's Modern Herbal11 states that the leaves, berries and oil of bay leaf possess narcotic, excitant, diaphoretic and emetic effects in large amounts. The berries and leaves were formerly used for treating amenorrhoea (irregular periods), hysteria and as an abortifacient (to induce abortions), but are very rarely used today outside of veterinary use. The oil is employed externally for sprains, bruises and inside ears for earache. The French used the berries as a carminative (to relieve flatulence). Bay leaf is not mentioned in the online encyclopaedia of traditional Chinese medicine,12 but an online source suggests that it is used to treat the meridians of the lung and stomach and calm the spirit.13 It is used for sore throats, coughs, and phlegm in the sinuses and the chest. It also helps with bloating and indigestion and can help reduce anxiety.

4.5

Chemistry, Nutrition and Food Science

Bay leaf has a bitter, spicy, strong and pungent flavour with a cooling undertone, and bitter aftertaste; the aroma is described as piney with hints of camphor-like aromatic notes.14 Bay leaf's aroma is due the presence of terpenes, and the major volatile oils are pinene, geraniol, eugenol, cineol, amongst others. A study compared wild and cultivated samples and showed the presence of linool, αterpinol, α-terpinyl acetate, thymol, caryophyllene, aromandrene, selinene, farnesene, and cadinene for cultivated samples, whilst wild bay leaf contained more eugenol and methyl eugenol, vitamin E, and sterols.1 Volatile compounds of fresh leaves, buds, flowers, and fruits from bay leaf (Laurus nobilis L.) obtained by solvent extraction were quantified by capillary gas chromatography–mass spectrometry (GC-MS) and the aroma quality was characterized by gas chromatography–olfactometry–mass spectrometry (HRGC-O-MS). Among the constituents identified, 1,8-cineole was the most abundant in fresh bay leaf, alphaterpinyl acetate, sabinene, alpha-pinene, beta-pinene, beta-elemene, alpha-terpineol, linalool, and eugenol were also identified. In the flowers, alpha-eudesmol, betaelemene, beta-caryophyllene, 1,8-cineole and the pinenes were the main components. In bay leaf fruits, (E)-beta-ocimene and bicyclogermacrene were the principal constituents, whilst (E)-beta-ocimene and germacrene D were the most abundant in the buds. The major aromatic compounds were: (Z)-3-hexenal (fresh green aroma), 1,8-cineole (eucalyptus aroma), linalool (flowery aroma), eugenol (clove aroma), (E)-isoeugenol (flowery aroma), and an unidentified compound (black pepper aroma). With regards to the nutritional quality of bay leaf, it is generally considered to be poor in the energy yielding nutrients (carbohydrate, fat and protein)15 (see Table 4.1). These nutritional values also have to be considered in relation to the proportion of the herb used in the diet, which is often a few leaves only. Nevertheless, bay leaf contains a number of essential nutrients, with reasonable amounts of calcium (8.3 mg g−1 dried herb), and iron (0.43 mg g−1 dried herb). Table 4.1

Nutrition composition of dried bay leaf.15 Adapted from https://www.gov.uk/government/publications/composition-of-foods-

integrated-dataset-cofid, under the terms of the Open Government license 3.0 Bay leaf (100 g) – UK data

Dried

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/mg Pantothenate/mg

313 48.6 Na 8.4(2.3) 7.6 5.4 —b 830 0.91 Na 43 120 8.2 110 530 Na 23 3.7 620 0.01 0.42 2 Na 0 0 Na —b Na

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

Food processing and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants, but data are lacking for bay leaf. The impact of different drying techniques (air dried, oven dried and microwave dried) on bay leaf was compared by measuring their antioxidant capacity (reducing power assay) and total phenolic content (Folin Assay). Bay leaf, air dried (4 days) and microwaved (300 W for 130 seconds), retained the highest antioxidant capacity and total phenolic content.16 Given the drying time required for each technique and the antioxidant parameters, the authors concluded that the microwave method was favoured to produce dried bay leaves. The use of herbs and spices as natural antioxidants in processed foods has become more widespread. These natural antioxidants work by reducing the oxidative degradation of constituents (usually lipids) and therefore preserve the nutritional composition of foods for longer. Cherrat, et al.17 investigated the chemical composition and antioxidant properties of bay leaf essential oil (EO) from Morocco and assessed its antimicrobial activity and potential for food preservation over time (7 days storage). Bay leaf EO showed successful inactivation of a panel of foodborne pathogens when tested in sous-vide (a technique in which the food is

placed in a vacuum sealed bag and cooked slowly at a low temperature) sea bass (Dicentrarchus labrax) fillets,18 where EO incurred no significant changes in composition, with sensory parameters remaining within acceptable ranges. However, sous-vide gave rise to a darker and more greenish-yellow colour. The authors concluded that the bay leaf EO was effective in maintaining oxidative stability and freshness in sous-vide sea bass fillets, but more specifically in earlier stages of storage. Another study showed promising results using bay leaf EO as a preservative in stored wheat, the fumigation with the EO reduced Aspergillus flavus, and the EO showed high antioxidant capacity offering a sustainable potential to extend shelf life during wheat storage.19 Coatings made of aqueous extract of bay leaf (0, 0.5, 1% w/w) added to chitosan solution (0, 0.5, 1% w/w) showed preservative effects in extending the stability and improving the shelf life of cashew nuts.20 Chaumun et al.21 studied the effects of microparticles (microparticles size ranged from 1.3 to 3.2 µm) containing bay leaf extract, using a spray-drying encapsulation technique with modified chitosan, sodium alginate and arabic gum, in protecting sensitive antioxidant polyphenols from external oxidation. The samples' total phenolic content of the bay leaf particles (expressed as Gallic Acid Equivalents – GAE) ranged from 400 to 430 mg GAE L−1 compared to the control (which ranged from 540 to 560 mg GAE L−1). The authors concluded that this was a successful encapsulation technique, with the potential to be applied in the food and pharmaceutical industry.

4.6

4.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

The antioxidant capacity of bay leaf, the plant and its essential oil, has been demonstrated in vitro, with levels in the plant seen to be relatively low compared to those of other herbs and spices including cloves, Mediterranean oregano, and cinnamon, and relatively high compared to those of parsley, dill, coriander, caraway, cumin and ginger. Its antioxidant capacity is comparable to those of thyme, sage, rosemary and mint. Although these comparisons do vary based on the type of extract and assay used. Extracts of bay leaf (chloroform, ether and ethyl acetate) are also reported to inhibit lipid peroxidation in vitro.22 The constituents of this plant that contribute to this property are its polyphenolic compounds including its phenolic acids, flavonoids and its volatile oils.22,32 However, values vary based on the nature of the preparation and the assays used. There appear to be no studies reported in peer reviewed literature that have investigated or determined the significance of bay leaf's antioxidant properties in humans. There is some evidence to suggest that this property could be linked to dopamine induced apoptosis in human neuroblastoma cells in vitro which was decreased alongside the levels of

intracellular reactive oxygen species following pre-treatment for 24 h with spirafolide – a compound obtained from the herb's leaves.33 In addition, it may also be linked to the hepatoprotective effects of bay leaf reported in vivo 22,34 (see section on Hepatoprotective Properties below).

4.6.2

Anti-inflammatory Properties

Extracts of the bay leaf plant are reported to possess anti-inflammatory activity based on the herb's ability to inhibit a number of pro-inflammatory mediators.23 Matsuda et al. 35 reported that extract (methanol) of bay leaf inhibited nitric oxide production by activated murine macrophages in vitro via its constituent sesquiterpenes. Pre-treatment of murine macrophages for 1 h with a polyphenol rich extract of bay leaf decreased the levels of pro-inflammatory enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase and their respective products prostaglandin E2 (PGE-2) and nitric oxide, following activation of these cells in vitro.36 Finally extracts (ethanol) of bay leaf decreased interleukin 6 (IL-6) release by the activated cells.37 Using human cells in vitro, specifically stimulated T helper type 1 cells, Bennet et al. 38 reported that processed bay leaf (the processing involved heat and enzymatic treatment, and emulsification) decreased the expression of interferon-gamma, with the effect of the processed herb being comparable to that of known anti-inflammatory agents, interleukin 10 and hydrocortisone. This preparation of bay leaf also inhibited the activity of the proinflammatory mediators COX-2 and 5 lipoxygenases in vitro. Although the antiinflammatory activities demonstrated provide some suggestion that bay leaf might possess some potential in treating/preventing conditions linked to inflammation, the therapeutic significance of this property has yet to be established further. However, there is evidence of an association between bay leaf's anti-inflammatory and anticancer properties (see section on Chemopreventive/Anti-cancer Properties below).

4.6.3

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

Studies have shown that extracts (ammonium hydroxide and/or ethanol) of commercially available bay leaf enhanced insulin dependent glucose oxidation in rat adipocytes and/or were able to inhibit protein glycation (protein glycation is a biomarker of diabetes and can lead to the vascular complications that result from this disease) in vitro.32,39,40 The insulin-like effects of bay leaf were likely due to its polyphenols, as these effects were removed by polyvinylpyrrolidone, which binds to aromatic hydroxyl groups.40 The glucose and lipid (cholesterol and triglyceride (TG)) lowering effects of bay leaf have also been reported in vivo in rats with chemically induced liver damage.34 The anti-diabetic and lipid lowering effects of this herb are not limited to in vitro and animal studies, as these effects have been demonstrated in humans albeit in a small number of studies. In a randomized placebo controlled trial41 (it is not made clear if the study was blinded) subjects with type 2 diabetes (T2D) were given either 1, 2 or 3 g of finely ground bay leaf in capsules per day, or a placebo, after breakfast and dinner, for 30

days followed by a 10 day washout period. All dosages of bay leaf significantly decreased serum glucose, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). High density lipoprotein cholesterol (HDL-C) was significantly decreased throughout the duration of the intervention in those taking the dosages of 1 g per day and 2 g per day. However, for the 3 g per day group, it was decreased albeit not significantly but this may be due to the fact that at baseline the subjects taking 3 g per day had HDL-C levels that were higher than for those taking 1 g per day and 2 g per day. The TG levels were also significantly decreased in those that took the dosages of 1 g per day and 2 g per day. For the 3 g per day group, there was a significant decrease in TG levels at day 10 of the intervention and also after the 10 day washout period. On the basis of this work, Khan et al. 42 investigated the acute effect of bay leaf on postprandial glycaemic response and appetite using a randomized crossover study with non-diabetic subjects. Post the consumption of three test foods (cookies, cookies containing 3% (w/w) bay leaf powder and cookies containing 6% (w/w) bay leaf powder) each equivalent to 50 g of carbohydrate, 1 to 2 weeks apart, it was found that the 6% bay leaf cookie decreased significantly blood glucose at 30 and 45 minutes compared to the control cookies. None of the bay leaf cookies impacted on appetite.

4.6.4

Chemopreventive/Anti-cancer Properties

There is a small amount of literature on the chemopreventive/anti-cancer effect of bay leaf on cancer cells in vitro.23 Berrington and Lall30 reported that acetone extracts of bay leaf strongly inhibited the proliferation of human cervical cancer (HeLa) cells, possibly via apoptosis. The pro-apoptotic action of bay leaf on cancer cells was supported by the work of Jaksevicius et al. 43 who reported that ethanol extracts of bay leaf inhibited the growth of human colorectal cancer (HCA7) cells via cell cycle arrest and apoptosis; its effect on the latter was comparable to that of etoposide, a chemotherapeutic agent that acts via the induction of apoptosis. In addition, they reported that the inhibitory effects of bay leaf were associated with its ability to significantly inhibit the expression of the pro-inflammatory mediator COX-2 in these cells, as well as its activity and the release of PGE-2. The aqueous extract was also reported to be a significant inhibitor of COX-2 activity and PGE-2 release. However, it was the ethanol extract's ability to inhibit COX-2 expression and activity and PGE-2 release that was comparable to that of celecoxib, a known specific COX-2 inhibitor. Bay leaf is also reported to inhibit the growth of other human colorectal cancer cell lines in vitro, namely HT-29, HCT-116, Caco-2 and SW-480, and also human liver (HepG2), stomach (AGS) and bladder (BL13) cancer cells via apoptosis.31,38 Its pro-apoptotic effects are suggested to be associated with the polyphenolic and essential oil fractions of the herb.38

4.6.5

Hepatoprotective Properties

Extracts of bay leaf are reported to confer protection against liver toxicity in animal studies.22,34 Death and/or tissue damage were prevented and there was also normalization of the liver function enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and of other markers of liver function,

including albumin, bilirubin and urea. In addition, lipid levels, specifically of cholesterol and TG decreased.22 Protection may have been conferred via prevention of the deterioration of antioxidant status, based on the maintenance of the activities of antioxidant enzymes including catalase and glutathione peroxidase, and prevention of an increase in oxidative stress. However, the potency of effect was shown to vary based on the nature of the extract.22

4.6.6

Anti-ulcer Properties

A single study by Afifi et al. 44 reported on the anti-ulcer properties of bay leaf (20 and 40% aqueous extracts of its seeds) in chemically induced gastric ulcers in rats.

4.6.7

Anti-convulsant Properties

The essential oil of bay leaf has been demonstrated to possess anti-convulsant properties in vivo, specifically in mice. It is believed that constituents of bay leaf's essential oil namely eugenol, pinene and methyleugenol protected the mice from induced seizures.45

4.6.8

Antimicrobial Properties

Bay leaf essential oil has been shown to inhibit the growth of bacteria and fungi pathogenic to humans, with evidence that its volatile constituents namely cinnamic aldehyde and eugenol are major contributors to this, particularly the anti-fungal, activity.46

4.6.8.1 Anti-bacterial Activity Regarding its anti-bacterial activity, bay leaf essential oil possesses activity against pathogenic gram-negative bacteria including Campylobacter jejuni, Escherichia coli (E coli) O157:H7, and uropathogenic E. coli, Klebsiella pneumoniae, Salmonella enterica and Salmonella typhimurium, and gram-positive pathogenic bacteria including Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus and Salmonella typhimurium, with potency varying based on the bacterium and the preparation of the herb.28,29 Bay leaf essential oil is also reported to inhibit the growth of Micrococcus luteus, which is considered to be non-pathogenic generally but can cause infection.47 In contrast, extract (ethanol) of diced, macerated and powdered herb were reported to not inhibit the growth of E. coli O157:H7.37 In addition, dried and ground bay leaf is reported to strongly promote the growth of Shigella sonnei, Shigella flexneri and E. coli.48 Interestingly, extract of bay leaf prepared by steeping the herb (10 g) in ethanol for 48 h at room temperature was noted as being quite a potent inhibitor of Clostridium botulinum, which produces botulinum toxin,49 when compared with other culinary herbs and spices including black pepper and nutmeg; it was more potent than thyme, oregano, cloves, rosemary.49 In addition, aqueous extract of bay leaf prepared by boiling the herb

(10 g) in 100 mL of sterile water (100 mL) inhibited the growth of clinical and oral bacterial isolates of/including E. coli, Staphylococcus aureus, Staphylococcus oralis, Streptococcus oralis, Salmonella typhimurium, Klebsiella punemonia, Proteus mirabilis and also Bacillus subtillis, which is generally non-pathogenic but has been found to be infectious in those that are immunocompromised.50,54 Evidence suggests that different preparations of the herb give rise to differential anti-microbial effects.50

4.6.8.2 Anti-fungal Activity Regarding its anti-fungal effect, bay leaf was reported to be amongst a group of herbs and spices that had a ‘relatively minor effect’ on the growth of the toxigenic (toxin producing) fungi Aspergillus flavus, Aspergillus ochraceus and Aspergillus versicolor and the production of their respective toxins.55 However, against Candida albicans, which causes oral candidiasis, extract (methanol) of powdered bay leaf inhibited its growth at levels comparable to that of black pepper, but it was not as potent as cumin and cinnamon.56 The essential oil of bay leaf is also reported to inhibit the growth of Candida albicans.29

4.6.9

Alcohol Lowering Properties

There is evidence that bay leaf lowers blood alcohol (ethanol) levels.23 An animal study by Matsuda et al. 57 reported on the alcohol (ethanol) lowering effects of bay leaf (methanol extracts 250 and 500 mg kg−1). This activity was shown to be confined to the ethyl acetate soluble fraction (the water fraction had no effect on blood ethanol levels). The bioactive constituents were identified as the sesquiterpenes within bay leaf,58 with the alpha-methylene-gamma-butyroloactone sesquiterpene structure identified as being the key constituent in preventing ethanol absorption, which was also influenced by the delay in gastric emptying by the bay leaf extract.

4.7

Safety and Adverse Effects

There are no reports concerning the adverse effects of bay leaf in the human studies detailed above. However, a number of cases of allergic reactions to bay leaf have been reported. Farkas59 reported that bay leaf, along with sweet marjoram and cinnamon, caused perioral dermatitis, a condition in which a rash develops on the skin around the mouth. Lemière et al. 60 reported a case of bay leaf, along with a group of other culinary herbs and spices including thyme and rosemary, causing a skin reaction when the subject came in contact with the herb; occupational asthma on inhalation was also reported. However, most reports concerning the safety of bay leaf are focused on the damage, and obstruction, it causes to the gastrointestinal and upper respiratory tract, with cases of bay leaf causing obstruction (due to it being stuck) of the hypopharynx (the lower part of the throat), oesophagus and duodenum, and also perforation of the small bowel of a patient with pancreatitis (inflammation

of the pancreas), and haemorrhaging of the upper gastrointestinal tract.61,66 Such cases are due to accidental inhalation or ingestion of bay leaf. Regarding the latter, bay leaf cannot be digested and so it should be removed from the food or meal which it has been used to prepare prior to consumption of the food or meal. Non peer reviewed online information states that bay leaf and its oil are likely safe when consumed as foods, and ground bay leaf is possibly safe when consumed over a short time in medicinal amounts (such as the amounts used in the study by Khan et al. 41).67 This information also states that there is insufficient information regarding the safety of bay leaf in pregnant and breast-feeding women. Other side effects reported online, which might in part be linked to some of its bioactive properties detailed above, concern its blood glucose lowering effects, and that it might slow down the central nervous system (CNS) which might be a concern for subjects in which bay leaf is combined with an anaesthetic. As a result of the latter possible side effect, it is advised that bay leaf not be taken with sedative medications which are also CNS antidepressants. It is also advised that bay leaf is not taken with pain medication as it might slow down their metabolism and subsequent excretion, thus increasing their effects and any side effects.67 However, it is unclear upon which evidence this particular precaution is based.

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39. R. P. Dearlove, P. Greenspan, D. K. Hartle, R. B. Swanson and J. L. Hargrove, J. Med. Food, 2008, 11, 275-281. 40. C. L. Broadhurst, M. M. Polansky and R. A. Anderson, J. Agric. Food Chem., 2000, 48, 849-852. 41. A. Khan, G. Zaman and R. A. Anderson, J. Clin. Biochem. Nutr., 2009, 44, 5256. 42. I. Khan, S. Shah, J. Ahmad, A. Abdullah and S. K. Johnson, J. Am. Coll. Nutr., 2017, 36, 514-519. 43. A. Jaksevicius, M. Carew, C. Mistry, H. Modjtahedi and E. Opara, Nutrients, 2017, 9, 1051. 44. F. U. Afifi, E. Khalil, S. O. Tamimi and A. Disi, J. Ethnopharmacol., 1997, 58, 9-14. 45. M. Sayyah, J. Valizadeh and M. Kamalinejad, Phytomedicine, 2002, 9, 212216. 46. Q. Liu, X. Meng, Y. Li, C.-N. Zhao, G.-Y. Tang and H.-B. Li, Int. J. Mol. Sci., 2017, 18, 1283. 47. C. von Eiff, N. Kuhn, M. Herrmann, S. Weber and G. Peters, Pediatr. Infect. Dis. J., 1996, 15, 711-713. 48. C. F. Bagamboula, M. Uyttendaele and J. Debevere, J. Food Prot., 2003, 66, 668-673. 49. C. N. Huhtanen, J. Food Prot., 1980, 43, 195-196. 50. F. Saeed, N. Kanwal, S. Nadeem and S. Hakim, J. Bangladesh Acad. Sci., 2013, 4, 30-35. 51. N. Masood Ahmed Chaudhry and P. Tariq, Pak. J. Pharm. Sci., 2006, 19, 214218. 52. EPA, 1997. https://www.epa.gov/sites/production/files/201509/documents/fra009.pdf, accessed 28 November 2020. 53. S. H. Shahcheraghi, J. Ayatollahi and M. Lotfi, Trop. J. Pharm. Res., 2015, 18, 1-4. 54. M. R. Oggioni, G. Pozzi, P. E. Valensin, P. Galieni and C. Bigazzi, J. Clin. Microbiol., 1998, 36, 325-326. 55. H. Hitokoto, S. Morozumi, T. Wauke, S. Sakai and H. Kurata, Appl. Environ. Microbiol., 1980, 39, 818-822. 56. P. Latti, S. Ramanarayanan and G. M. Prashant, Indian J. Community Med., 2019, 44, S77-S80. 57. H. Matsuda, H. Shimoda, T. Uemura and M. Yoshikawa, Bioorg. Med. Chem. Lett., 1999, 9, 2647-2652. 58. M. Yoshikawa, H. Shimoda, T. Uemura, T. Morikawa, Y. Kawahara and H. Matsuda, Bioorg. Med. Chem., 2000, 8, 2071-2077. 59. J. Farkas, Contact Dermatitis, 1981, 7, 121. 60. C. Lemière, A. Cartier, S. B. Lehre and J.-L. Malo, Allergy, 1996, 51, 647-649. 61. T. K. Tsang, M. J. Flais and G. Hsin, Ann. Intern. Med., 1999, 130, 701-702. 62. S. K. Buto, T. K. Tsang, G. W. Sielaff, L. L. Gutstein and M. S. Meiselman, Ann. Intern. Med., 1990, 113, 82-83. 63. D. C. Awerbuck, T. D. R. Briant and M. K. Wax, Otolaryngol.--Head Neck Surg., 1994, 110, 338-340. 64. K. Ahmed and M. S. McCormick, J. Laryngol. Otol., 1993, 107, 153-154. 65. T. Lingenfelser, G. Adams, D. Solomons and I. N. Marks, J. Clin. Gastroenterol., 1992, 14, 174-176. 66. P. Skok, Endoscopy, 1998, 30, S40-S41.

67. WebMD, Bay Leaf, https://www.webmd.com/vitamins/ai/ingredientmono685/bay-leaf, accessed 18 November 2020.

CHAPTER 5

Black Pepper (Piper nigrum L) 5.1

Names

English: Black pepper Bengali: Golmoris Chinese: Hei hu jiao French: Poivre noir Hausa: Masoro German: Pfeffer Korean: Huchu, pepeo, pepo India: Kali mirka Spanish: Pimienta negra

5.2

Taxonomy

Order: Piperales Family: Piperaceae Genus: Piper Species: Piper nigrum

5.3

Origin, Description and Adulteration

Black pepper (Piper nigrum) is indigenous to Southern India, it is cultivated on the Malay Archipelago islands and islands off the coast of Africa such as Madagascar. Malabar black pepper comes from the Malabar coast of southwest India, and Lampong black pepper is from Sumatra, Indonesia. Piper nigrum is a climber with short roots, called adventitious roots, which connect to surrounding supports. It grows to a height/length of about 10 m. Once established it grows side shoots to create a bushy column with almond-shaped leaves, tapering towards the tip. These are dark green and shiny above and paler green below, and are arranged alternately on the stem. The flowers form clusters along the stalks known as spikes, which are 50–150 in number whitish to yellow– green. The fruits/berries, each with a single seed, up to 6 mm in diameter (there are 50–60 on each spike), are green at first but turn red as they ripen. Fruits are picked green/immature to produce green pepper; when fully grown but still green and shiny they are used to produce black pepper; and slightly more ripe to produce white pepper.1 Black pepper is a tropical vine that thrives in well drained rich soils and so needs to be grown indoors in temperate regions. It can be grown as a houseplant to

produce peppercorns (it takes several years to bear fruit), and the plants are not usually affected by pests or diseases (even aphids, small sap-sucking insects, dislike the taste of the leaves).2 The berries are picked while still green, allowed to ferment and are then sundried until they shrivel and turn a brownish-black colour. These fermented and sundried berries have a hot and biting taste with a sharp and woody, pine-like aroma, and they are used to add flavour to foods all over the world.1 As black pepper is one of the most valued spices, it is no surprise that adulterations have been reported, a common filler for black pepper is berry black papaya seeds.3 The principal producers and exporters of black pepper are India (Malabar and Tellicherry Pepper), Indonesia (Lampong Pepper), Brazil and Malaysia. Tellicherry is a type of Malabar Pepper with a bold size and uniform appearance. The flavour and aroma of Lampong Pepper are similar to those of Malabar. The Malaysian and Brazilian varieties have milder flavours.1 According to the Food and Agriculture Organization (FAO), there were 690 467  000 tonnes of black pepper produced in 2017, 68.6% from Asia (mainly Vietnam, Indonesia and India), 13.9% from Europe (mainly Bulgaria), and 13.5% from the Americas (mostly Brazil).4

5.4

Historical and Current Uses

Black pepper has a long history of use in Indian culture for many ailments and even featured as an aphrodisiac in the Kamasutra.5 Archaeological finds date back to 2000 BCE in India, from where black pepper was exported, with evidence of an ancient black pepper trade from India to Egypt. Furthermore, peppercorns were found in the nostrils of Ramses the Great's mummy (1303–1213 BCE).6 The Romans led the trade in spices, including black pepper, and they loved black pepper.7 Garum was a sauce made of salted, fermented fish to which herbs and spices like black pepper might be added during fermentation with four basic ingredients: water, oil, vinegar, and wine. Garum was known as early as the 5th century BCE in Greece, but it came into use in Italy later where it was a universal ingredient in every sauce for fish, meat, fowl, and vegetables. Black pepper, pine nuts and asafoetida (gum resin with a strong odour obtained from the roots of plants of the genus Ferula) were used in the stuffing for the Roman delicacy baked dormouse.8 When Rome was captured, to lift the siege of the Visigoths in 410 CE, a sum of 3000 pounds of black pepper was the ransom. Black pepper was so precious in Western and Eastern societies of ancient times that it was used to pay taxes, rents, tributes and wedding dowries. It was sometimes referred to as “black gold”. With the fall of Rome's imperialism, Arabs began to take over the spice trade. To maintain the monopoly, and the demand, they created a myth around black pepper. They claimed it was grown in India guarded by poisonous serpents, and trees had to be burned to drive the snakes away so that the precious spice could be harvested. By the 10th century, black pepper was expensive and in high demand in Europe.6 In the Middle Ages, black pepper was used in seasoning and for hiding the strong

flavour of salted cured meat. Peppercorns can be stored for years without losing their flavour and aroma, so they were given the title of “the master spice”. In the 14th century, over 40% of the value of all that entered Genoa (a principal centre of commerce) from Alexandria came from black pepper, and by the next century, black pepper made its way to Venice. The Portuguese king Manuel sent Vasco da Gama to India to find “Christians and spices”, and as they did, they took over the spice trade, which they lost by the 16th century due to lack of military control/power. The Dutch took over the trade in the 16th century (as they had colonies in Bantam, Ceylon, Java, Lampong and Malabar). The British Empire then took control of the spice trade through organised commercial trade groups with the producers, and strong military power.6 There are hundreds of references to black pepper in the famous Apicius Roman cookbook,9 with black pepper included in a large majority of the recipes, from spiced wine to many types of plants or meats, eggs, fish based dishes, sauces and condiment mixtures. It was recommended in a mixture for indigestion, to “move bowels, against all illness and pestilence”, which also contained ground salt, ammoniac (ammonium) salt, ground white pepper, ginger, thyme seeds, celery seeds or parsley seeds, sweet marjoram, hyssop, anise seed and saffron. Silphium was a plant, now extinct, with a powerful sulfurous smell, and the root (laser root) was used by Romans in foods and medicine. Laser flavour was a broth in which laser root was mixed with other spices (black pepper, parsley, dried mint, honey, vinegar and broth) to accompany other dishes. The 14th and 15th centuries' Medieval cookbook Le Viandier de Taillevent, also mentions black pepper extensively, for example in its famous recipe for Black Pepper Sauce.10 Black pepper features in the Book of Herbs (1903) by Rosalind Northcote,11 who described alternatives used prior to black pepper becoming more affordable. Lovage was an example, and Northcote states, “The Germans and other nations in times past used both the roots and seeds instead of pepper to season their meats and broths, and found them as comfortable and warming”. Another example was dittander/pepperwort, described as “poor man's pepper”, which was sometimes used in sauce or with salted meat stew, but was too hot, bitter and strong for everyone's taste. Today, it seems difficult to find a prepared dish (retailed or home made) without some black pepper, and for those not fond of black pepper, dishes must be ordered specifically without it when dining out, as it is widely assumed that black pepper will be well received by the majority. Black pepper is an ingredient in foods from all continents, in fact it even made its way to space; the National Aeronautics and Space Administration (NASA)12 sends astronauts with liquid forms of salt and pepper (so that the ground forms do not get stuck in their eyes or airways due to the lack of gravity). Black pepper is therefore today still an essential condiment, an element of numerous sauces, formulations and seasonings, such as Masala (meaning spice mix). Curry powder is an example, although ingredients vary due to traditions and brands. Curry usually includes black pepper, cardamon, cumin, coriander, cinnamon, fenugreek, ginger and turmeric. Examples of sauces that contain black pepper include the Poivrade game sauce (pepper is poivre in French), which also contains onions, shallots, garlic, bay leaf, thyme, vinegar, leaf stock, red wine, parsley and olive oil. Tourangelle sauce is prepared with butter, onions, carrots,

shallots, garlic, red wine, beef and chicken stocks, black pepper, parsley, thyme and bay leaf. African and Caribbean dishes often contain black pepper, sometimes with other pungent agents for an extra hot effect, such as chilli peppers. For example, Nigerian pepper soup may include aniseed, coriander, cumin, fennel seeds and black peppercorns as well as red chilli. It appears the Japanese tend to prefer the use of Sansho pepper (Zanthoxylum piperitum, also known as Japanese pepper) as a pungent agent in their traditional cuisine instead of black pepper. The Oriental five spice blend (or Chinese five spice blend) typically includes cinnamon, cloves, fennel, star anise and Szechuan peppercorns, which are not black peppercorns but fruits from a citrus tree that is related to the Japanese Sansho pepper.13 Black pepper does not feature in the list of Commission E monographs of approved spices for herbal medicines, nor in the expanded version.14 There is a patent (2010) for the use of a blend of black pepper and ginger as an anti-infective agent for topical preparations which is reported to successfully treat athlete's foot, jock itch, ringworm, favus (a severe, chronic ringworm of the scalp and nails) and other yeasts such as Candida. The patent claims that the product is cheaper, more effective, and a less toxic form of treatment for fungal infections in humans and livestock animals than conventional medications.15 Black pepper essential oil is used in aromatherapy, blended with vegetable oils, for massaging sore muscles and improving circulation. It is thought to work as a rubefacient (produces redness of the skin, by causing dilation of the capillaries and an increase in blood circulation). It is also placed in boiled water and the vapour is inhaled, for bronchitis for example. Some studies investigated the use of black pepper with smoking cessation with success reported for reducing cravings.16 Black pepper features in the online encyclopaedia of traditional Chinese medicine,17 described as hot and pungent, it is used for the large intestine and stomach meridians. Hei Hu Jiao, where Hu Jiao translates as “Barbarian Pepper”, and Hu Jiao Li which means “peppercorns” is used to warm the stomach/insides and expel the cold (used for colds and fevers). Prescribed to calm a “rebellious qi” to reduce abdominal pain, indigestion, diarrhoea, constipation, food stagnation, nausea and intestinal cramping, it is also used as an antimalarial agent.18

5.5

Chemistry, Nutrition and Food Science

Black pepper contains phenolic acids and flavonols glycosides, with 1piperonylpiperazine being the major bioactive component.19 Black pepper's essential oil is obtained from hydrodistillation or steam distillation of crushed peppercorns. The main constituents are piperine and eugenol. Other essential oil components include pinene, limonene, and caryophyllene. Piperine and its isomers (compounds with the same molecular formula as piperine but different chemical structures) are mostly responsible for the pungency and irritant effects of black pepper. The UK and US databases provide the same nutrient values for black pepper (see Table 5.1).20,21 It is poor in the energy yielding nutrients (carbohydrate, fat, protein), especially in the context of the amount used in cooking (which is small). The phytosterol content is 0.92 mg g−1 (see Table 5.1), therefore black pepper may

make a significant contribution to the 2 g per day of dietary phytosterol recommended for the prevention of cardiovascular disease if consumed regularly.22 Table 5.1

Nutrition composition of ground black pepper.20,21 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0

Black pepper – ground (100 g)

UK data

US data

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Iron/mg Copper/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin K1/µg Pantothenate/mg

Na Na 25.3 3.3 (0.6) 10.4 12.5 92 443 9.71 1.33 171 12.75 158 1329 5 20 1.2 55 0.11 0.18 1.1 0.29 0 17 163.7 1.4

251 63.95 25.3 3.3 (0.6) 10.4 12.5 —b 443 9.71 1.33 171 12.75 158 1329 5 20 1.2 55 0.11 0.18 1.1 0.29 0 17 163.7 1.4

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. Piperine, in black pepper, has been shown to increase the bioavailability of curcuminoids (from turmeric) in animal and human studies. Suresh et al. 23 set out to determine the impact of domestic cooking on constituents in turmeric and pepper, and compared the impact of boiling the spices for 10 min and 20 min with pressure cooking, for 10 min; they quantified the constituents using high pressure liquid chromatography (HPLC). For black pepper, untreated samples (55.8 mg piperine g−1 of spice) were higher in piperine than black pepper boiled for 10 min (27% loss) and boiled for 20 min (27.9% loss) and even greater losses were observed with pressure cooking for 10 min (33.9% loss). These results indicate that cooking, specifically boiling and pressure cooking, decrease the amount of a major biological constituent of the spice.

A study24 investigated whether adding black pepper to turmeric would further inhibit lipid peroxidation (oxidation of fats that reduces the shelf life of foodstuffs), measured via the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay, in meat patties prior to cooking. Results showed the antioxidant capacity of black pepper was 20fold lower compared to turmeric with significant decreases in the lipid peroxidation in meat when the two spices were combined. However, as piperine did not exhibit any antioxidant capacity, the authors concluded that other black pepper constituents caused this increased antioxidant capacity in the mixture with turmeric. The essential oil of black pepper possesses antioxidant and antimicrobial actions, and has been demonstrated to have good preservative potential in orange juice25 and meat products,26 such as pork sausages.26,27

5.6

5.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

Black pepper, both ground and whole, possesses antioxidant capacity in vitro, with the former displaying a capacity which is slightly higher.28 The leaf, essential oil and oleoresins of black pepper all possess antioxidant capacity. In contrast to the study23 summarised above, piperine is reported to be a significant contributor to this property.29 Commercially available black pepper ranked 21st out of 38 dried and commercially available culinary herbs and spices for antioxidant capacity in vitro.30,31 However, values for antioxidant capacity vary due to the nature of the spice preparation and the assay used.32 Black pepper oil is reported to inhibit lipid peroxidation, a marker of oxidative stress,33 in vitro; and in vivo, in animal models of diabetes and hyperlipidemia, it decreased oxidative stress and increased and/or normalized the activity of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD).34,35 Furthermore, black pepper oil increased the levels of SOD, CAT and GPx in mice in which the production of superoxide radicals, which are free radicals, by macrophages had been elicited.33 A study by Prakash and Srinivasan36 reported that in rats, both normal and in a state of oxidative stress, fed diets that included black pepper as well as red pepper, ginger and capsaicin (a constituent of red chilli pepper) the activities of antioxidant enzymes, including SOD and CAT, were increased in the gastric and intestinal mucosa of both groups of animals, suggesting that the spices both confer protection against, and lessen the impact of, oxidative stress on the gut. Human studies using black pepper are limited in number: Percival et al. 37 demonstrated that black pepper consumed by healthy humans at a dosage of 2.8 g per day (administered in capsule form) for 7 days (19.6 g in total) did not result in any detectable increase in antioxidant capacity of the serum of these subjects.

Furthermore, the serum of subjects who consumed the black pepper capsules did not appear to protect against hydrogen peroxide, a reactive oxygen species, induced DNA damage. Li et al. 38 reported that black pepper (0.7 g) in combination with other herbs and spices (cloves (0.5 g), cinnamon (0.5 g), Mediterranean oregano (3 g), rosemary (0.5 g), ginger (1.2 g), paprika (3.4 g) and garlic powder (1.5 g)), when added as a herb and spice blend to hamburger meat, resulted in a decrease in the levels of malondialdehyde (MDA) – a reactive aldehyde and a marker of oxidative stress – in the plasma and urine of the healthy subjects who consumed the herb and spice rich hamburger meat, suggesting that such a blend (of which black pepper made up 6.5%) could protect against disease processes that result from oxidative stress, specifically carcinogenesis and atherogenesis.38 Interestingly, however, a similar herb and spice blend with a slightly higher quantity of black pepper (0.91 g) (and cinnamon 0.61 g, cloves 0.61 g, garlic powder 1.181 g, ginger 1.51 g, Mediterranean oregano 2.26 g, paprika 2.85 g, rosemary 0.61 g but also included turmeric (2.79 g)) affected some but not all the markers of antioxidant status measured in healthy, overweight subjects. Overall, the findings of this study suggest that an antioxidant rich herb and spice blend improves antioxidant status. However, due the inconsistency of outcome, this study raises questions about the usefulness of antioxidant assays when used to ascertain antioxidant activity in vivo.39,40 In subjects with type 2 diabetes (T2D), black pepper (0.79 g) consumed as part of a herb and spice blend consisting of cloves (0.45 g), cinnamon (0.45 g), Mediterranean oregano (2.925 g), rosemary (0.45 g), ginger (1.2375 g), paprika (3.375 g) and garlic powder (1.4625 g) added to ground beef, caused a reduction in MDA, and thus oxidative stress, alongside an improvement in endothelial vascular function. Endothelial dysfunction can increase the risk of cardiovascular disease so it is tempting to surmise that the improvement may have been due to the ability of the herbs and spices, including black pepper (7% of the blend) to confer some degree of protection. Although whether this protection is due to its antioxidant properties is unclear.41

5.6.2

Anti-inflammatory Properties

The anti-inflammatory properties of black pepper have been demonstrated in animal models with evidence that this property is primarily due to its bioactive constituent piperine.30,42,43 A study by Majadalaweih and Carr44 reported that aqueous extracts of black pepper significantly increased the release of pro-inflammatory cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) from stimulated murine macrophages and increased the release of the pro-inflammatory mediator nitric oxide (NO) by unstimulated and stimulated macrophages. Black pepper also suppressed the release of interleukins 4 and 10 (IL-4 and IL-10) from stimulated, but not unstimulated, splenocytes, which consist of a variety of white blood cells including T and B lymphocytes, dendritic cells and macrophages. Black pepper also increased the release of interferon gamma (IFN-γ) from unstimulated and stimulated splenocytes, and enhanced natural killer (NK) cell cytotoxicity. These cells are known to play a role in the early detection and control of cancer, and are able to kill

cancer cells.45 The extract also increased proliferation of splenocytes in a dosedependent manner. Tasleem et al. 46 reported that black pepper extracts inhibited inflammation (based on inhibition of oedema) in rats. The effect of the extracts was similar to that of piperine at doses of 10 and 15 mg kg−1 of body weight, and their effect lasted 120 minutes as opposed to the 60 minute effect of the piperine; thus providing evidence that the spice was more potent and longer lasting than its main bioactive constituent. Black pepper essential oil has also been shown to possess antiinflammatory activity, as demonstrated in a murine (mouse) model of acute inflammation; its effect was dose-dependent and also comparable to that of the nonsteroidal anti-inflammatory drug diclofenac. Furthermore, the oil inhibited chronic inflammation with a potency comparable to that of diclofenac.33 In contrast to the findings of these animal studies, Percival et al. 37 reported that black pepper 2.8 g per day (administered in capsules) for 7 days (19.6 g in total) did not affect the expression of the pro-inflammatory cytokines TNF-α, interleukin-1 alpha (IL-α) and IL-6 in stimulated human monocytes. It is clear that more human studies are required to ascertain the beneficial significance of black pepper's antiinflammatory activity.

5.6.3

Glucose Lowering, Anti-diabetic, Lipid Lowering Properties and Effect on Appetite

Black pepper possesses glucose and lipid lowering activity, and is also reported to influence appetite. These activities suggest that the spice may have a role to play in the prevention and management of T2D and metabolic syndrome (MetS) and, as a consequence, cardiovascular disease. In addition, its ability to affect appetite provides some support for its potential inclusion in weight management strategies. However, evidence of these effects in humans is very limited due to the paucity of studies42 and mixed results, which could be due to differences in study design, specifically with regards to the subjects used and the nature of the dietary intervention. Concerning its glucose lowering effect and anti-diabetic potential, a study in vitro by Naderi et al. 47 reported that black pepper extracts inhibited the glycation of haemoglobin, which is a biomarker of diabetes and can lead to the vascular complications that result from this disease. Animal studies have reported that aqueous extracts of the seed and ethanolic extracts of the leaf of the black pepper plant lowered blood glucose levels in diabetic rats.35,48 In a study in healthy humans by Zanzer et al.,49 a beverage of flavoured water containing extract of black pepper (subjects consumed 220 mL of the drink, which was from 100 mL of black pepper extract obtained from 20 g of black pepper extracted with heat, at 90 °C for 3 minutes, diluted with 900 mL of flavoured water; the drink was consumed, within 5 minutes, after which subjects, who were on a low phenolic diet but had fasted 10 h before the intervention, consumed white bread containing 50 g of carbohydrates within 10 minutes) had no effect on glucose and insulin responses and insulin sensitivity, although there was a trend towards a reduction in insulin response at 30 minutes after the start of the consumption of the white bread but the reduction was not significant. When the authors investigated the effect on appetite,

no changes to gut and thyroid hormones were reported. However, the beverage lowered ‘hunger’, ‘desire to eat’ and ‘prospective consumption’ and increased ‘satiety’ and ‘fullness’. The findings concerning the effect on insulin are supported by a study by O'Connor et al.,50 in which there were no significant differences in blood glucose, insulin and gut peptides following the consumption of the spice (a total of 1.5 g) as part of a meal consisting of low-sodium V8® vegetable juice (meals were consumed on 3 separate study days with 0.5 g of black pepper being consumed each time). There was a decrease in insulin response but this was not significant. Gregersen et al. 51 reported that a mixed meal in which 1.5 g of black pepper was consumed by normal weight subjects, as part of a meal consisting of pasta with meat sauce, multi-fruit juice and crackers, had no effect on appetite. A study by Skulas-Ray et al. 39 briefly described above (see section on Antioxidant Properties) in which some evidence of improvements in antioxidant status in overweight healthy men was noted, reported that a herb and spice blend containing black pepper (0.91 g) significantly improved triglyceride (TG) and insulin responses but had no effect on blood glucose. The authors suggested that the low glycaemic effect of the meal to which the herb and spice blend was added may explain the lack of glucose response by the subjects following consumption of the meal plus the blend. The lipid lowering effects of black pepper have been reported in animal studies. Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), free fatty acid, phospholipid and/or TG levels were significantly decreased following the administration of extracts of black pepper and/or piperine.52,54 High density lipoprotein–cholesterol (HDL-C) was also significantly increased. One of the effective doses of black pepper used, 250 mg kg−1 of body weight, was based on the average daily intake of the spice in India. Piperine also affected key enzymes involved in cholesterol and fat metabolism which may explain its effect, as well as that of black pepper, on the levels of these lipids.54 McCrea et al.,55 using the same herb and spice blend used by Skulas et al. which included black pepper, reported a lipid lowering effect in healthy overweight subjects. However, the reduction in postprandial (post meal) TG levels occurred only when the period after the consumption of the meal included a rest period. When the post meal period included a series of tasks that gave rise to stress there was no evidence of the reduction in postprandial TG. These different outcomes suggested to the authors that psychological stress may lessen any protective effect of the herb and spice blend on cardiovascular risk via its effect on postprandial TG. The study also suggested that the herb and spice blend may affect TG levels via inhibition of TG digestion, as the blend inhibited enzymes involved in this process, namely pancreatic lipase and phospholipase A2 in vitro. Li et al.,41 in another culinary herb and spice blend study (see above for details) did not report significant changes in TG, glucose and insulin levels in subjects with T2D post consumption of hamburger meat seasoned with the blend. It was suggested that this finding could be due to the small impact the hamburger meat on its own had on postprandial TG.

5.6.4

Chemopreventive/anti-cancer Properties

Black pepper possesses potent chemopreventive/anti-cancer activity with extracts of the root and fruit having cytotoxic effects on human cancer cells including leukaemic (HL60), breast cancer (MCF-7 and MDA-MB-2312), prostate cancer (PNT1A, 22RVI, PC3) and colorectal cancer (HT-29, HCT116 and HCT15) cells.56,57 Piperine, as well as other bioactive black pepper constituents, namely (−)-kusunokinin and piperlonguminine, isolated from the fruit, and pellitorine, which is found in the root of the black pepper plant, have been identified as eliciting cytotoxic effects on breast cancer, cervical cancer (HeLa), colorectal cancer and/or prostate cancer (LnCaP, PC-3, DU145 cells) cells. Furthermore, evidence indicates that some of these actions may be due to their pro-apoptotic, cell cycle and intracellular signalling regulatory properties.58,60 Of these constituents, piperine has been the most investigated, with additional studies demonstrating its ability to promote autophagy, re-sensitise multidrug resistant proteins, which are overexpressed in cancer cells and confer resistance of these cells to anti-cancer drugs such as doxorubicin and mitoxantrone, and also re-sensitise multi-drug resistant breast and lung (A-549) cancer cells.43,61 Furthermore, piperine is reported to inhibit chemically induced lung cancer in mice.62 Interestingly, a piperine free extract of black pepper, which displayed cytotoxic effects against breast cancer cells in vitro, was more selective against these cells than colorectal cancer, lung cancer and neuroblastoma (nerve cancer) cells. In addition, the extract, when given to animal models of breast cancer, decreased the incidence of tumour bearing rats and inhibited mammary tumorigenesis (tumour production). This study reinforces the contribution of other constituents of black pepper to its anti-cancer activity.63 There is clear evidence that black pepper and its constituents possess potent chemopreventive/anti-cancer activity, however the clinical significance of this spice, and thus its potential in the treatment of cancer, is yet to be established fully.

5.6.5

Neuroprotective Properties

There are a small number of animal studies that report the anxiolytic (anti-anxiety), antidepressant and/or cognition enhancing properties of black pepper extract and its constituent piperine.30 The fruit extract studies by Hritcu et al. 64,65 suggest that the neuroprotective properties of black pepper are possibly conferred via its antioxidant properties, as the extract was able to normalise the antioxidant status, by decreasing neuronal oxidative stress, of animal models of Alzheimer's.

5.6.6

Antinociceptive/Analgesic and Anti-convulsant Properties

The analgesic properties of black pepper have been established in animal studies. Ethanol and hexane extracts of the spice elicited significant pain relief, with piperine eliciting a stronger analgesic effect.46 Black pepper essential oil is also reported to exhibit pain relief, again in animals.33 The anti-convulsant effects of black pepper have also been demonstrated in animal studies. Ethanol and hexane extracts of black pepper powder are reported to decrease seizure duration.66

5.6.7

Digestive Properties and Gastrointestinal Stimulant

The digestive/gastrointestinal properties of black pepper have been demonstrated in animals and humans,67 with animal studies reporting its effect and/or that of piperine on bile/bile acid secretion, digestive enzymes, including lipase, sucrase and maltase, which are involved in the digestion of TG, and the sugars sucrose and maltose, respectively, and intestinal transit times.67,72 A human study by Glatzel73 reported that black pepper enhanced the secretion of salivary amylase (which is involved in the digestion of starch). In addition, Myers et al. 74 reported that consumption of test meals containing black pepper (1.5 g) in healthy volunteers resulted in increased gastric secretions and gastric epithelial cell exfoliation (a normal physiological process which involves the removal of dead cells; it has an important role to play in the maintenance of the gastric mucosa (stomach lining)). However, this study also reported some adverse effects (see section on Safety and Adverse Effects).

5.6.8

Prebiotic Potential

Evidence is now emerging that culinary herbs and spices may work to maintain digestive health via their prebiotic potential. A prebiotic is a dietary constituent that is defined as “a selectively fermented ingredient that results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health”.75,76 However, these possible benefits extend beyond maintaining digestive health to protecting against the development of chronic noncommunicable diseases.77 Although herbs and spices are not fermented, and are thus not prebiotics based on the definition above, their prebiotic potential, that is their ability to beneficially modify human gut microbiota, has been demonstrated in recent studies by Lu et al. 78 in vitro, and in humans by Peterson et al. 79 (the amounts used were not specified in this study) and Lu et al. 78 for black pepper (0.85 g) in combination with cinnamon (1 g), Mediterranean oregano (1.5 g), ginger (1.5 g) and cayenne pepper (0.15 g). However, larger, longer term, and diet controlled (as diet influences the profile of gut microbiota) studies are required to better establish the prebiotic potential of black pepper. With the role of a diverse microbiome being linked to protection against the development of chronic non communicable diseases,80 this is an exciting area of research.

5.6.9

Antimicrobial Properties

There is extensive evidence supporting the anti-microbial activity of black pepper which is not only due to piperine but also 3,4-dihydroxyphenyl ethanol and 3,4dihydroxy-6-(N-ethylamino) benzamide, which were reported to inhibit the growth of bacteria present in food.29 This activity varies based on the nature of the preparation81 and the type of bacteria,43 with gram-positive bacteria shown to be more susceptible to black pepper than gram-negative bacteria.82

5.6.9.1 Anti-bacterial Activity Extracts (aqueous, ethanol, methanol, ethyl acetate, ethanol and chloroform) of the fruit, fruit leaf, and leaf stem, as well as the essential oil, are all reported to inhibit the growth of bacteria pathogenic to humans,43 including the gram-negative, Salmonella typhi, Klebsiella pneumoniae and Pseudomonas aeruginosa, and the gram-positive Bacillus cereus, Streptococcus faecalis, Streptococcus mutans and Staphylococcus aureus.83,84 The formation of biofilms of bacteria is also reported to be inhibited by extracts (methanol) of black pepper via its action on a process called quorum sensing, a process in which bacteria release chemicals that act as signalling molecules via which bacteria are able to sense the number of bacteria and as a consequence behaviour; in the case of pathogenic bacteria this behaviour is virulence, which is the severity of the infection.85,86

5.6.9.2 Antifungal Activity Extracts of black pepper also act against pathogenic fungi including species of Mucor fungi, which can cause a range of infections including gastritis and pulmonary and renal infections.83,84 Acetone extract and black pepper essential oil were reported to be effective against the toxigenic (toxin producing) Aspergillus niger (A. niger), A. flavus and A. ochraceus, with the extract proving to be more potent.32

5.7

Safety and Adverse Effects

There is little in the literature concerning adverse effects following consumption of black pepper. In animals (rats) aqueous extracts of the dried fruits of black pepper are reported to result in no adverse effects when given orally at a dosage of 5 g kg−1 of body weight in one go. Furthermore, in the same study, no adverse events were reported when the extract was given orally daily at dosages of 300, 600 and 1200 mg kg−1 of body weight for 90 days.87 Myers et al. reported that test meals containing 1.5 g of black pepper caused mucosal micro-bleeding (small chronic hemorrhaging of the lining of the gut) and gastric bleeding in some of the healthy volunteers used. None of the other human studies discussed above, in which the amount of black pepper consumed either on its own or in combination with other culinary herbs and spices ranged from 0.78 g (in one go) to 2.8 g per day for 7 days, provided any information about adverse effects.37,39,41,49,51,79 Black pepper's constituent piperine is reported to cause irritation, drowsiness and paralysis at doses of 25, 50 and 75 mg kg−1 of body weight in mice within 3 hours of intraperitoneal administration. At the highest dosage, the mice died within 24 hours and after 48 hours at the lower doses.46 Acute toxicity to piperine has been reported in mice and other rodents, with LD50 (lethal dose for 50% of the test sample used) values ranging from 15–400 mg kg−1 of body weight, following intraperitoneal, intravenous, subcutaneous, intragastric and intramuscular administration, with animals dying due to respiratory paralysis within 3–17 minutes

of administration of the lethal dose.88

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CHAPTER 6

Caraway (Carum carvi) 6.1

Names

English: Caraway Albanian: Qimnoni Burmese: Ziya French: Cumin des près Spanish: Alcaravea Norwegian: Karve The word caraway probably derives from the Latin carui, from the Arabic alkarāwiyā, and from the Greek karon meaning cumin.

6.2

Taxonomy

Order: Apiales Family: Apiaceae Genus: Carum Species: Carum carvi

6.3

Origin, Description and Adulteration

Caraway (Carum carvi) is native to western Asia, Europe, North Africa, and the eastern regions of Iran, where it is called black cumin; Iran is one of the main exporters.1 Caraway is not to be confused with Nigella Sativa of the Ranunculaceae family, also called black cumin seeds and with a different chemical composition. Caraway is a biennial plant (it takes two years to complete its life cycle from the growth of its roots and stems to flowering, producing seeds and dying) of the family Apiaceae, and as with other species in the carrot family, the plant has feathery leaves with thread-like divisions, growing upright, with empty stems. The thin light green leaves are aromatic, divided into linear segments with lobes arranged on either side of a central axis like a feather, and small white to pink flowers in umbels bloom in summer, from which aromatic fruits develop. The fruits (referred to as seeds) are long, narrow, curved, ridged, brown in colour and fragrant. Caraway grows better in light, fertile well-drained soil and in full sun exposure in flower borders and bed cottages and reaches 0.1–0.5 m in height and 0.1–0.5 m in spread, and is normally pest free and disease free, but it dislikes transplanting.2 Adulteration of caraway has been identified using another plant called black cumin, Carum bulbocastanum, even though these two plants have significantly different characteristics; caraway is shorter, thinner and has a much smaller volume

than black cumin seeds.1

6.4

Historical and Current Uses

Early literature from China, Egypt, Sumeria and India describes the uses of caraway, as well as anise, mustard, mint, saffron, thyme, cardamom, turmeric, cloves and pepper.3 Caraway has been consumed in Europe4 for longer than other herbs and spices, as evidenced by archeological finds in Switzerland,5 and it was cultivated across Europe in the Middle ages. Caraway is also mentioned in Shakespeare's Henry IV. The Romans were interested in cultivating caraway because of their love for tasty foods. It has been speculated that lead intake leaching out from pipes and pots may have caused a metallic taste and loss of appetite so usage of peppercorns, ginger, cumin, caraway and mustard was highly sought to improve flavour. However, caraway is not mentioned in the book of Ancient Herbs6 and it is only mentioned once in the Apicius Roman cookbook7 for use as an alternative spice to the famous Roman laser. Silphium was a plant, now extinct, with a powerful sulfurous smell; the root (laser root) was used by Romans in foods and medicine. Laser flavour was a broth where laser root was mixed with other spices to accompany other dishes; it was prepared with black pepper, parsley, dried mint, honey, vinegar and broth, and sometimes caraway was also added. In the Book of Herbs (1903) Northcote refers to caraway as one of the chief herbs used in present times, and states that in “Elizabethan days” caraway seeds were appreciated.8 Caraway seeds are used in Eastern European countries to flavour rye breads, and to bake caraway seed cakes and other sweet patisseries. It is sometimes combined with apples and added to stews, potato and meat dishes, such as roast or braised pork dishes,9 as well as to cheeses, sauerkraut and pickled foods. It is an ingredient of the Arabic spicy blend Tabil, which is popular in Algeria and Tunisia, and contains coriander, caraway and chilli flakes. Caraway is also a component of harissa paste, with chilli peppers, garlic, coriander, salt, and sometimes rose petals. Caraway is present in Indian and Burmese curry blends. Alcoholic drinks infused with caraway include the German–Scandanvian Aquavit and Kümmel schnaps. Caraway usage was widespread in diverse folk medicine practices in Europe, Russia, Iran, Indonesia and North America. Some of these practices still remain today, and form the bases for several modern research studies discussed later. It is an important remedy in Ayurvedic traditional medicine for a variety of ailments such as coughing and rheumatism. In Moroccan traditional medicine, caraway seeds are used as diuretics (increase urination); in Russia caraway is used for pneumonia (lung infection); and in Indonesia it is used to treat eczema (inflamed itchy skin condition). In Poland, it is employed for indigestion and used as a galactagogue (a food which increases or promotes the flow of breast milk).10 It is sometimes referred to as “Persian cumin”, in addition to being called black cumin, in Iran where it is said to possess a variety of purported health benefits, which include antiinflammatory, spasmolytic, antimicrobial, antioxidant, and carminative properties.11 The British Herbal Compendium states that the main medical uses of caraway seeds are for dyspeptic complaints including flatulence, eructation

(belching), bloating and mild spasmodic pains in the gastrointestinal tract, plus loss of appetite.12 Caraway essential oil has been recorded to possess antibacterial, fungicidal, insecticidal, and diuretic properties. Caraway is not mentioned in traditional Chinese medicine texts but appeared in a Tibetan medicinal herbal remedies search for plateau diseases (chronic atrophic gastritis) as part of a herbal blend.13 The United States Department of Agriculture granted caraway a Generally Recognized as Safe (GRAS) certification when used as food and granted caraway essential oil GRAS certification when used as a food additive.14 The Commission E monographs15 states that amounts of 1.5–6 g seeds per day are considered safe, without interactions, side effects or contraindications reported (please see section Safety and Adverse Effects).

6.5

Chemistry, Nutrition and Food Science

According to Phenol Explorer,16 caraway contains several phytochemicals, including the flavonoid kaempferol and the phenolic acid caffeic acid. Caraway's anise-like aroma is due to terpenes carvone (44.5–95.9%) and limonene (1.5– 51.3%), which are the most abundant compounds. Other compounds, including βmyrcene, trans-dihydrocarvone, trans-carveole, α-pinene, sabinene, n-octanal, trans-β-ocimene, γ-terpinene, linalool, cis- and trans-limonene oxide, cisdihydrocarvone, cis-carveol, perillaldehyde, trans-anethole, and trans-βcaryophyllene, have also been detected.17 Caraway's essential oil is obtained from distillation of the dried fruit, or alternatively via supercritical fluid extraction, and possesses significant antimicrobial, antifungal and pesticidal activities. The European Pharmacopoeia (EP),18 states that caraway fruit should contain a minimum essential oil content of 30 mL kg−1 (∼3%), and caraway oil 50.0–65.0% carvone, 30.0–45.0% limonene, 0.1–1.0% β-myrcene, and a maximum of 2.5% trans-dihydrocarvone and 2.5% trans-carveol. With regards to the nutritional quality of caraway, it is generally considered to be poor in the energy yielding nutrients (carbohydrate, fat and protein). The nutrition composition needs to be considered with the proportion of the spice used in the diet, often a pinch of seeds or two. Nevertheless, caraway seeds can be considered high in calcium (9.5 mg g−1), and iron (0.32 mg g−1), see Table 6.1.19,20 Table 6.1

Nutrition composition of caraway seeds.19,20 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid under the terms of the Open Government license 3.0

Caraway (100 g)

UK data

US data

Energy/kcal Carbohydrates/g Dietary fibre Fat/g (Saturated/g) Protein/g

Na Na Na 14.6(0.6) 19.8

333 49.9 38 14.59(0.62) 19.77

Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

9.9 76 950 1.06 Na 32.3 260 2.5 510 1350 N 17 5.2 36 0.38 0.38 3.6 Na 0 0 Na 0 Na

9.87 —b 689 0.91 16.23 258 1.3 558 1351 12.1 17 5.5 18 0.383 0.379 3.606 0.36 21 10 2.5 0 —b

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

The main nutritional interest of caraway (as with other herbs and spices) lies in its phytochemicals. Phytosterols (0.76 mg g−1, see Table 6.1) (presented here with the main nutrients) are of interest in nutrition for their cholesterol reducing effects, as evidence has shown 2 g per day is associated with a significant reduction in levels of low-density lipoprotein cholesterol (LDL-cholesterol) of 8–10%, which is linked to a reduction in cardiovascular disease risk.21 Plant foods, such as caraway seeds therefore may contribute to the 2 g per day dietary phytosterol recommended intake. There is little evidence on the effects of domestic processing on caraway and its constituents, so further research is warranted. The use of herbs and spices as natural antioxidants in processed foods has become more widespread. The presence of caraway was shown to reduce the total biogenic-amine (assessed by highperformance liquid chromatography) compared to control samples without an additive, in sauerkraut, during a fermentation process at 18 °C or 31 °C for 14 days, followed by storage of 12 weeks at 4 °C. Caraway essential oil possesses antioxidant, antifungal and antimicrobial activities22 and is used instead of synthetic antioxidants (butylated hydroxyanisole – BHA, butylated hydroxytoluene – BHT) for preserving food. The constituents of caraway essential oil were evaluated by gas chromatography–mass spectrometry (GC-MS), and then the oil was tested for its preservative capacity in cakes stored for 60 days at 25 °C.23 The major components were (Z)-anethole (26.34%), carvone (17.85%), limonene (15.45%), hydrocinnamyl acetate (8.29%) and carvacrol (6.68%). The rate of oxidation in cake with caraway oil was not significantly different from those with the commonly used synthetic preservative BHA at 0.02%; the authors suggested that the effect of the caraway oil may be due to the presence of carvone, limonene

and carvacrol. A concentration of 0.10% and 0.15% of caraway essential oil also prevented the growth of fungi without altering organoleptic (sensory) properties compared to controls, therefore caraway essential oil could be used as a natural preservative in food, especially foods high in lipids.

6.6

6.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

Caraway seed, root extract and its essential oil possess antioxidant capacity in vitro.10,24,28 Regarding its seed, the antioxidant capacity is much lower (approximately 30–100 times lower) than that of clove, and in the same magnitude as those of coriander (seed), parsley, cumin and ginger in vitro; the relatively low values are likely due to its relatively low total phenolic content. However, values varied based on the nature of the preparation and the antioxidant assay used.29,31 For the essential oil, the antioxidant capacity is reported to be high which is likely due to its flavonoids as well as other constituents, including linalool, carvacrol, anethole, estragole and monoterpene alcohols.24,32,34 Based on animal studies, evidence suggests that the antioxidant capacity of caraway essential oil and/or seed extract may confer protection against oxidative stress in diabetes, hepato- and nephro-toxicity, colon cancer, and oral mucositis via its antioxidant properties (see relevant sections below). Markers of antioxidant status improved and/or decreased in all the animal models of the conditions listed above, which are associated with oxidative stress. Markers of antioxidant status used included superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione S-transferase (GST), ascorbic acid and/or tocopherol (vitamin E). Markers of oxidative stress included thiobarbituric acid reactive species (TBARS), malondialdehyde (MDA), myeloperoxidase (MPO), conjugated dienes and/or lipid hyperoxides. Furthermore, the improvements in antioxidant status were associated with improvement in either organ (for example hepatic or renal) function, prevention of/amelioration of symptoms of sepsis, a decrease in the extent and severity of colon cancer lesions and improved histological parameters, including reduced oedema, ulceration and inflammation in the case of oral mucositis (redness and ulceration of the lining of the oral cavity) (see sections below Anti-inflammatory, Chemopreventive/Anti-cancer and Hepatoprotective Properties).35,41 It has also been suggested that caraway's antioxidant capacity may be of significance in the management of obesity (see section below on Use of Caraway in the Management of Obesity).

6.6.2

Anti-inflammatory Properties

Animal studies have been used to demonstrate caraway's, both its extracts (hydroalcoholic) and essential oil, ability to decrease inflammation in vivo. Using

animal models of inflammation, caraway is reported to decrease the levels of proinflammatory mediators, specifically the cytokines interferon gamma (IFN-γ), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α). Caraway is also reported to decrease the level of severity of colitis with an efficacy comparable to prednisolone (a steroid medication used to treat allergies as well as inflammatory conditions) and Asacol® (also known as mesalazine, a medication used to treat mild to severe Crohn's disease and ulcerative colitis, which are forms of inflammatory bowel disease (IBD)) and/or decrease the levels of inflammation of the intestinal mucosa and sub-mucosa.42,43 It is believed that a number of constituents within the caraway plant could contribute to its anti-inflammatory activity, including carvone, which is a terpenoid – a compound which is reported to inhibit the activity of inflammatory mediators including cyclooxygenase – flavonoids and its fatty acids.43 In addition, it is possible that caraway's antioxidant properties may also contribute to its anti-inflammatory properties, as indicated in the section above on antioxidant properties.43 The results of the colitis study led to the authors suggesting that caraway could be used as an alternative treatment for IBD, and although clinical trials have not yet been carried out, some have been done to determine the therapeutic efficacy of caraway on those with irritable bowel syndrome (see section below on Use of Caraway in the Management of Irritable Bowel Syndrome (IBS)).43 Caraway's anti-inflammatory activity may also have a role to play in the management of obesity (see section below on the Therapeutic Potential of Caraway in the Management of Obesity, Functional Dyspepsia and Irritable Bowel Syndrome).

6.6.3

Glucose-lowering, Anti-diabetic and Lipid Lowering Properties

There is in vitro evidence of the effects of caraway on the glycation of haemoglobin (a biomarker of diabetes that can lead to the vascular complications that result from this disease).44 Naderi et al. 44 investigated the anti-glycaemic effects of caraway extract (methanol) in vitro via their anti-glycating activity. They reported that caraway was a very potent anti-glycation agent. In fact, it was more potent than extracts of black pepper, cinnamon, clove and turmeric. It was suggested by the authors that the antioxidant properties of the spices might play a role in their anti-glycating activity, particularly as hyperglycaemia gives rise to oxidative stress.45,46 It was also suggested that the metal-chelating properties (the ability to form tight bonds with metals) of the spices have a role to play. The glucose lowering, anti-diabetic and lipid lowering properties of caraway extract in animal models (normal and diabetic) have also been reported in the literature.47,49 Eddouks et al. 47 reported that aqueous caraway seed extract significantly lowered blood glucose levels in diabetic rats, with the levels of blood glucose normalising 2 weeks after receiving the extract. However, no significant decrease occurred in the blood glucose of normal rats, and furthermore the caraway extract had no significant effect on the blood insulin levels of the normal and diabetic rats, thus suggesting that the glucose lowering effect of caraway was insulin independent.

Lemhadri et al. 48 reported that aqueous extract of caraway significantly decreased lipid levels – cholesterol and triglyceride (TG) – in both normal and diabetic rats. Haidari et al. 49 reported that caraway extract also significantly lowered blood glucose, total cholesterol and low density lipoprotein cholesterol (LDL-C) in diabetic rats. However, it had no significant effect on TG and high density lipoprotein cholesterol (HDL-C) levels. Sadjadi et al. 50 reported that aqueous caraway extract lowered total cholesterol, LDL-C, the LDL-C/HDL-C ratio (an atherogenic index, which is used as a marker of abnormal lipid levels and an indicator of risk of developing cardiovascular disease) and blood glucose; the levels were lower than in the untreated diabetic rats.51,53 However, the extract had no effect on the levels of C-reactive protein, which is a marker of inflammation, in the diabetic rats which contrasts with the evidence concerning caraway's antiinflammatory effects reviewed above. The inflammatory process is a complex one with a number of different mediators so it may be that caraway only acts on certain mediators and/or inflammation that arises as a consequence of specific conditions. Caraway essential oil is also reported to lower blood glucose in an animal model of diabetes.37 In addition, it also improved antioxidant status supporting the suggestion above that caraway's glucose lowering/anti-diabetic effect is mediated via its antioxidant action against the oxidative stress caused by hyperglycaemia.37,45,46 In an earlier study, Ene et al. 54 reported that caraway oil lowered fasting blood glucose and 2 h postprandial glucose in diabetic rats. It was suggested that the oil mimics the action of insulin via increasing glucose uptake and utilization, and that such a mechanism could be due to the oil's medium chain fatty acids and their (the fatty acids) possible effect (an increase) on resting glucose oxidation. However, it is not entirely clear if they actually used oil from caraway as they state that black caraway was used but then used the botanical name for caraway (Carum carvi). Black caraway and caraway are not the same spice. The former's botanical name is Bunium pericum Boiss. The lipid lowering effects of caraway demonstrated in animals may be of therapeutic significance, specifically with regards to the management of obesity (see section below on the Therapeutic Potential of Caraway in the Management of Obesity, Functional Dyspepsia and Irritable Bowel Syndrome).

6.6.4

Chemopreventive/Anti-cancer Properties

Caraway seed, its extracts and its essential oil, exhibit anti-cancer and also antimutagenic activities in vitro and/or in vivo, the latter in animal models. In an early study, Shwaireb55 reported that in mice with chemically induced skin tumours, when fed a diet supplemented with caraway oil or had caraway oil applied to their skin, skin carcinomas decreased in number, and the growth, development and number of papillomas (benign tumours) also decreased. The authors reported that topical application was more effective than consumption via the supplemented diet. In a later study, Shwaireb et al. 56 reported that consumption of caraway seeds protected rats from the development of chemically induced mammary gland tumorigenesis (breast cancer). The mean number of tumours, as well as the percentage of rats with tumours, were significantly decreased in rats fed the caraway supplemented diet. In addition, there was a significant increase in the mean

latency period of tumour appearance in these rats. In both studies, carcinogenesis was induced by 7,12-dimethylbenz(alpha)anthracene (DMBA) (a polycyclic aromatic hydrocarbon, which forms DNA adducts which can result in DNA mutation; this chemical can thus act as an initiator of carcinogenesis – the cancer process).57,58 Furthermore, DMBA can give rise to increased lipid peroxidation, which may contribute to carcinogenesis via the action of reactive oxygen species (ROS) on DNA.58,59 Both studies, therefore, and studies carried out in vitro, provide evidence of a mechanism of action of caraway that involves an antimutagenic effect/its ability to inhibit the formation of DNA adducts, including those caused by ROS, although the former activity may be selective for some, and not all, mutagens.60,62 Kamalesswari and Nalini38 reported improved antioxidant status in rats with chemically induced colon cancer following consumption of a caraway supplemented diet for 30 weeks, with the 60 mg kg−1 of body weight dosage having the optimal effect. This dose, as well as decreasing oxidative stress, also had an optimal effect on suppressing aberrant crypt foci (ACF) formation, which can lead to the development of colorectal cancer.63 Dadkhah et al.41 reported a similar effect of caraway essential oil on ACF in vivo in colon cancer rats, however they did not report any impact of the oil on antioxidant status and lipid peroxidation. What they did report was the inhibition of the phase 1 enzyme cytochrome P450 isoenzyme hepatic P4501A1 (CYP1A1) and activation of the phase 2 detoxification enzyme hepatic glutathione S-transferase (GST). Both enzymes are involved in the activation and removal of pro-carcinogens respectively.64 The activation of detoxifying enzymes, including GST, by constituents of caraway oil, including carvone, in vitro is reported in the literature.65 This possible route via which caraway acts to prevent and/or inhibit carcinogenesis is further reinforced by a study by Aqil et al. 66 in which a diet supplemented with caraway (powdered seeds) given to female rats before they were given oestrogen to induce mammary tumorigenesis, inhibited the expression of cytochrome P450 isoenzymes CYP1B1 and CYP1A1 in these rats. Oestrogen metabolites that result from the action of these enzymes have been linked to breast cancer.67 In addition, caraway inhibited other elements of oestrogen mediated mammary tumorigenesis, including expression of cyclin D1 (overexpression of this protein, which is involved in regulating progression through the cell cycle, is linked to cancer68) although this decrease was not significant, oestrogen mediated mammary cell proliferation, and oestrogen receptor expression, which plays a key role in mediating the effects of oestrogen and agents used to treat breast cancer. It therefore serves as an effective marker of treatment efficacy.69 Caraway also lowered circulating levels of oestrogen and prolactin; exposure to high levels of both increases the risk of developing breast cancer, although for prolactin this appears to be the case for post menopausal breast cancer and breast cancers that are oestrogen receptor and progesterone receptor negative.70,71 In addition to studying the effect of caraway on the development of skin, breast and colon cancer in animals, some recent work has reported the antiproliferative effect of caraway seed extract on human prostate cancer cells in vitro. Lackova et al.,72 following an investigation of the effect of extracts (methanol) of a number of

culinary herbs and spices, including caraway, on immortalized normal adult prostatic epithelial (PNT1A), androgen independent (PC3) and androgen dependent (22RV1) prostate cancer cells, reported that caraway had the most potent inhibitory effect on these cells. They also identified the polyphenol neochlorogenic acid as a possible candidate for caraway's anti-proliferative effect.

6.6.5

Hepato- and Nephro-protective Properties

Caraway seed extracts (hydroalcoholic) and essential oil confer protection against liver and kidney damage/toxicity associated with increased oxidative stress. A small number of animal studies35,39,41,73,74 have reported decreased renal and/or hepatic damage alongside improvements in/normalization of markers of liver and/or kidney function, including the liver function enzymes aspartate amino-transferase and alanine aminotransferase (although in the study by Dadkhah et al.,74 no normalization of alanine aminotransferase and alkaline phosphatase was reported in response to the administration of caraway essential oil), and creatinine and urea. Improvements in antioxidant status, based on increased reduced glutathione (GSH) levels and total antioxidant capacity (although no increase in plasma antioxidant capacity was reported by Dadkhah et al. 74), and/or decreased oxidative stress, based on a lowering of lipid peroxidation, were also reported.

6.6.6

Anti-convulsant and Anti-epileptic Properties

A lone study by Showraki et al. 75 studied the anticonvulsant/antiepileptic effect of caraway based on its traditional use in Iran, which is steeped in ancient and folk medicine and also social beliefs.76 Aqueous extracts of caraway seeds and its essential oil given to a murine (mouse) model of chemically induced seizures had a dose-dependent effect on delaying the onset of seizures, specifically myoclonic (muscle) and clonic (rhythmic) seizures. Both forms of caraway prevented tonic seizures (tensing of body, arm and/or legs). There was no evidence that these effects were mediated via a muscle relaxant activity. The essential oil was shown to be more potent and more effective than the aqueous extract.

6.6.7

Diuretic Properties

As with the anti-convulsant study, research on caraway's diuretic effects is based on its traditional use, this time in North Africa, specifically Morocco. Lahlou et al. 77 reported that aqueous extract of dried and powdered caraway seed, given to rats, significantly increased urine output after a single dose. After 24 h the total volume of urine excreted was similar to that for rats given the diuretic drug furosemide, alongside an increase in the urinary levels of both potassium and sodium for caraway (the furosemide increased urinary sodium and decreased urinary potassium). Further investigations suggest that the spice may act via a mechanism similar to that of furosemide.

6.6.8

Effect on Reproductive Organs

The claim in Egyptian folk medicine that caraway modulates female fertility, and its traditional use as an anti-fertility agent in Indian tribes, formed in part the bases for studies by Thakur et al. 78 and Abdel-Wahab et al. 39 The former study reported that for female rats given ethanol or aqueous extracts of powdered caraway seeds, oestrogen levels increased and follicular stimulating hormone (FSH), which stimulates the production of ovarian follicles, and luteinizing hormone (LH) levels, which triggers ovulation, decreased significantly. The preparations also blocked the oestrous (ovulating) phase and significantly increased the ovary and uterus weight of these animals. These results were similar to those of the drug ethinyl estradiol, which is used in contraceptive pills. The results suggested to the authors that caraway showed oestrogenic effects, with the inhibitory effect on FSH and LH possibly due to caraway increasing the levels of oestrogen in these animals as oestrogen regulates follicle maturation via a feedback mechanism, which results in the suppression of FSH and LH and subsequently ovulation. Abdel-Wahab et al. 39 reported similar findings: a diet supplemented with aqueous extract of powdered caraway consumed by female rats increased oestrogen, and decreased progesterone and FSH levels (it had no effect on LH) at the proestrus phase (when pre and peri-ovulatory development in the ovaries takes place in nonhuman female mammals). In addition, treatment with the caraway extract resulted in follicular and granulosa cell degeneration.

6.6.9

Impact on Drug Bioavailability

Caraway is reported to alter/affect the disposition of a number of drugs in animals and humans. Intraperitoneal (i.p.) administration of caraway oil for 5 days increased exposure of mice to paracetamol. However, in contrast, oral administration of the oil decreased exposure to paracetamol.79 Caraway seed extract (100 mg in a capsule) increased the plasma levels of the anti-tuberculosis drugs rifampin, isoniazid and pyrazinamide in rats and also healthy volunteers.80,81 This effect did not appear to be due to mucosal toxicity as there was no evidence of membrane damage. However, ex vivo studies (done using jejunum taken from rats given caraway seed extract) suggested that the butanol fraction of the extract may enhance/influence intestinal permeability and thus the bioavailability of these drugs.80 Caraway may also inhibit the absorption of a drug used to treat hypothyroidism – levothyroxine, which is used to replace thyroid hormone (T4) and subsequently triiodothyronine hormone (T3) in those who have hypothyroidism. A case report from Iran in which caraway was reported to be responsible for increasing thyroid stimulating hormone (TSH) in a patient with advanced cancer of the thyroid gland who had their thyroid gland removed and was receiving levothyroxine,82 led to a very small clinical trial of the effect of caraway on thyroid status. Capsules of powdered caraway (1800 mg per day, divided into 3 and taken for 6 weeks by a participant with a history of hypothyroidism and taking levothyroxine) increased TSH levels but decreased T3 and T4 despite the fact that TSH stimulates the production of T4 and T3. When caraway consumption was stopped but levothyroxine continued, TSH levels decreased and T3 and T4 levels increased, suggesting some form of interference of the bioavailability of the drug by

caraway.82 Interestingly, in rat studies, caraway seed extracts (hydroalcoholic) decreased TSH significantly at 1600 mg kg−1 of body weight given for 45 days but increased both T4 and T3 at 800 and 1600 mg kg−1 of body weight, again given for 45 days. The body weight of the rats also decreased significantly at 800 and 1600 mg kg−1 of body weight for 45 days. In light of these effects, it is possible that when used for the purposes of weight loss, caraway promotes a hyperthyroid state in those who are euthyroid (have normal thyroid function).

6.6.10

Therapeutic Potential of Caraway in the Management of Obesity, Functional Dyspepsia and Irritable Bowel Syndrome

6.6.10.1 Use of Caraway in the Management of Obesity Caraway is recommended for weight loss in traditional Iranian medicine. In their review on the medicinal properties of caraway, Mahboubi24 states that obese patients are recommended to use 20 mL of caraway water or distillate (extract) of caraway, twice, with 5 g of Safoof-e-Muhazzil – a formulation investigated for its reported lipid lowering and anti-hypertensive effects.83 Clinical trials have therefore investigated the efficacy of caraway in the management of obesity. Kazemipoor et al. 84 in a triple blind randomized placebo controlled trial (also referred to as a randomized controlled trial – RCT) gave caraway aqueous extract (30 mL per day) for 90 days to physically active, overweight and obese women (who did moderate aerobic training for 180 minutes a week); the placebo was 30 mL per day of edible caraway essence dissolved in water. The intervention significantly decreased body weight, body mass index (BMI), percentage body fat and waist to hip ratio (WHR), which can be used as a predictor of cardiovascular disease risk,85 compared to the placebo however there was no change in lipid profile (in contrast to the findings of the animal studies discussed above). There was also no change in blood pressure.84 The main constituents of the caraway extract were known bioactive compounds including limonene, γ-terpinene, trans-carveol, carvone, thymol and carvacrol. Although it is unclear how exactly they contributed to the effects of the caraway intervention, the authors suggested that the effect on body weight and body fat could be linked to their anti-inflammatory and antioxidant activities. There is also evidence that some of the constituents of caraway could reduce fat, specifically adipose tissue mass, via induction of the apoptosis of preadipocytes, inhibition of adipogenesis (production of adipocytes) and enhancing lipolysis (TG breakdown) in adipocytes.86,89 The authors of this study also linked the effects reported to the anti-microbial effects of caraway although it is not clear how such a property would contribute to weight loss. In another study by Kazemipoor et al.,90 in which the same extract, at the same amount and for the same duration, was used, the appetite and carbohydrate intake of aerobically trained overweight and obese women decreased, compared to the placebo. The intervention also resulted in significantly decreased waist, hip and thigh circumferences, WHR and mid upper arm circumference. Again, the authors

linked the mechanism of action to the bioactive compounds listed above. The authors also speculated that as caraway is used as a digestive aid and is reported to be of therapeutic benefit in the management of disorders of the GI tract91 (see section on the Use of Caraway in the Management of Dyspepsia) it could elicit a probiotic or prebiotic effect. Such a point might be valid, especially as there is growing evidence of the role of gut microbiota in the development and prevention of obesity.92 However, although there is evidence of the prebiotic effect of some culinary herbs and spices, there is currently no information concerning caraway.93,94

6.6.10.2 Use of Caraway in the Management of Dyspepsia Caraway's use as a digestive aid is recommended in Middle Eastern (including Iran and Jordan) and North African (Morocco) countries as a traditional medicine. It is also reported to be used for this purpose in Europe (Poland and UK) and the US.25,90 This traditional use, and evidence that caraway proved to be an effective analgesic in relieving visceral pain brought on by functional gastrointestinal conditions, are likely to have, in part, formed the basis for a number of clinical trials investigating the efficacy of caraway in the management of functional dyspepsia (FD), a gastrointestinal disorder which gives rise to epigastric pain (pain localised to the upper abdominal region of the gut), bloating, flatus and heartburn.95 These trials have investigated the efficacy of caraway in combination with peppermint oil or its constituent l-menthol. A small number of preliminary clinical trials investigating the efficacy of caraway oil in combination with either peppermint oil or menthol have been summarised in the review by Mahboubi.25 The studies reported that the combinations 50 mg of caraway oil and 41.5 mg of peppermint oil, or 50 mg of caraway oil and 90 mg of peppermint oil, or 25 mg of caraway oil and 20.75 mg of menthol, were effective in relieving/improving symptoms of FD following treatment for up to 4 weeks.96,102 Furthermore, in a double blind multi-centered RCT using a multi-herbal formulation, STW 5-II (also referred to as Iberogast®), which contains caraway (and also peppermint leaves, liquorice root, lemon balm, bitter candytuft and matricaria flower), patients with FD who took the formulation reported improvements in gastrointestinal symptoms at 4 and 8 weeks of taking the formula compared to those who received the placebo.103 The ability of constituents of caraway to modulate gut motility, and also their antioxidant and antiinflammatory properties have been suggested to contribute to the effect of this formulation.104 In a recent systematic review and meta-analysis of the efficacy of caraway and peppermint oil/menthol combinations Li et al. 105 reviewed a small number of studies that were placebo controlled multi-centered RCTs all with a duration of 4 weeks.98,106,109 The combinations were 25 mg caraway and 20.75 mg of menthol (equivalent to 50 mg of peppermint oil) (combination 1) or 50 mg of caraway oil and 90 mg of peppermint oil (combination 2). All were provided in capsules, which were given as follows: two capsules twice daily (combination 1), one capsule twice daily (combination 2), one capsule per day (combination 2) or one capsule three

times a day (combination 2). Li et al. concluded that the combinations were effective for short term treatment. It was suggested that caraway's antiinflammatory properties and also its ability to inhibit the formation of gastric ulcers in rats (at dosages of 100–300 mg kg−1 of body weight) could have contributed to the positive outcomes of these studies.43,110 However, although there was no significant heterogeneity between the studies, the small sample sizes (45–228 participants), the varied criteria for diagnosing FD, the lack of clarity over whether all of the studies excluded patients with IBS (as there is evidence of a beneficial effect of caraway oil in patients with IBS (see section below)), the small number of RCTs reviewed and analysed, issues with randomization and allocation concealment of the interventions and placebos, which could give rise to selection bias, and reporting bias concerning the possibility of selective reporting (which affected the quality of all the studies) limit the significance of these conclusions. It is therefore clear that bigger studies of longer duration are required to establish more fully the therapeutic significance of caraway oil in the management of FD.105

6.6.10.3 Use of Caraway in the Management of Irritable Bowel Syndrome (IBS) Evidence concerning the clinical efficacy of caraway in the management of IBS, a condition with a number of symptoms, the main ones being diarrhoea, constipation, bloating, abdominal pain, and stomach cramps, is limited. Lauche et al.,111 in an open label crossover RCT, reported that when applied as a hot poultice (a crude or fresh herb/spice preparation applied to the skin) by patients with diarrhoea IBS for 3 weeks followed by a 2 week washout period and the application of hot and cold olive oil poultices, the patients reported a significant difference in symptom severity with the caraway poultice compared to the cold olive oil poultice only. Although it was unclear if the effectiveness reported was due to caraway or the use of caraway as a hot poultice, it is possible that via its gut motility modulatory properties that caraway could elicit a beneficial effect.104 Based on the current evidence, it is clear that the therapeutic potential of this spice with regards the management of IBS requires further research.

6.6.11

Antimicrobial Properties

The antimicrobial activity of caraway essential oil and also its seed extract has been demonstrated in vitro against bacteria and fungi pathogenic to humans. The polyphenolic constituents of caraway may contribute to its antibacterial activity. In addition, a major constituent of caraway essential oil, limonene, appears to contribute to caraway's antibacterial and antifungal activity. However, evidence suggests that there may be a negative correlation between the amount of another constituent, carvone, and the antibacterial activity of caraway.112

6.6.11.1 Anti-bacterial Activity Regarding bacteria, caraway essential oil acts against pathogenic gram-negative bacteria including Escherichia coli (O157:H7), uropathogenic E.coli, Helicobacter

pylori, Pseudomonas aeruginosa and Salmonella typhimurium, and gram-positive pathogenic bacteria, including Listeria innocua and Staphylococcus aureus. Hydroalcoholic extract of caraway inhibited the growth of Staphylococcus epidermidis and Streptococcus intermedius in the animal model of oral mucositis discussed above.113,117 Thus, the beneficial effects of caraway in this animal model are not limited to its antioxidant property.40 Ethanol extract of the seed showed little to no inhibition of Clostridium botulinum.118

6.6.11.2 Anti-fungal Activity Caraway essential oil also inhibits pathogenic and toxigenic (toxin producing) fungi, including Candida albicans and species of Aspergillus including Aspergillus niger.113,117,119 In addition, powdered caraway seed is reported to inhibit, partially, the growth of Aspergillus ochraceus and completely inhibit the production of its mycotoxin, ochratoxin.120 However, caraway essential oil has also been shown not to affect the growth of Aspergillus parasiticus despite inhibiting the production of its mycotoxins aflatoxin B1 and aflatoxin G1.121

6.7

Safety and Adverse Effects

The Council of Europe classified caraway fruit as a ‘natural source of flavouring category 1, i.e. plant parts or products thereof, normally consumed as food items, herbs or species in Europe for which it is considered that there should be no restriction on use’ (cited in the assessment report (July 2015) of the European Medicines Agency (EMA)).122 Regarding caraway oil, the EMA states that it can be used in cosmetics. However, at the time of the assessment there was no information available concerning the safe amount of the oil in cosmetics. In traditional Iranian medicine, caraway is recommended for weight loss but it is reported that long term use can lead to symptoms associated with hyperthyroidism including increased hair loss, sweating and increased body temperature as well as tremors.25,82 A study on the safety and efficacy of caraway aqueous extract and a study on the effect of caraway oil and peppermint oil on gastric emptying, gall bladder emptying and small intestine transit in healthy human subjects, reported no serious/significant adverse effects.84,90,105,111,123,124 In their assessment of the safety of caraway aqueous extract, Kazemipoor et al. 123 reported no adverse effects of significance when aqueous extract of caraway (30 mL) was consumed daily for 12 weeks. In addition, heart rate and blood pressure were not affected. However, the red blood cell count increased significantly and platelet distribution width (which is an indication of platelet size) decreased significantly compared to the placebo group but there was no significant difference between the intervention and placebo groups when it came to their general health. In their systematic review and meta-analysis of the efficacy of caraway oil in combination with peppermint oil or menthol, Lin et al. 105 noted that studies reported adverse effects that were not serious. These included nausea and belching

but there was no significant difference in these events between the interventions and the placebo. In the study by Lauche et al.,111 one adverse effect, a gastrointestinal infection, was reported during the caraway poultice intervention phase. There is some evidence that caraway may give rise to allergic reactions. Cross reactivity (where an antibody specific to one allergen, recognizes other allergens due to structural similarities), based on specific IgE results, has been identified between caraway and other members of the Apiaceae family (aniseed, dill, coriander, carrot and celery). The EMA states that due to the cross reactivity between caraway and other spices and plant foods from the same family, its use is contraindicated in patients with allergies to these foods. However, the clinical significance of this cross reactivity is unclear. Positive skin prick tests and specific IgE to spices from the Apiaceae family have been reported in patients with allergies to birch pollen and mugwort pollen.125,127 Although there have been reports of symptoms arising due to such cross reactivities, these are mild and not that frequent.126 The use of caraway for medicinal purposes may give rise to adverse effects. According to the EMA there have been a small number of spontaneous reports of suspected adverse drug reactions associated with caraway or its oil.121 Due to the inhibitory effect of caraway oil in combination with peppermint oil on gall bladder emptying in healthy human subjects, the EMA advises that caraway should not be used in patients with biliary diseases including gallstones, liver disease and inflammation of the bile duct system. Regarding the use of caraway in children, for children under the age of 12, oral use of the fruit has not yet been established by the EMA due to the lack of adequate data and therefore its use in this group cannot be recommended. The same applies to the oral use of caraway oil in those under the age of 18, and this is also due to the lack of adequate data. Furthermore, although there are no data concerning the safety of the medicinal use of caraway fruit and oil during pregnancy and lactation, their use is not recommended, again due to a lack of sufficient data. The EMA concluded in its 2015 assessment that the genotoxicity, carcinogenicity, reproductive and developmental toxicology of caraway fruit and oil have yet to be fully evaluated; although there is no evidence to date of its genotoxicity and carcinogenicity (based on in vitro and animal studies).60,128,132 A call for scientific data as part of the periodic review of the EMA's assessment of caraway fruit and oil went out on 31/01/20. The call closed on 30/04/20.

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CHAPTER 7

Cardamom – Small Cardamom, Green Cardamom, True Cardamom, Ceylon Cardamom, Malabar Cardamom (Elettaria cardamomum) 7.1

Names

English: Cardamom Armenian: Shooshmir, shushmir and andritak French: Cardamome Hindi: Choti Tamil: Elakkai Tibetan: Sug smel and sugme Cardamon, the name, comes from the Latin cardamomum, which is from the Greek kardamomon, kardamon meaning cress and amomon meaning the spice plant.1

7.2

Taxonomy

Order: Zingiberales Family: Zingiberaceae Genus: Elettaria Species: Elettaria cardamomum2

7.3

Origin, Description and Adulteration

Cardamom is a sub-tropical evergreen perennial (long-lived plant) indigenous to the Himalayas, and an ecologically friendly spice crop.3 It is referred to as the ‘Queen of Spices’ in India, and is a zingiberaceae, as are ginger and turmeric.4 Cardamom,2 produces upright shoots with long, narrow, dark green leaves and thick rhizomes 1.5–2.5 m high and 1.5–2.5 m wide, and is fully grown in 5–10 years. Cardamom requires tropical conditions to fruit but can grow lush foliage under glass. It grows best in fertile, moist, well drained loam-based soil with partial shade and with high humidity. It is cultivated at an altitude of 600 m to 1200 m above sea level with 1500 mm to 4000 mm annual rainfall and temperatures of 10 °C to 35 °C.3 In summer, white and orchid-like flowers bloom with purple, pink or

yellow markings. The fruits are small pods, aromatic, and light green with a characteristic scent, described as camphoraceous, sweet, aromatic and spicy with a warm, slightly pungent taste.4 Cardamom is generally pest free and disease free, although it may be affected by thrips (minute insects) and viral infections. Cardamom has one of the highest price tags among spices, after saffron and vanilla.4 Adulteration of cardamom seeds has been reported with Amomum aromaticum, A. subulatum and cardamom powdered hull. Cardamom fruits have been adulterated with orange seeds, unroasted coffee seeds and small pebbles. India was the largest producer, consumer and exporter of cardamom until 1980,5 after which the monopoly was taken over by Guatemala, where the crop was introduced in 1920.6

7.4

Historical and Current Uses

Cardamom is an ancient spice and medicine with evidence of use dating back to the 4th century BCE in India (its birthplace) where it is an integral part of ethnomedicine and spiritual practices, and in the Middle East. Cardamom was grown in the royal gardens of Babylon in 721 BCE and featured in an Egyptian papyrus as early as 1550 BCE concerning its medicinal uses. The ancient Greeks and Romans also used it as a spice, medicine and also perfume. The Scandinavians, who still use cardamom today in traditional food, were introduced to the spice when Vikings discovered it in India.3 Cardamom was imported to Europe in 1214, where it was used in pomanders (small decorated vessels with holes that held fragrant blends mixed with beeswax or clay, they were worn as a pendant around the neck or the belt) and as an aphrodisiac. Nicolas Culpeper, a 17th century English physician and botanist, assigned cardamom to Venus, although others have ascribed it to Mars, describing it as warming and stimulating.7 It can be found in love and protection charms, and is said to uplift the spirits, calm the nerves, and help clarify thinking.3 The ancient Roman author Pliny the elder (23/24–79 CE), reported that cardamom was an ingredient in the Egyptian perfume Metopium (which was made with Egyptian almond oil, green olive oil, rush juice, reed juice, cardamom, honey, wine, myrrh, balsam seeds and galbanum and terebinth tree aromatic resins), with which Cleopatra was thought to be obsessed.8 The Romans combined cardamom scent with saffron and myrrh in their perfumes.9 Cardamom oils are still used nowadays in formulations of plant-based hand creams and soaps.10 Cardamom is mentioned in the Apicius Roman cookbook as one of the “spices that should be in the house on hand so that there may be nothing wanting”, which suggests it was desirable. Cardamom was used as an alternative spice to flavour meatballs and was a component of Oxigarum, an aid to digestion, (similar to garum) which contained black pepper, Silphium (a plant, now extinct, with a powerful sulfurous smell, the root was called laser root), cumin and dry mint, mixed with honey, broth and vinegar.11 Northcote's (1903) the Book of Herbs does not mention cardamom, nor does the Book of Ancient Herbs by D'Andrea (1982),12,13 suggesting it was not always popular in Europe.

Cardamom is used in Indian cuisine as an essential ingredient in Garam Masala (masala meaning spice mix) and is commonly chewed after a spicy meal to freshen the breath and aid digestion. In the Middle East, cardamom is used as an aphrodisiac. Scandinavians use cardamom to flavour “Danish pastry” and other patisseries, and also meatballs. Cardamom is also used in German cookies. It can be added to jellies and marmalades and is drunk as a simple tea and added to flavour coffee. Hot milky turmeric and cardamom or warm honey cardamon are popular soft drinks in India. It is not uncommon to be offered cardamom flavoured sweets or cardamon pods mixed with sweets as part of religious celebrations such as Diwali (festival of light). Indian winter (cardamom syrup, vodka, egg white, star aniseed and lemon juice) and cardamon blush/cardamom rose cocktail, with grapefruit, cardamom and gin or vodka are popular alcoholic drinks.3 Descriptions of oral hygiene practices using cardamom date back to the Sumerians in 3000 BCE, and an ancient text of India (the Charaka Samhita) has descriptions of toothbrushing using a chewed frayed stick called “Dantashakti”, as prescribed by Sushruta (an ancient Indian physician from 600 BCE), containing astringent, pungent or bitter compounds (and used twice a day). Teeth cleaning was also done with betel leaves, camphor, and cardamom.14 Seeds were chewed to avoid bad breath and to help with vomiting and indigestion. In Ayurvedic medicine, cardamom seeds are boiled in milk sweetened with honey to make a drink to treat impotence and depression. In addition, inhalation of steam produced from boiling cardamom is used to treat headaches.15 In Ayurveda, spices/fruits of Elettaria cardamomum (L.) Maton (Green cardamom in India), and Amomum subulatum Roxb. (Black cardamom in India) are both used to improve digestion. Cardamom is an essential component of the traditional Betel Quid (which is similar to chewed tobacco), and there are cardamom flavoured smoking cessation gums.14 Cardamom seeds are used to reduce the caffeine constituent in coffee Gahwa which is a popular Arabic remedy for headaches and stress.10 In Tibetan traditional medicine, cardamom capsules blended with cinnamon and long pepper are used to treat obesity, glycemic imbalance, liver, kidney and heart disease. Eladigana is a cardamom herbal preparation used to cure arthritis, congestion and itching, and for treating skin diseases in children.16 In traditional Chinese medicine, false cardamom – Bai Dou Kou (Amomum aromaticum) –is used but not E. cardamomum. A. aromaticum is considered warming, and is known for promoting energy flow and circulation, dispersing cold, resolving dampness, and clearing phlegm. It is thought to help with the meridians of the lung, stomach, spleen.17 Cardamom was incorporated into European medicine during the Renaissance. A recipe for a vaginal suppository designed to induce abortion (from the ancient Greek physicians Dioscorides and Soranus) included cardamom crushed with sulfur, wormwood, myrrh, mold and water.18 Cardamom was also a common flavouring for masking bitter botanical medicines in the 19th century.10 The United States Department of Agriculture (USDA) granted cardamom a Generally Recognized as Safe (GRAS) certification when used as food and granted cardamon seed essential oil GRAS certification when used as a food additive.19 Cardamom features in the list of approved spices for herbal medicines in the German Commission E monographs,20 is indicated for dyspepsia with a daily

amount of 1–2 g, and it is contraindicated for those with gallstones. It does not feature in the monographs' extended version.

7.5

Chemistry, Nutrition and Food Science

Phenol Explorer21 provides data showing that cardamom contains the phenolic acids p-coumaric and protocatechuic acid. Cardamom's aroma is due to another class of phytochemicals, the terpenes ether, 1,8-cineole, and esters, oc-terpinyl and linalyl acetate. Seeds of cardamom contain 6–8% essential oil, in contrast, seeds of black/false cardamom (Amomum subulatum) contain less than 3.5% oil and have a harsh camphor aroma.4 With regards to the nutritional quality of cardamom, it is generally considered to be poor in the energy yielding nutrients (carbohydrate, fat, protein). Its other nutrient values (see Table 7.1) have to be considered with the proportion of spice used in the diet, often a pinch or two of ground cardamon. Nevertheless, cardamom can be considered rich in a number of nutrients including magnesium (2.3 mg g−1), iron (1 mg g−1) and potassium (11.2 mg g−1), see Table 7.1.22 The USDA database provides nutritional values for cardamom per 100 g ground spice, energy 311 Kcal, carbohydrates 68.47 g, dietary fibre 28 g, fat 6.7 g (of which 0.68 g is saturated), and protein 10.76 g.23 Table 7.1

Nutrition composition of ground cardamom.22 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0

Cardamom (100 g)

Ground (UK data)

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg

Na Na Na 6.7 (Na) 10.8 8.3 46 130 1.3 Na 100 230 8.9 170 1120 Na 18 2.6 0 0.2 0.18 Na Na

Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

0 0 Na —b Na

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

However, the main nutritional interest of cardamom (as with other herbs and spices) lies in its phytochemicals. Phytosterols, presented here with the main nutrients (see Table 7.1), are of interest in nutrition as evidence has shown that 2 g per day is associated with a significant reduction in levels of low-density lipoprotein cholesterol (LDL-C) of 8–10%, which is linked to a reduction in cardiovascular disease risk.24 Cardamom (0.46 mg g−1, see Table 7.1) therefore it may contribute to the recommended 2 g per day of dietary phytosterol intake. The effects of cooking and food processing on constituents of cardamom have been poorly reported in the literature and warrant further research. However, there is evidence of the impact of different extraction methods on the quality of cardamom essential oil.25 Work to improve food flavour by encapsulating cardamom's essential oil has been investigated. One study used spray dried encapsulation of the essential oil, and another study used food grade nano-structured lipid carrier of cardamom essential oil with cocoa butter, both showed promising results.26,27 The antimicrobial effect of cardamom seed and essential oil has been demonstrated.10 A study showed cardamom seed extract was effective against a panel of food borne microorganisms with the best results (in descending order) for Staphylococcus aureus, Salmonella typhimurium, Candida albicans, Mycobacterium smegmatis and Micrococcus luteus.28 Positive results were obtained in improving the shelf life and reducing microbial growth in chilled meat for up to 12 days using cardamom essential oil (0.25%, 0.5% and 1%), with better results with higher concentrations.29 Essential oil of black/false cardamom (Amomum subulatum) was shown to be effective in controlling spoilage due to microorganism growth when added to sweet orange juice, which remained nontoxic and safe, and therefore the oil is thought to be an acceptable alternative to chemical preservatives.30

7.6

7.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

Cardamom, namely its pods, seeds and essential oil, has been shown to possess antioxidant capacity in vitro with actual values varying due to the nature of the

preparation and the antioxidant assay used.10,31,37 When compared to the antioxidant capacities of other culinary herbs and spices, cardamom's ranking is low.31,38 Some studies suggest that cardamom's antioxidant properties may be of significance in the prevention and/or management/treatment of some chronic noncommunicable diseases, including type 2 diabetes (T2D), cardiovascular disease, obesity and other conditions associated with abnormal/high lipid levels, including metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD),39,40 and also conditions that cause liver damage, and certain cancers (see sections below on Anti-inflammatory Properties and Glucose Lowering, Anti-diabetic, Lipid Lowering and Other Cardioprotective Properties).

7.6.2

Anti-inflammatory Properties

Studies in vitro have demonstrated the anti-inflammatory, and also immunomodulatory, activity of cardamom.41 Majdalaweih and Carr reported that cardamom extract (aqueous) of dried and ground seeds inhibited the release of proinflammatory cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFα) from stimulated murine macrophages.42 Cardamom increased the proliferation of unstimulated and stimulated splenocytes, which consist of a variety of white blood cells including T and B lymphocytes, dendritic cells and macrophages, in a dosedependent manner following 24 and 72 h of exposure. Cardamom also inhibited the release of nitric oxide (NO) a pro-inflammatory mediator but from stimulated macrophages only.43 Cardamom, also in a dose-dependent manner, increased and inhibited, respectively, the release of the T helper cell type 2 (Th2) cytokines, interleukins 4 and 10 (IL-4 and IL-10), and the T helper cell type 1 (Th1) cytokine, interferon gamma (IFN-γ) from splenocytes (stimulated and unstimulated for the Th2, and stimulated only for the Th1). Interestingly, cardamom enhanced the cytotoxic action of natural killer (NK) cells, which are known to play a role in the early detection and control of cancer, and are able to kill cancer cells.44 The authors of this study put forward eugenol, a constituent of cardamom, as a main contributor to the actions of cardamom in this study, as it is reported to be able to modulate the immune response, is anti-inflammatory and can activate NK cell activity.45,48 Another constituent that may be of significance in the anti-inflammatory effect of cardamom is cardamonin, which is also found in other plant species.49 Ahmad et al. 50 reported that this compound inhibited the release of pro-inflammatory mediators NO and prostaglandin E2 PGE-2, which is a product of the cyclooxygenase 2 (COX-2) reaction, from stimulated murine macrophages. It also inhibited the release of thromboxane B2 (a product of COX-2; elevated levels are associated with inflammation51) from stimulated whole blood. The action of cardamonin appeared to be selective for the inhibition of thromboxane B2 release mediated by COX-2. It also inhibited reactive oxygen species (ROS) production and TNF-α release in a dose-dependent manner, and moderately inhibited the production of lipoxygenases, which catalyse the oxidation of polyunsaturated fatty acids.52 Cardamom, specifically its fruit and seed extracts, are also reported to inhibit the release of TNF-α and other pro-inflammatory cytokines, specifically interleukin-1 (IL-1) and interleukin-8 (IL-8), in vitro from stimulated macrophages.53

The anti-inflammatory activity of cardamom has also been demonstrated in vivo in animal studies.41 Kandikattu et al. 54 reported that cardamom extract (hexane) inhibited oedema, and down-regulated COX-2, IL-6 and TNF-α, in peripheral blood mononuclear cells (PMNC) taken from the rats, and also inhibited inducible nitric oxide synthase (iNOS) mediated NO synthesis. The effect of cardamom was comparable to that of the non-steroidal anti-inflammatory drug diclofenac. Clinical trials concerning the significance of cardamom's anti-inflammatory activity have also been conducted.41 In a randomized clinical trial (RCT), Kazemi et al. 55 investigated the effect of cardamom supplement on lipid levels, markers of oxidative stress and inflammation in subjects at risk of developing cardiovascular disease (CVD), specifically overweight and obese, hyperlipidemic pre-diabetic women (the subjects had elevated blood glucose that had not yet reached diabetic levels; the WHO identifies such people as having intermediate hyperglycaemia56). A single capsule of cardamom powder (1 g per capsule) was given to the subjects 3 times a day with meals for 8 weeks (the amount used was based on a previous study by Verma et al. 57). Cardamom decreased the level of C-reactive protein (CRP), a marker of inflammation, and oxidative stress (based on malondialdehyde (MDA) levels) significantly. However, it did not have a significant effect on other markers of inflammation, namely TNF-α and IL-6, in contrast to the findings in vitro and in animal studies summarised above. It also had no effect on total antioxidant capacity and the antioxidant enzymes, superoxide dismutase (SOD) and glutathione reductase (GR). The authors therefore concluded that cardamom was only effective on some and not all the markers of inflammation and antioxidant status. Factors such as the short duration, small sample size (80 subjects) and the dosage were highlighted as limitations. However, despite the varied outcomes the authors suggested, based on the MDA and CRP results, that cardamom could be of potential benefit in reducing the risk of diseases associated with chronic inflammation such as CVD in pre-diabetic subjects. The suggestion that cardamom's anti-inflammatory activity is of clinical significance is not limited to CVD. Research also provides some evidence that cardamom's anti-inflammatory activity may be of benefit and/or therapeutic significance in the prevention and/or management/treatment of other conditions associated with chronic inflammation including MetS, NAFLD and certain cancers. Daneshi-Maskooni et al. 58 carried out an RCT, specifically one that was double blind and placebo controlled, using subjects with NAFLD who were also overweight or obese. Giving capsules of cardamom (500 mg of whole cardamom per capsule) 3 times a day with meals for 3 months, they reported that compared to the placebo group, and also baseline levels, cardamom decreased the degree of fatty liver. This effect was associated with significant decreases in markers of inflammation – serum CRP, TNF-α and IL-6- and increase in NAD-dependent deacetylase sirtuin-1 (SIRT1), an enzyme that possesses anti-inflammatory activity, activation of this enzyme may be used as a therapeutic target for the treatment of chronic inflammatory diseases.59,61 The authors of this study also provided a number of possible mechanisms by which cardamom elicits an anti-inflammatory response in addition to inhibiting the release of pro-inflammatory markers. These include decreasing infiltration by inflammatory cells, decreasing oxidative stress via inhibition of lipid peroxidation and the production of advanced protein oxidation products, improving antioxidant

status and enhancing NK cell activity.42,62,68 The constituents of cardamom highlighted by the authors as being possible contributors to this anti-inflammatory activity are its polyphenols and also its volatile oils, including 1,8-cineol, a major constituent of cardamom, geraniol and beta-pinene.68 The study also reported evidence of improved liver function based on normalization of alanine aminotransferase activity (ALT) and aspartate aminotransferase (AST), although the change in the latter was not significant. This finding provides support for cardamom's hepatoprotective properties (see section on hepatoprotection below). The authors suggested that improvement in ALT and the decrease in the degree of fatty liver could be due to cardamom's ability to lower lipid peroxidation and improve antioxidant status. The same bioactive compounds of cardamom believed to contribute its anti-inflammatory effects in this study, were also put forward as being responsible for improvements in liver function via their antioxidant actions, alongside its minerals, copper and manganese.62,69,73 In light of the improvements reported, the authors concluded that cardamom may help in the management of NAFLD, although they acknowledged that the small sample size (80), the short duration, the lack of information about the bioavailability of cardamom and measures of body composition (body weight and body mass index (BMI) were measured but there were no changes) were limitations.

7.6.3

Glucose Lowering, Anti-diabetic, Lipid Lowering and Other Cardioprotective Properties

There are a number of in vitro, animal and clinical studies which demonstrate cardamom's potential to protect against the development of, and or management/treatment of, T2D, MetS and/or NAFLD via the lowering of glucose, improved glycaemic control, and/or decreased insulin resistance, and/or the lowering/normalization of lipid levels.41 Although the findings are mixed, a number of these studies suggest that due to the role that inflammation plays in the development of these conditions, cardamom's anti-inflammatory, and also antioxidant, properties may be linked/contribute to these effects.74,75 However, the effect of cardamom and its constituents on carbohydrate and fat digestion and/or absorption, cholesterol synthesis and insulin sensitivity may also play a role based on the evidence. Cardamom's cardioprotective effects may also involve a decrease in apoptosis, within cardiac tissue, and the lowering of blood pressure, cardiac muscle enzymes, collagen deposition, angiogenesis (the formation of new blood cells) and fibrinolysis (a process that regulates and controls blood clotting, and thus prevents blood clots that increase and lead to cardiovascular disease (CVD)). Naderi et al. 76 reported that cardamom extract inhibited the glycation of haemoglobin, which is a biomarker of diabetes and can lead to the vascular complications that result from this disease, in vitro in red blood cells. However, the level of inhibition was marked at the lowest concentration. Studies in vitro also provide evidence that cardamom may exert glucose lowering and anti-diabetic effects via its inhibition of enzymes involved in carbohydrate digestion. Ahmed et al. 77 reported that extracts (aqueous and methanol) of whole cardamom inhibited

α-glucosidase and α-amylase activity, with inhibition of the latter enzyme reported to be far greater. El-Yamani et al. 78 reported that feeding hyperglycaemic rats with cardamom on its own or in combination with cinnamon and ginger decreased their blood glucose. Serum creatinine, urea and uric acid were also decreased indicating that cardamom improved renal function in these animals. The enzymes AST and ALT were normalised and triglyceride (TG), total cholesterol (TC), low density lipoproteincholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) were decreased. High density lipoprotein cholesterol (HDL-C) was normalised by cardamom and the combination. Nitasha-Bhat et al. 72 compared the effect of cardamom to that of the drug pioglitazone, which is used to treat T2D, in rats chemically induced to also have hepatic steatosis (accumulation of TG in liver, which results in liver enlargement and dysfunction), dyslipidemia (abnormal, normally high, lipid levels) and hyperglycaemia. The authors of the study reported that both cardamom and the drug significantly decreased the enlargement of the liver, increased body weight and lowered fasting blood glucose (FBG) and normalised lipid levels (they lowered TG and TC and increased HDL-C). The effect of the spice was comparable to that of the drug. Winarsi et al. 79 reported similar findings in diabetic rats with both significant decreases in blood glucose and TC. However, there was no significant change in body weight. Alshammari investigated the effect of whole cardamom added to Arabic coffee (also referred to as Coffee Arabica/Turkish Coffee/Saudi Coffee; it is normally made using lightly roasted Arabian coffee seeds, which are mixed with cardamom) in diabetic mice (diabetes was induced via the consumption of a high fat diet).80 The authors included Arabic coffee in the investigation as its consumption in rats has been linked to lowering lipid levels and decreasing liver damage.81 Furthermore, coffee may protect against the development of chronic noncommunicable diseases including T2D.82 Compared to diabetic mice not given Arabic coffee, the cardamom/Arabic coffee combination, or the cardamom, clove and Arabic coffee combination, significantly decreased blood glucose along with insulin and glycated haemoglobin. Arabic coffee, the cardamom/Arabic coffee combination and the cardamom, clove and Arabic coffee combination also affected the activities of enzymes involved in regulating blood glucose levels namely glucokinase, glucose 6 phosphatase and fructose 1,6 bisphosphatase: they increased the activity of glucokinase and decreased the activity of hepatic and renal glucose 6 phosphatase and fructose 1,6, bisphosphatase. Glycogen levels were increased in the liver by the combinations. These effects indicate that Arabic coffee and cardamom promoted glucose storage as a way of lowering blood glucose in this animal model via an increase in insulin sensitivity. Interestingly, Arabic coffee appeared to have the greatest effect, with the cardamom, clove and Arabic coffee combination having a greater effect than the cardamon and Arabic coffee combination. Arabic coffee, the cardamom/Arabic coffee combination and the cardamom, clove and Arabic coffee combination also lowered TC, TG, and free fatty acid (FFA) as well as LDL-C and VLDL-C. They also increased/normalised HDL-C levels. In a study involving rats fed a high carbohydrate and high fat diet (the diet resulted in glucose intolerance and fat deposition), Rahman et al. 62 reported that when rats consumed the diet with ground cardamom, glucose intolerance improved

significantly and peritoneal (pertaining to the peritoneum – a membrane that lines the abdominal cavity and covers the surface of abdominal organs including the liver and intestines) fat deposition was less (although deposition of mesenteric fat (fat attached to the intestines83) and epididymal fat (fat in rodents attached to the testis) were not affected). Cardamom also significantly ameliorated the dyslipidemia in the rats – TC, TG and LDL-C were lowered; HDL-C was elevated compared to that in rats fed only the high carbohydrate, high fat diet. Cardamom also reduced significantly hepatic inflammation (based on decreased infiltration of the liver by inflammatory cells). The high carbohydrate, high fat diet decreased antioxidant status and increased oxidative stress. With cardamom included in the diet, antioxidant status based on elevated antioxidant enzymes SOD, catalase (CAT) and also reduced glutathione (GSH), improved; oxidative stress, based on decreased NO levels, decreased lipid peroxidation and decreased advanced protein oxidation products, decreased. Hepatic fibrosis (accumulation of collagen as a result of chronic inflammation) also decreased. Rahman et al. 62 suggested that cardamom's polyphenols had a significant role to play in the improvements reported, particularly via their reduction of oxidative stress and their anti-inflammatory properties, based on previous animal studies on the effect of cardamom on dyslipidemia and diabetes (some of which are discussed below84,85). They carried out an analysis of an ethanol extract of the cardamom used and identified epicatechin, vanillin, para-coumaric acid, ellagic acid and transferulic acid. Although, as identified by the authors, the major constituents of cardamom (the volatile compounds including 1,8-cineole, limonene and α-terpinyl acetate) may have a role to play. Rahman et al. 62 also suggested that the decrease in hepatic fibrosis may also be due to the antioxidant properties of cardamom based on evidence that an increase in ROS production due to fat accumulation in the liver stimulates hepatic collagen production.86 In a more recent study, Paul et al. 87 reported that supercritical carbon dioxide extracts of cardamom encapsulated as nanoliposomes, which are essentially a delivery system for foods and nutraceuticals and bioactive compounds, rich in 1,8 cineole and given orally to rats induced with T2D and hypercholesterolemia (elevated cholesterol levels) normalised fasting blood glucose and serum lipid profiles treatment.88 Cardamom's lipid lowering potential has also been investigated in animal models of abnormal lipid profiles only. In a study by Bhaswant et al.,89 in which the lipid lowering effects of dried powdered forms of cardamom and also black cardamom (Amomum subulatum, also known as great cardamom, big cardamom, brown cardamom, hill cardamom, winged cardamom, Bengal cardamom, Indian cardamom and Nepal cardamom) were investigated and compared in a rat model of MetS caused by the consumption of a high carbohydrate and high fat diet, the results suggested that for cardamom there appeared to be an increased risk in promoting disease development. For rats receiving black cardamom, abdominal fatness, total body fat mass, systolic blood pressure (SBP) and TG were significantly lowered and there was a marked decrease in the level of cardiac and liver damage, with a decrease in inflammatory cell infiltration in the liver. In contrast, cardamom significantly increased abdominal fatness, total body fat mass and the degree of cardiac and liver damage. Concerning the latter finding, there was evidence of increased infiltration with inflammatory cells, which is at odds with the anti-inflammatory effects reported in other studies. Cardamom significantly

lowered SBP. Neither cardamom nor black cardamom improved the level of glucose intolerance. Analysis of both black cardamom and cardamom showed that the former's main constituent was 1,8 cineole, which was approximately six times higher than that in cardamom. For cardamom, the main constituent was α-terpinyl acetate, which was not found in black cardamom and was approximately seven times higher than 1,8 cineole in cardamom. However, both compounds have been identified as possessing activities suggestive of benefit.42,62,66,68 The authors suggested that the high amount, which was approximately equivalent to 1.5 g kg−1 of body weight, may explain the detrimental effects of cardamom, as a half of this amount was reported to give rise to oxidative stress in mice90 (see section on Safety and Adverse Effects). In the context of human consumption, the authors, by comparing the body surface area of rats and humans, calculated that the amount given was approximately 20 g per day, an amount that they correctly identified as being far in excess of what is normally used for either cardamoms. Ultimately, the authors argued that black cardamom could be of use in conferring some degree of benefit in the management of MetS as part of the diet when consumed in combination with other functional foods. Nagashree et al. 91 studied the effect of whole cardamom powder, cardamom oil and de-oiled cardamom (the remaining residue after cardamom oil was extracted) in rats with hypercholesterolemia caused by the consumption of a high cholesterol diet. Of note in this study is the fact that cardamom oil was the most effective of all the forms of cardamom in improving the lipid profile, and also the antioxidant status, of these rats. Cardamom oil, and also whole cardamom, significantly decreased the serum levels of TC, TG and LDL-C levels, with de-oiled only significantly lowering TG levels. For all forms, serum HDL-C was lowered but none had a significant effect. None of the forms of cardamom had an effect on hepatic cholesterol. However, both cardamom oil and de-oiled cardamom significantly lowered hepatic TG. Whole cardamom also lowered hepatic TG but this effect was not significant. In cardiac muscle, the only lipid that was significantly decreased was cholesterol and this was due to cardamom oil. Antioxidant status was improved based on increased serum and hepatic antioxidant enzymes SOD and CAT. For the antioxidant enzyme glutathione peroxidase (GPx) cardamom oil gave rise to the greatest increase but this was only for serum GPx. None of the forms of cardamom had a significant effect on serum and hepatic glutathione reductase (GR) activity or on any of these enzymes in cardiac muscle. All forms of cardamom increased levels of serum ascorbic acid significantly. Interestingly, all forms of cardamom lowered hepatic ascorbic acid levels, with the oil and whole forms doing so significantly. In cardiac muscle, no form of cardamom had an effect on ascorbic acid levels. For reduced glutathione (GSH) levels, the only significant effect was had by whole cardamom and this was in cardiac muscle. Only the oil significantly decreased oxidative stress, based on lipid peroxidation, in serum, liver and cardiac muscle. Alongside lipid profiles and antioxidant status, the study looked at the impact of the different forms of cardamom on a marker of atherosclerosis – the atherogenic index, which is used as a marker of abnormal lipid levels and an indicator of the risk of developing cardiovascular disease. Both cardamom oil and whole cardamom decreased the index however the de-oiled form had no effect. The study pointed to the volatile compounds of cardamom as having a key role in its ability to confer protection against the effects of a high cholesterol diet.

The cardioprotective potential of cardamom has also been demonstrated in vitro and also in vivo using animal models of hypertension, atherogenesis and cardiotoxicity (heart damage caused by harmful chemicals). Crude extracts of dried whole cardamom in water are reported to lower arterial blood pressure in vivo (in rats), and to elicit vascular relaxation (relaxation of smooth muscle in blood vessels) and have a cardio-depressant (depresses heart function and lowers blood pressure) effect in vitro. In a study involving an animal model of myocardial injury (damage to heart muscle), an aqueous extract of cardamom decreased the extent of damage, loss of function, inflammation and apoptosis in cardiac muscle. Angiogenesis (formation of new blood vessels) was also increased, and the activities of the enzymes lactate dehydrogenase and creatine kinase in cardiac muscle (markers used to determine if someone has suffered a heart attack), and collagen deposition, were decreased. These effects were associated with a decrease in oxidative stress and an improvement in antioxidant status.92 In another study, Goyal et al. 93 reported that extract (aqueous) of whole cardamom prior to the induction of myocardial injury protected against cardiac muscle damage, slowed down heart rate and blood pressure, and also decreased lipid peroxidation, and thus oxidative stress. Winarsi et al. 94 reported that cardamom extract (ethanol) lowered oxidized LDL levels (oxidized LDL is produced as a result of ROS damage and contributes to the formation of athersclerotic plaques) and TG, and increased HDL-C in a rat model of atherosclerosis. The extract also proved to be more effective at lowering TC than the statin simvastatin, suggesting that cardamom may work via the inhibition of cholesterol absorption. However, differences in the baseline data between the experimental groups could have affected the analysis of the post intervention data. The extract also decreased oxidative stress and improved antioxidant status, based on increased SOD. It also lowered markers of inflammation, specifically CRP and IL-6.63,94 Overall, the findings of these in vitro and animal studies provide further evidence for cardamom eliciting an anti-atherogenic/cardioprotective effect which is possibly mediated via mechanisms that include the inhibition of inflammation and oxidative stress and also the inhibition of cholesterol synthesis and/or absorption. These actions may involve cardamom's flavonoid constituents.95,96 Clinical trials have also been carried out to investigate the protective/management/therapeutic potential of cardamom for T2D, MetS, NAFLD and CVD. Verma et al.57 investigated the effect of cardamom powder in capsule form (750 mg per capsule, 2 capsules were given twice a day for 12 weeks, so a total of 3 g given daily). The authors stated that the dosage was based on ethnomedical recommendations on blood pressure in subjects newly diagnosed with stage 1 hypertension (blood pressure between ≥140/90 to 159/99 mm Hg). Over the 12 week period, systolic blood pressure (SBP) decreased, diastolic blood pressure (DBP) remained unchanged, and fibrinolysis (the breakdown of the protein fibrin in blood clots) increased but fibrinogen levels also remained unchanged (fibrinogen is a glycoprotein utilized in the production of blood clots, it is a substrate of thrombin, which is a protease enzyme, and is converted to the protein fibrin). The cardamom constituent 1,8 cineole was suggested as the compound responsible for the BP lowering effect, as concentrations of between 0.3 and 10 mg kg−1 of body weight are reported to lower aortic blood pressure (the aorta is the main artery that carries blood away from the heart to the rest of the body) in a dose-dependent manner,

possibly via vascular relaxation,97 and based on previous research the authors stated that the concentration of 1,8 cineole in their cardamom preparation was within this concentration range (1.44 mg kg−1 of body weight). However, they also acknowledge the possible role of other cardamom constituents, including limonene, terpinolene and mycrene, as well as its flavonoids, which are reported to lower BP.98,99 Verma et al. 100 also studied the cardioprotective potential of black cardamom101 using patients with ischemic heart disease, a form of CVD also referred to as coronary heart disease. The dosage and duration were again 3g per day and 12 weeks, respectively. Significant decreases in the atherogenic index, TC, VLDL-C and LDL-C levels occurred but there was no significant change in HDL-C. As with cardamom, black cardamom increased fibrinolytic activity and antioxidant status. Azimi et al. 102 carried out a single blind RCT in which they investigated the effect of cardamom on inflammation, oxidative stress, glycaemic control and lipid profile in subjects with T2D. Subjects were given 3 glasses of black tea with 3 g of cardamom (powder of seeds), or the control of 3 glasses of black tea, for 8 weeks. Cardamom was stewed with the black tea for ten minutes prior to consumption. Concerning the glycaemic markers (FGB, insulin and glycated haemoglobin HbA1c), cardamom had no significant effect compared to the control or baseline values. Furthermore, cardamom had no significant effect on CRP and F2-isoprostan – a marker of oxidative stress. With regards to the lipid values, when compared to the control, cardamom significantly decreased TC and LDL-C, and increased HDLC. It also decreased TG levels compared to the control, but this was not significant. However, when compared to their respective baseline (prior to consumption of the tea plus cardamom) lipid values were not significantly decreased. One limitation of the study was that the baseline levels varied considerably between each of the groups despite the analyses of the data being controlled for age and weight, which differed significantly between the groups. In another single blind RCT using at risk subjects, specifically 204 patients with T2D, Azimi et al. 103 reported that cardamom (3 g), given in black tea for 8 weeks had no effect on intercellular adhesion molecule-1 (ICAM-1), which is an intracellular adhesion molecule and a marker of endothelial function (function of the endothelium, which is the lining of the inside of heart and blood vessels), SBP and DBP and body weight. The authors did report a decrease in waist circumference (WC) but this was not significant. Fatemeh et al.104 investigated the effect of cardamom on glycaemic indices, lipid levels and also blood pressure in overweight and obese subjects with intermediary hyperglycaemia (they were pre-diabetic). Cardamom was given in capsule form (each capsule contained 1 g of cardamom) and 3 g (3 capsules) of cardamom was given daily with meals for 8 weeks (the amount given was based on those used in another study100 in which the cardioprotective properties of cardamom were investigated). Cardamom had no effect on body weight, BMI, and FGB. Waist circumference was significantly decreased after adjusting for baseline data. Compared to baseline data, insulin resistance decreased but this was not significant. There was also no difference in FBG. However, insulin sensitivity was significantly increased. Regarding the lipids, TC and LDL-C were decreased as were TG levels, but the decrease was only significant for TC and LDL-C. The levels of HDL-C were also unchanged as were both SBP and DBP. As with the studies cited above,

cardamom's polyphenols and its volatile compounds were put forward as contributing to the effects reported, based in part on their anti-inflammatory and antioxidant properties, and also their activity as vascular relaxants.105 The decreases in TG levels, although not significant, were attributed to the inhibition of pancreatic lipase activity by flavonoids106,108 and their (the flavonoids') ability to inhibit TG absorption. Furthermore, there is evidence that flavonoids are able to regulate/modify cholesterol synthesis.109 Regarding the overall outcome of the study, the authors cited the small sample size (80), the short duration and using only females as limitations. In a RCT involving patients with T2D, Aghasi et al., 110 using capsules of powdered cardamom (0.5 g of cardamom per capsule, 2 capsules with 3 meals for a duration of 10 weeks; the amount of cardamom used was based on previous studies111,112), reported a significant decrease in HbA1c, insulin, insulin resistance and TG levels. There was no change in TC, LDL-C and HDL-C compared to the placebo. Cardamom also increased the serum levels of sirtuin-1 (SIRT1) which, in addition to its anti-inflammatory activity, is reported to play a role in the regulation of glucose and lipid metabolism via its action on insulin signalling. Evidence indicates that it improves insulin sensitivity of liver and muscle. It may therefore have a role to play in protecting against the development of insulin resistance and ultimately T2D diabetes.59,61 There is also evidence that activation of SIRT1 via polyphenols is of benefit in the regulation of oxidative stress and also inflammation.113 Thus, the increase in SIRT1 by cardamom, specifically by its polyphenols, may confer benefit/be of therapeutic significance in the management of T2D. Danashi-Maskooni et al. 58 investigated the effect of cardamom on glycaemic indices, lipid profile and a peptide called irisin in overweight and obese subjects with NAFLD. (Irisin is secreted by muscle cells and adipocytes, and is reported to affect insulin sensitivity and influence glucose and lipid metabolism.114,117 Exercise is reported to increase levels of this peptide and an inverse relationship between irisin and hepatic TG levels has been reported.114,118) Subjects (87) were given 2 × 500 mg capsules of powdered cardamom 3 times a day with meals for 12 weeks. When analysis was adjusted for vitamin E and vitamin B6 intakes, which were higher in the cardamom group, cardamom increased irisn, HDL-C and also insulin sensitivity. It also lowered fasting blood insulin and TC. However, although it lowered insulin resistance, changes in fatty liver, TG, BMI and LDL-C were not significant. The authors, based on the literature, some of which is summarised here, put forward an argument for a number of mechanisms of action of cardamom involving its phenolic constituents acting as: antioxidants to lower oxidative stress; anti-inflammatory agents; compounds that inhibit the absorption and metabolism of glucose and lipids; inhibitors of cholesterol synthesis; and enhancers of insulin sensitivity.62,70,72,79,80,94,104,106,107,109,119,120 Shekarchizadeh-Esfahani et al. 121 carried out a systematic review and metaanalysis of clinical trials (all double blinded RCTs) which investigated the effect of cardamom on lipid profiles. All the clinical trials included have been summarised above. They used similar dosages of cardamom – 3 g of powder per day in capsule form or 3 g per day with black tea (specifically 3 glasses of black tea) and durations were between 8 and 12 weeks. The subjects' conditions were ischemic heart disease,

T2D, intermediate hyperglycaemia (pre-diabetes), and NAFLD. The authors reported that overall, cardamom lowered TC and LDL-C, but not significantly, lowered TG significantly, and normalised HDL-C but not significantly. When the authors stratified based on duration (greater than 8 weeks) and age (equal to and older than 50 years of age) they reported a significant lowering of TG and increase in HDL-C in the non-diabetic subjects. This effect was possibly due to the fact that the TG and HDL-C levels at baseline were much higher and lower, respectively, in this group of subjects, therefore the effect of cardamom resulted in a much bigger change than in the T2D subjects. The authors argued that, despite the general low risk of bias in the studies analysed, the small number of studies, the fact that not all the studies were multi-centered, the lack of sub-analysis based on the subjects' BMIs, and subject compliance concerning the consumption of cardamom, the conclusion that the spice may be effective at lowering TG levels needed to be treated with caution, especially when removal of the largest weighted study110 from the analysis resulted in the decrease in TG becoming non-significant. Furthermore, one of the studies concerned black cardamom.100 The mixed findings concerning the purported protective effect of cardamom in humans is also highlighted in a study by Badkook and Shrourou,122 who reported that consumption by healthy humans of cardamom (125 ml and 200 ml) in Arabic coffee (375 ml and 300 ml respectively), 5 days a week for 4 weeks, elevated TG for the lower amount only, but this increase was not significant, significantly increased TC for both amounts and increased LDL-C for the higher amount. Cardamom at both amounts had no effect on blood pressure, CRP and the cardiac enzymes creatine kinase and lactate dehydrogenase. Although the spice appeared to be beneficial to liver function based on both amounts decreasing the enzyme gamma glutamyl transpeptidase (GGT), for which elevated levels are a marker of liver damage and are also said to be indicative of risk of T2D and CVD,123,124 neither amount had an effect on other enzymes used as markers of liver function, specifically ALT and ASP. Based on these findings, the authors suggested that regular consumption of Arabic coffee with amounts of cardamom similar to those used in the study could increase the risk of conditions associated with elevated TC, TG and LDL-C. Although the general trend concerning cardamom is that it appears to confer protection, in light of the conflicting findings of human studies, including clinical trials, which may in part be due to heterogeneity regarding study design, the evidence concerning the beneficial/therapeutic significance of the glucose lowering, anti-diabetic and lipid lowering effect of cardamom has yet to be established fully.

7.6.4

Chemopreventive/Anti-cancer Properties

Cardamom fruit, seeds and its essential oil are reported to possess chemopreventive/anti-cancer and anti-mutagenic properties,41 and some evidence suggests that its chemopreventive action is linked to the spice's antioxidant and antiinflammatory properties.10,125,127 However, other mechanisms may also be involved including apoptosis, induction of detoxification enzymes, inhibition of phase 1 activation enzymes,128 anti-invasive and antiangiogenic activities, and natural killer (NK) cell activity.42 As with some of the bioactive properties already

summarised above, its constituents, including 1,8 cineole and limonene, and also eugenol and geraniol, have been put forward as contributing to its chemopreventive/anti-cancer properties.42,129 Hashim et al. 128 reported that cardamom essential oil inhibited the production of DNA adducts by the fungal toxin aflatoxin B1 (AFB1) in a dose-dependent manner in vitro, and that this inhibition may involve enzyme inhibition. The fungal toxin used requires conversion to an active metabolite (AFB1 exo-8,9 epoxide) to be carcinogenic via the action of the phase 1 enzyme cytochrome P450 3A4.130 A study by Banerjee et al. 131 provided support for this mechanism of action, as they reported that cardamom essential oil induced the phase 2 detoxification enzyme hepatic glutathione-S-transferase (GST) and decreased hepatic cytochrome P450 activity in vivo in mice given cardamom essential oil. This effect has also been identified for the whole extract. Ho et al. 132 reported that dried, ground and powdered cardamom extracted in methanol protected against DNA damage as well as lipid peroxidation and protein damage in vitro. An early in vivo study by Abraham et al. 133 reported that cardamom given in combination with cinnamon, pepper, cumin and clove as an aqueous extract to mice, given a genotoxin (a compound that causes DNA damage) at the same time, prevented inhibition of GST and also decreased the frequency of micronucleated polychromatic red blood cells (micronuclei develop as a result of DNA repair impairment and the subsequent accumulation of damaged DNA and chromosomal aberrations caused by genotoxins134). However, the authors were not able to establish if the two actions were linked. A small number of studies have investigated cardamom's effect on colon cancer and skin cancer using animal models. Bhattacharjee et al. 135 investigated cardamom in combination with cinnamon. The combination was given from day 1, of mice being given a chemical carcinogen to induce colon carcinogenesis, for 8 weeks. They reported that the combination enhanced GST activity and reduced oxidative stress by lowering lipid peroxidation, and thus provided evidence in vivo of cardamom's ability to induce phase 2 detoxification enzymes in a model of carcinogenesis. A study by Sengupta et al. 136 provided evidence of the association between cardamom's anti-inflammatory and chemopreventive properties in vivo. In a murine model of chemically induced colonic aberrant crypt foci (ACF) which is a precursor for the development of colon carcinogenesis, cardamom given as an aqueous suspension significantly decreased the occurrence of new ACF and the expression of pro-inflammatory mediators COX-2 and inducible nitric oxide synthase (iNOS) alongside a significant increase in apoptosis of colon cancer cells. Das et al. 66 reported that cardamom (aqueous extracts of ground fruit) given to mice with chemically induced skin papillomagenesis, an animal model that closely resembles human non-melanoma skin cancer, upregulated GST in the skin lysates of the cardamom treated mice. This result was associated with increased expression of nuclear factor erythroid 2 related factor (Nrf2) and kelch-like ECH-associated protein-1 (Keap 1) in the skin tissue of the cardamom treated rats. Nuclear factor erythroid 2 related factor is involved in the regulation of phase 2 detoxification enzyme induction during oxidative stress137 and Keap 1 is involved in regulating Nrf2,138 and its expression in cancer patients is reported to be mutated or low.139

Therefore, the induction of the phase 2 enzymes, the authors suggested, could be via the increased expression of Nrf2 and Keap-1. Cardamom also improved antioxidant status, decreased oxidative stress, blocked the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which is a key step in triggering an inflammatory response as it induces the genes that express proinflammatory cytokines,140 down regulated COX-2, and also decreased the size and number of the skin papillomas. Qiblawi et al. 41 also reported similar findings, specifically activation of GST, improved antioxidant status (it increased levels of SOD, CAT, GR and GPx in skin lysates) and decreased oxidative stress alongside a decrease in tumour incidence, burden and multiplicity (the mean number of tumours), in a murine model of forestomach papillomagenesis. Using a rodent model of liver cancer, Elguindy et al. 127 reported that cardamom extract (oil extracted from fruit and seeds) and one of its constituents, geraniol, decreased the level of liver injury, based on normalization of AST and ALT levels, improved antioxidant status based on improved levels of the hepatic antioxidant enzymes SOD, CAT, GR and GPx, induced the phase 2 detoxification enzyme GST in the liver, and decreased the level of oxidative stress via the lowering of MDA. These effects were alongside a decrease in the inflammatory markers serum TNF-α, serum IL-1β and also NF-κB expression in the nuclear extract of liver cells. The authors also noted that cardamom and geraniol inhibited the activity of a potential target for chemotherapy, the enzyme ornithine decarboxylase (ODC) which has been shown to play a role in supporting tumour growth.141 There was also improved hepatic histology, which confirmed the biochemical results. Infiltration of the liver by inflammatory cells was decreased as were the levels of necrosis and hepatic steatosis. Kumari and Dutta142 investigated cardamom's ability to ameliorate the effects of pan masala in rats. Pan masala is chewing tobacco and, via its constituents' cytotoxic, genotoxic and mutagenic properties, is reported to cause cancer.143,144 When given to rats at the same time that they were being ‘treated’ with pan masala and then continuing with cardamom for another 3 months, cardamom lessened the extent of the development of lung adenocarcinoma (a type of lung cancer), oedema (fluid retention) and inflammation. All of these in vivo studies highlight cardamom's significant chemopreventive abilities. However, to date the therapeutic significance of this protective effect has yet to be established.

7.6.5

Hepatoprotective Properties

As stated above, the antioxidant activity of cardamom has been linked to its reported hepatoprotective effects, which has been demonstrated in animal models, with 1,8 cineole, α-terpineol, its polyphenols, and its minerals copper and manganese highlighted as being the major contributors to this (antioxidant) activity and thus its hepatoprotective effects.145 El-Segaey et al. 145 reported that cardamom conferred protection against hepatotoxicity induced by ethanol by lowering oxidative stress, improving antioxidant status (it increased SOD and GR activity) and normalising the activity of liver function enzymes. Sadeek and El-Razek71 investigated the effect of a cardamom supplemented diet given to rats with iron overload induced liver damage.

The liver enzymes ALT, AST and alkaline phosphatase (ALP) normalized, as did the serum lipids (TC, TG, LDL-C and VLDL-C decreased significantly, and HDLC increased significantly), oxidative stress decreased (based on the marked lowering of MDA) and antioxidant status increased based on increased CAT activity. In addition, the level of iron deposition in the liver decreased. Darwish et al.70 reported that cardamom when given to mice before the induction of liver damage (and also heart damage) caused by exposure to gamma radiation, decreased oxidative stress and improved antioxidant status in the liver and heart. The authors also reported that TG, TC and LDL-C were lowered, and HDL-C was normalised in the livers of irradiated mice that had received cardamom. Aboelnaga69 reported cardamom's protective effect on chemically (carbon tetrachloride (CCL4) which is hepatotoxic) induced liver damage in rats. Consumption of diets supplemented with cardamom prior to administration of CCL4 led to significant improvements (a decrease) in liver enzymes, AST, ALT and ALP. Glucose levels and lipid (TC, TG, LDL-cholesterol, VLDL cholesterol and HDL-cholesterol) profiles also improved significantly, with the extent of blood glucose and LDL-C decreases increasing with the level of supplementation. Aqueous extract of cardamom is also reported to confer protection on the liver and to improve the lipid profile of rats exposed to gentamicin (used to induce liver damage), whilst consuming a diet supplemented with cardamom.146 This study, in conjunction with another animal study, which reported that hydroethanolic extract of cardamom also conferred protection on the liver, alongside decreased oxidative stress and improved antioxidant status, provide further support for this protection being associated with an antioxidant effect involving cardamom's phenolic constituents.65 Ethanol, iron overload, gamma radiation, CCL4 and gentamicin are reported to cause damage via oxidative stress. Therefore a role for cardamom's antioxidant properties in improving liver function makes sense.147,150 However, some of these agents can also lead to inflammation, impairment of hepatic mitochondrial fatty acid oxidation and liver enlargement.147,148,151,152 In light of the properties of cardamom already summarised above, it is possible that it confers protection via other mechanisms, for example suppression of inflammation and/or influencing hepatic lipid profile. However, it should be borne in mind that oxidative stress can lead to mitochondrial dysfunction,153 and the literature recognises an interplay between oxidative stress and inflammation.154

7.6.6

Gastroprotective Activity

Crude cardamom extract (methanol) and its fractions (petroleum ether, and the fractions left following extraction with petroleum ether – labelled the insoluble fraction) and its essential oil155 are all reported to inhibit the development of gastric ulcers in animal models of chemically (aspirin or ethanol) and/or physically (via pyloric ligation) induced ulceration. The petroleum ether fraction and the essential oil were reported to be the most potent, and were more effective than ranitidine, a drug used to decrease the production of stomach acid but which is currently unavailable in the US and UK as it contains N-nitrosodimethylamine (NDMA),

which is classed as a probable carcinogen.156 Although the constituents responsible for this effect were not identified in the study, compounds including 1,8 cineole and limonene and α-terpinyl acetate that are present in cardamom essential oil may have contributed to the effects reported. Regarding a mechanism of action, the petroleum ether fraction and cardamom essential oil may act by decreasing gastric motility (movement of food along the gastro-intestinal tract, the decrease of which is associated with the prevention of gastric lesions (damage to the stomach)) by flattening the mucosal folds of the stomach.157,158 Black cardamom (crude methanol extract and its fractions (petroleum ether, ethyl acetate, methanol, the remaining residue after extraction with petroleum ether, ethyl acetate and methanol, and its essential oil (200 mg kg−1 of body weight)) is also reported to protect against the formation of gastric ulcers in animal models.159,160 As with cardamom, it is reported to be more effective than ranitidine, and as a hot aqueous extract used in combination with turmeric and sembung leaf (a medicinal plant used for its gastroprotective properties161), its effects were comparable to that of sucralfate, which is used to treat gastric ulcers. In addition to its ability to lower gastric motility, black cardamom, specifically the ethyl acetate fraction of the crude methanol extract, increased mucus production by gastric epithelial cells, which could result in protection against ulceration.159 Black cardamom also decreased inflammatory cell infiltration in the gastric mucosa. Its gastroprotective role may, as the authors suggested, involve the anti-inflammatory action of its polyphenol constituents.160,162

7.6.7

Gut Modulatory and Anti-nausea Properties

Cardamom has been shown to possess some gut modulatory effects, both inhibitory and excitatory, in vitro which suggest that it could be used in the treatment of diarrhoea, abdominal spasms, dyspepsia and constipation.163 In a very small number of clinical trials, cardamom, on its own as a powder, and as an essential oil, in combination with other essential oils, is reported to reduce nausea during pregnancy and post-surgery. In a double blind RCT, Ozgholy et al. 164 reported that cardamom powder taken in capsule form (1 capsule taken 3 times a day half an hour before meals; each capsule contained 500 g of cardamom powder) for 4 days was effective at decreasing nausea and vomiting in pregnancy. The essential oil combination study investigated a blend of cardamom, ginger and peppermint oils, as well as ginger oil on its own in a RCT using patients with postoperative nausea.165 The patients who were instructed to inhale the oil combination or ginger oil deeply 3 times reported making significantly fewer requests for antiemetic medication, which is used to prevent vomiting and nausea, compared to the placebo group. In addition, both the combination and ginger oil were reported to decrease the level of nausea, with the combination oil doing so more effectively than the ginger oil on its own. The amount of the constituent oils in the combination group was not provided so the possible contribution of the cardamom and peppermint oils could not be established. Furthermore, the authors acknowledged that the duration of inhalation, 5 minutes, was short, the sample size (301) was small, and there was some evidence of degradation of the oil blend.

7.6.8

Neuroprotective Properties and Impact on Behaviour, Learning, Memory and Development

Auti and Kulkarni166 reported on the neuroprotective effect of cardamom essential oil in aluminium induced neurotoxicity in rats. The oil improved cognitive impairment and anxiety, and there was also significant inhibition of neuronal damage, acetylcholine esterase (AChe) activity, and the formation of amyloid β plaques alongside a decrease in oxidative stress. (AChe is an enzyme which hydrolyses, breaks down, the neurotransmitter acetylcholine and plays a role in the pathogenesis of Alzheimer's disease (AD). Amyloid β plaques, commonly referred to as amyloid plaques, are aggregates of proteins that form between nerve cells (neurons). Evidence points to their formation, initially in regions of the brain that are involved in cognitive functions including memory, contributing to the development of Alzheimer's disease.) The effects reported for cardamom essential oil were comparable to that of donepezil, which is used to treat AD, and the major constituent of the oil used in the study was identified as α-terpinyl acetate, which has recently been shown to have the same effect.167 Thus, based on these findings, cardamom via this constituent appears to have the potential to confer neuroprotection via a number of mechanisms and may be of use in the prevention and/or management of neurodegenerative diseases such as AD. However, clinical trials are needed to ascertain more fully the preventive and therapeutic potential of the spice with regard to neurodegenerative diseases. Animal studies suggest that cardamom may affect social behaviour, learning, memory and development.168,169 Delays were reported in the opening of eyes, hair development, the maturation of neuro-motor skills, and in enhanced learning and memory in the offspring of mice fed cardamom supplemented diets from the first day of pregnancy to 15 days after birth. In addition to increasing the levels of reduced GSH and lowering the level of lipid peroxidation, neurotransmitter, specifically dopamine and serotonin, activity was increased in what appeared to be a dose-dependent manner. Bearing in mind the very small number of studies, it is difficult to ascertain the significance of these findings in relation to humans.

7.6.9

Anticonvulsant Properties

Masoumi-Ardakani et al. 170 reported that cardamom essential oil's anticonvulsant effect (shown in animal models) was probably elicited via constituents known to act as anticonvulsants including myrcene and linalool.171,173 In contrast, cardamom extract (methanol) was not effective in demonstrating such an effect. The authors concluded that the lack of effect was possible because the amounts of the main contributory constituents were too low in the extract.

7.6.10

Anti-microbial Activity

Extracts of whole cardamom and its essential oil possess antimicrobial activity against bacteria and fungi pathogenic to humans. The major constituents of cardamom, 1,8 cineole and α-terpinyl acetate, have been identified as being the major contributors to cardamom's antimicrobial activity.

7.6.10.1 Antibacterial Properties Cardamom extracts (aqueous, ethanol, methanol and supercritical fluid) and/or its essential oil have been shown to inhibit the growth of gram-negative and grampositive pathogenic bacteria, including multidrug resistant bacteria, at levels comparable to antibiotics including amoxicillin, ampicillin, penicillin and neomycin.174,176 However, the essential oil has also been shown not to possess antimicrobial activity.177 The pathogenic bacteria include those known to cause gum disease, including Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum and Porphiromonas gingivalis, all of which are gram-negative, providing evidence of the therapeutic potential of the spice in the treatment of gum disease.53 Other pathogenic bacteria include the gram-negative Salmonella typhimurium, Klebsiella pneumoniae, Shigella sonnei,90,174 Esc herichia coli O157:H7, Campylobacter jejuni and Vibrio cholerae,36,175,178 and the grampositive Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus and Streptococcus pyogenes 179 and clinical isolates of enterococci (although cardamom was not effective on all the strains used; in fact only 6 of the 100 clinical isolates used were sensitive to cardamom (ethanol extracts)).176,180,181 In this study ethanol extracts of cinnamon, clove and ginger were far more potent. A review of the studies revealed that for some microorganisms the level of potency of/inhibition by cardamom was not consistent. For example, Pseudomonas aeruginosa was reported in one study to be resistant to cardamom essential oil,178 but the oil, and also ethanol extracts of cardamom, were reported to inhibit the growth of this pathogen in other studies.90,174,175 Studies suggest that cardamom's major constituents inhibit bacterial growth via a mechanism of action that includes disruption of the cell wall of bacteria.53,182 There is also evidence to suggest that cardamom, specifically its essential oil, might act to limit the virulence of pathogenic bacteria via the inhibition of quorum sensing,178 a process in which bacteria release chemicals that act as signalling molecules via which bacteria are able to sense the number of bacteria and as a consequence behaviour, in the case of pathogenic bacteria this behaviour is virulence, which is the severity of the infection.

7.6.10.2 Antifungal Activity Cardamom also inhibits the growth of pathogenic and toxigenic (toxin producing) fungi, respectively, Candida albicans and Aspergillus niger (A. niger).174,175 However, the inhibitory effect of cardamom extracts on the growth of other species of Aspergillus, namely A. flavus, A. ochraceus and A. versicolor, and the production of their respective toxins, was reported as being ‘relatively’ minor compared to other culinary herbs and spices including thyme, dill seeds, turmeric, sweet marjoram, basil, caraway and coriander seeds.183 Cardamom essential oil's inhibitory effect against Candida albicans is reported to be comparable to that of the antifungal agent amphotericin.175 Black cardamom, both its extracts (methanol) and its essential oil, also possesses

anti-microbial activity against pathogenic gram-negative bacteria (including Pseudomonas aeruginosa), gram-postive bacteria (including Staphylococcus aureus and Staphylococcus epidermidis), pathogenic fungi (Candida albicans) and toxigenic fungi (Aspergillus niger) at levels comparable to antibiotics (ciprofloxacin) and anti-fungal agents (fluconazole).175,184

7.7

Safety and Adverse Effects

Cardamom is considered to be safe when consumed as food, specifically to flavour/enhance the taste of food. However, larger amounts are reported to give rise to symptoms associated with allergic reactions, including contact dermatitis and systemic dermatitis (in which an individual is sensitised to an allergen cutaneously but will react to the same allergen via a different route185), rash, skin irritation, angioedema, and respiratory problems.186,188 These reactions are reported to be rare. Cardamom given with Arabic coffee (500 mL, at a ratio of 3 coffee : 2 cardamom) may promote atherogenesis via increases in TC and LDLcholesterol.122 In addition, cardamom is reported to increase visceral adiposity and total fat mass, and cause cardiac liver damage at amounts equivalent to 20 g per day.89 These findings come from one human study and one animal study. In clinical trials concerning the efficacy of cardamom, only a few adverse effects, including constipation, nausea, inflammation of the skin, which was mild, glossitis (inflammation of the tongue) and heartburn (for cardamom essential oil), were reported.58,104,164,165,189,190 A non peer reviewed online source states that cardamom taken in amounts larger than those used for food preparation and consumption might cause miscarriage and trigger gallstones191 but nothing appears to have been reported on these effects in peer reviewed literature.

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CHAPTER 8

Chives (Allium schoenoprasum) 8.1

Names

English: Chives, Allium schoenoprasum. French: Civette Gaelic: Cebolete Spanish: Cebollino Spanish: Cebollin Vietnamese: Hanh tam, Hanh trang The word chives was first given by Carl Linnaeus in his work Species Plantarum (1753) and is derived from the French word cive, itself from the Latin cepa which means onion.1 Schoenoprasum comes from the Greek word skhoinos meaning sedge and prason meaning onion which translates to rush-leek in Latin.2

8.2

Taxonomy

Order: Asparagales Family: Amaridicacea Genus: Allium Species: Allium schoenoprasum

8.3

Origin, Description and Adulteration

The origin of Allium schoenoprasum (chives) is unknown but is possibly Russia.3 Allium schoenoprasum of the genus Allium of the Amaridicacea family, is a perennial (long-lived) plant related to onion, garlic, shallot, leek, scallion, and Chinese onion. The edible evergreen herb is slim, with dark green leaves, hollow cylindrical or semi cylindrical and pale purple “pom–pom” shaped pedicel flowers (pedicles hold individual flowers in place) that bloom in early summer.3 The high sulfur compound content makes the herb a useful insect repellent. The flowers are edible, decorative and offer an attractive nectar for pollinators. Chives need to be well watered, especially during dry summer spells and can grow up to 0.45 m high and 0.1 m wide in well-drained fertile soil in sunny or partially shaded areas outdoors or in pots. Chives are cold and hardy (resist cold) but can suffer from aphids (small sap-sucking insects) and leek rust (a common fungal disease).4 As chives are normally grown locally and the herb is usually consumed fresh rather than dried, and extracted or processed prior to purchase (although dried chives are sold), adulteration does not appear to be a major issue, although it is not

impossible. Copper (heavy metal contamination) was found in samples of chives in an Indian study that investigated female infertility due to food adulteration.5

8.4

Historical and Current Uses

Chives have probably been cultivated in Europe since the 16th century;3 the herb grows wild in most of the northern hemisphere and is consumed fresh, and used to flavour salads, soups or stews, with a fragrance typical of edible alliums (such as garlic and onion).3 Chives are, with tarragon, chervil and parsley, one of the four “fine herbs” used in French cuisine today, as they have been for generations to flavour foods, such as cucumber and cream salad, and to garnish dishes. Traditionally chives accompany ingredients to cheese, such as quark in Germany and other parts of Eastern Europe. In Sweden, it is used with sour cream to flavour herrings. Chives feature in the Apicius Roman cookbook,6 for a recipe of cheese and honey, and to season cottage cheese. Chives also feature In “The Book of Herbs” (1903); in this book Rosalind Northcote,7 states that: “Gives, or Chives, or Selves, are used with seabass”. Chives were said to be found in a 15th century recipe book and were very popular in the 17th century in London, where they were “esteemed milder than onions,” and of a “quick relish,” but then their popularity declined to occasional use to flavour soups, salads and omelettes in the 18th century. The 17th century English physician Nicolas Culpepper referred to “cives” as “rush leeks” in his book Complete Herbal.8 Chives have been used since the time of Ancient Rome to help heal sunburn and as a diuretic (increase urination), but Culpeper was not too fond of the plant, stating: “When eaten raw… they send up very hurtful vapour to the brain, … causing troublesome sleep and spoiling the eyesight.”2 The United States Department of Agriculture (USDA) granted chives a Generally Recognized as Safe (GRAS) certification when used as food.9 Chives do not feature on the list of Commission E monographs or extended versions of the monographs as approved herbs, or on the list of unapproved herbs.10 A source states that chives were used in traditional Chinese medicine (TCM) as an antidote to poison,2 although the herb does not feature in the online encyclopedia of TCM11 or any other online source of information on TCM.

8.5

Chemistry, Nutrition and Food Science

Phenol Explorer,12 shows that fresh chives contain flavonoids (luteolin, isorhamnetin, kaempferol, quercetin). The chives' fragrance is due to allyls sulfides and alkyls sulfoxides, similar to those in garlic but in lower amounts,2 and more particularly the vitamin B1 derivative allithiamine, as well as propyl-aliin and methyl-aliin.3 UK nutrition composition data are similar to US data for dried samples but with

additional information in the latter listed below (see Table 8.1). With regards to the nutritional quality of chives, they are generally considered to be poor in the energy yielding nutrients (carbohydrate, fat, protein) nutrients, however it may make important dietary contributions towards folate (1.05 µg g−1 fresh herbs) and provitamin A (4.35 µg g−1) with the presence of vitamin C contributing, with provitamin A, to some of the herb's antioxidant activity.13,14 The US database also reports chives containing vitamin K. Phytosterol levels in chives are low (0.09 mg g −1) (see Table 8.1), therefore it may make a small contribution to the 2 g per day of dietary phytosterol recommended for the prevention of cardiovascular disease, if consumed regularly.15 Table 8.1

Nutrition composition of fresh chives.13,14 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0

Chives (100 g)

Fresh (UK Data)

Fresh (US Data)

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

27 1.9 2.5 0.7(0.15) 3.3 90.7 9 92 0.16 Na 1.6 42 0.37 58 296 Trc 3 0.6 435 0.08 0.12 0.7 0.14 58 105 0.21 —b 0.33

30 4.35 2.5 0.73(0.146) 3.27 90.65 9 92 1.157 —b 1.6 42 0.373 58 296 0.9 3 0.56 218 0.078 0.115 0.647 0.138 58.1 105 0 212.7 0.324

aN: Present in significant amounts but not determined. b—: Not assessed or not present. cTr: Trace.

A study investigated the nutritional characteristics of the flowers of chive,16 and reported high values for vitamin C – 108.48 mg per 100 g; the total phenolic

content measured via the Folin Assay (expressed in gallic acid (a phenolic acid) equivalents – GAE – units used to quantify phenolic content) was 375.76 mg GAE per 100 g. The flowers are also a good source of saturated (12.4–49.86%) and unsaturated (7.75–13.81%) fatty acids, sterols (4.72–8.67%), vitamin E (0.16– 0.49%) and sulfur-containing compounds (0.39–0.81%). Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. Freezing the fresh herbs is a common way to keep chives for longer in domestic kitchens. The impact of freezing chives at −18 °C for 4 months, either blanched and non-blanched, was compared against fresh samples for levels of vitamin C, chlorophylls (chlorophyll a and chlorophyll b) and carotenoids. Results were mixed: the vitamin C content of fresh chives was 56.48 mg per 100 g, with 49.91% loss for frozen non-blanched samples and 15.88% loss for frozen blanched samples. The total chlorophylls' concentration in fresh chives was 268.15 µg g−1, (205.00 µg g−1 chlorophyll a and 63.15 µg g−1 chlorophyll b); 18.95% loss of total chlorophyll was observed in frozen non-blanched samples, which is more than for the pre-blanched frozen samples, which lost 9.58% of total chlorophylls compared to fresh chives. Fresh chives had 36.41 µg g−1 carotenoids, which was reduced by 31.86% in frozen nonblanched chives and by 16.97% in frozen blanched chives.17

8.6

8.6.1

Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research Antioxidant Properties

Chives possess antioxidant capacity in vitro, although it is reported to be low in relation to those of other culinary herbs and spices including clove, allspice, rosemary, thyme, sweet marjoram, Mediterranean oregano, ginger, basil and tarragon.18,21 However, the actual capacity varies with the nature of the preparation, for example the antioxidant capacity of extracts of the flower (leaves) has been shown to be higher than those of extracts of the stem and bulb of the plant.22 Antioxidant capacity also varies with the type of assay used.18,21 Chives' antioxidant capacity in vitro is high in comparison with other members of the allium family namely shallots, garlic, onion and bunching onion – Allium fistulosum 20,23,24 (also referred to as Welsh onion and Japanese bunching onion). The phenolic compounds of the plant are the main contributors to its antioxidant properties. There is also evidence that the plant, specifically leaf extracts, possesses antioxidant enzyme activity including superoxide dismutase (SOD) and glutathione peroxidase (GPx).25 Reduced glutathione (GSH) has also been measured in leaf extracts.25 Extracts of chives diluted in water inhibit the conversion of ferrous ion (Fe2+) to ferric ion (Fe3+) in the presence of hydrogen peroxide, a reactive oxygen species (ROS), and also the rate of production of the hydroxyl radical (a free

radical).20 Some evidence suggests that chives' antioxidant properties may contribute to its chemopreventive and anti-mutagenic properties, which are reviewed below.

8.6.2

Anti-inflammatory Properties

Parvu et al. 20 reported on the anti-inflammatory properties of chives, specifically its leaf extract, in an animal model of inflammation. Leaf extract inhibited phagocytic activity (the engulfing/ingestion of bacteria, harmful foreign particles and dead and dying cells) and decreased production of the pro-inflammatory mediator, nitric oxide (NO). The anti-inflammatory effect was comparable to that of the non-steroidal anti-inflammatory drug indomethacin. Furthermore, it appears to be independent of the radical scavenging activity of chives. The authors of this study suggested that allicin and the polyphenols in chives contributed to its antiinflammatory activity.

8.6.3

Lipid Lowering Properties

The hypolipidemic properties of chives have been discussed in a review by Jingfan.26 Evidence of chives' lipid lowering properties – lowering of serum and hepatic lipids, cholesterol and triglyceride (TG), in hyperlipidemic rats27 and serum cholesterol and TG in hyperlipidemic humans28 have been reported. In the human study, chives were given as part of a hypolipidemic diet that included garlic, legumes, nuts and also seafood. However, although the species of chives is not specified, these effects may actually be due to Chinese chive (Allium tuberosum).26 Chinese chives have also been reported to inhibit the differentiation of preadipocytes (3T3-L1 cells) and also inhibit lipid accumulation in differentiated adipocytes, although it was reported to have no effect on lipolysis.29

8.6.4

Anti-hypertensive Properties

A single study by Amalia et al. 30 reported on extract (ethanol) of the herb's bulb increasing NO levels in vivo (in normotensive rats). Based on the traditional use of chives to lower blood pressure, the authors suggest that the increase in NO supports its anti-hypertensive property, as NO causes blood vessels to relax and dilate resulting in the lowering of blood pressure.31 However, these actions of NO were not demonstrated in the study.

8.6.5

Anti-platelet Activity

Alongside other alliums, namely garlic and shallot, chives' antiplatelet activity is considered to be quite potent. Evidence suggests that this activity is due to its organo-sulfur and phenolic compounds.23 For the latter group these include ferulic acid, chlorogenic acid, the catechins and kaempferol. Platelet aggregation, the clumping together of platelets, plays an important role in the development of arterial thrombosis. However, the beneficial/preventive significance of chives in

humans, particularly in those at risk of blood clots, remains to be established.

8.6.6

Chemopreventive/Anti-cancer Properties

Chives are reported to possess anti-proliferative effects on cell growth, specifically immortalized skin cells – HaCaT, possibly via their phenolic compounds including ferulic acid, coumaric acid, gallic acid and rutin.32 Chives (in the form of a juice) are also reported to possess a not inconsiderable anti-mutagenic effect in vitro. However, the level of potency depends on the mutagen and the form of the juice, as heat partially reduced its anti-mutagenic activity.33,34 Epidemiological research provides some evidence of an association between levels of intake of allium vegetables, including chives, and gastric, colon, oesophageal and prostate cancer risk, indicating that this herb may have a chemopreventive effect.35,41 However, the majority of this evidence appears to be focussed on Chinese chives (although it was not always made clear in some of the literature reviewed). Furthermore, for some studies, a number of limitations were identified which has led to a cautious interpretation of their findings in the context of intake and risk.40 Proposed mechanisms of action put forward in a review on the chemopreventive properties of allium vegetables include inhibition of mutagenesis (mutation of DNA), activation of detoxification phase 2 enzymes, for example glutathione Stransferase, and inhibition of carcinogen activating phase 1 enzymes, for example cytochrome P450, inhibition of DNA adduct formation, scavenging of free radicals, anti-proliferative effects on human cancer cells lines, inhibition of tumour growth via cell cycle arrest and apoptosis.35 For Chinese chive, its glycolipids and/or its organo-sulfur compounds, specifically its thiosulfinates, are reported to inhibit the proliferation of human cancer cell lines (gastric, leukaemic, breast, colorectal, liver, lung and prostate) via cell cycle arrest and apoptosis.29,42,44 The thiosulfinates are also reported to increase the survival time of tumour bearing mice.43

8.6.7

Anti-microbial Activity

A small number of studies indicate that chives, the leaf extract and the essential oil, possess anti-microbial activity against bacteria and fungi pathogenic to humans, but it is the oil that appears to be the most potent.

8.6.7.1 Anti-bacterial Activity Huhtanen45 reported that ethanol extract of chives inhibits the growth of the grampositive pathogen Clostridium botulinum. However, its potency is limited. In contrast, the essential oil proved to be a more potent inhibitor of the same, and other, pathogens namely the gram-negative Escherichia coli O157:H7, Salmonella enterica and Vibrio cholera, and the gram-positive Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus. The compounds believed to contribute to the activity of the essential oil are the diallyl sulfides, namely the diallyl

disulfide, diallyl trisulfide and diallyl tetrasulfide.46

8.6.7.2 Anti-fungal Activity One study by Parvu et al. 47 has reported on the anti-fungal activity of chives' leaf extract on toxigenic (toxin producing) fungi Aspergillus niger. This activity was comparable to those of the anti-fungal medicine fluconazole and chives' constituent allicin.

8.6.8

Anti-parasitic Activity

Chives in powder form is reported to decrease worm numbers in the intestines of mice infected with the parasite Trichuris muris.48 As this parasite is very similar to the human roundworm parasite Trichuris trichiura, it is used as a model of gastrointestinal parasitic infection.49

8.7

Safety and Adverse Effects

There is little to no peer reviewed literature concerning the safety or adverse effects of chives. One online resource states that it is safe when consumed in amounts used in the preparation and cooking of foods.50 There is a lack of information about the effect of the herb when taken for medicinal purposes. However, sensitization to chives has been reported in peer-reviewed literature.51 It has been reported online that it might give rise to stomach problems50 but a review of peer reviewed literature provided no information about chives and these adverse effects.

References 1. Oxford Advanced Learner’s Dictionary, Chives Noun – Definition, Pictures, Pronunciation and Usage Notes at OxfordLearnersDictionaries.com, https://www.oxfordlearnersdictionaries.com/definition/english/chives? q=chives, accessed 19 November 2020. 2. J.Staub, 75 Exceptional Herbs for Your Garden, Gibbs Smith, 2008. 3. J. L.Brewster and H. D.Rabinowitch, Onions and Allied Crops: Volume III: Biochemistry, Food Science, and Minor Crops, CRC Press, 2020. 4. RHS Plants, Buy Chives/Allium Schoenoprasum Chives, https://www.rhsplants.co.uk/plants/_/chives/classid.2000012599/, accessed 19 November 2020. 5. N. Wahab and F. Sultana, J. Asian Afr. Soc. Sci. Humanit., 2017, 3, 12-28. 6. J. D.Vehling, The Project Gutenberg eBook of Apicius: Cookery and Dining in Imperial Rome. A Bibliography, Critical Review and Translation of the Ancient Book known as Apicius de re Coquinaria, https://www.gutenberg.org/files/29728/29728-h/29728-h.htm, accessed 16 November 2020. 7. R.Northcote, The Book of Herbs, John Lane: The Bodley Head, London and

New York, 1903. 8. N.Culpeper, Culpeper's Complete Herbal, and English Physician, Gareth Powell Limited, 1826. 9. US Food and Drug Administration, CFR – Code of Federal Regulations Title 21, https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=182&showFR=1, accessed 19 November 2020. 10. American Botanical Council, Commission E: Unapproved Herbs, http://cms.herbalgram.org/commissione/HerbIndex/unapprovedherbs.html#C, accessed 19 November 2020. 11. H.-Y. Xu, Y.-Q. Zhang, Z.-M. Liu, T. Chen, C.-Y. Lv, S.-H. Tang, X.-B. Zhang, W. Zhang, Z.-Y. Li, R.-R. Zhou, H.-J. Yang, X.-J. Wang and L.-Q. Huang, Nucleic Acids Res., 2019, 47, D976-D982. 12. V. Neveu, J. Perez-Jiménez, F. Vos, V. Crespy, L. du Chaffaut, L. Mennen, C. Knox, R. Eisner, J. Cruz, D. Wishart and A. Scalbert, Database, 2010, 2010, bap024. 13. J.Bodner-Montville, J. K. C.Ahuja, L. A.Ingwersen, E. S.Haggerty, C. W.Enns and B. P.Perloff, USDA Food and Nutrient Database for Dietary Studies: Released on the Web, https://pubag.nal.usda.gov/catalog/7356, accessed 21 November 2020. 14. M. Roe, H. Pinchen, S. Church and P. Finglas, Nutr. Bull., 2015, 40, 36-39. 15. C. E. Cabral and M. R. S. T. Klein, Arq. Bras. Cardiol., 2017, 109, 475-482. 16. M. Grzeszczuk, A. Wesoáowska, D. Jadczak and B. Jakubowska, Acta Sci. Pol., Hortorum Cultus., 2011, 10, 85-94. 17. A. Iosin, D.-N. Raba, C. Moldovan, V.-M. Popa and D.-G. Dumbravă, Sci. Technol. Bull., Ser. Chem. Food Sci. Eng., 2017, 14, 49-52. 18. S. Dragland, H. Senoo, K. Wake, K. Holte and R. Blomhoff, J. Nutr., 2003, 133, 1286-1290. 19. W. Zheng and S. Y. Wang, J. Agric. Food Chem., 2001, 49, 5165-5170. 20. A. E. Parvu, M. Parvu, L. Vlase, P. Miclea, A. C. Mot and R. SilaghiDumitrescu, J. Physiol. Pharmacol., 2014, 65, 309-315. 21. S. Z. Viña and E. L. Cerimele, J. Food Qual., 2009, 32, 747-759. 22. A. Mollica, G. Zengin, M. Locatelli, C. M. N. Picot-Allain and M. F. Mahomoodally, Food Res. Int., 2018, 108, 641-649. 23. H. V. Beretta, F. Bannoud, M. Insani, F. Berli, P. Hirschegger, C. R. Galmarini and P. F. Cavagnaro, Food Technol. Biotechnol., 2017, 55, 266-275. 24. E. Souri, Gh. Amin, H. Farsam and S. Andaji, Fitoterapia, 2004, 75, 585-588. 25. D. Štajner, J. Čanadanović‐Brunet and A. Pavlović, Phytother. Res., 2004, 18, 522-524. 26. G. Jingfan, Asia Pac. J. Clin. Nutr., 1996, 5, 249-253. 27. M. Sun, J. Xiao, Z. Yang, Y. Liu, X. Li and X. Guo, Acta Nutr. Sin., 1982, 4, 45. 28. M. Sun, J. Xiao, S. Zhang, Y. Liu and S. Li, Acta Nutr. Sin., 1984, 6, 127. 29. H. S. Park, E. J. Choi, J.-H. Lee and G.-H. Kim, J. Life Sci., 2013, 5, 127-132. 30. L. Amalia, E. Sukandar, R. Roesli and J. Sigit, Int. J. Pharmacol., 2008, 4, 487-491. 31. M. Hermann, A. Flammer and T. F. Lüscher, J. Clin. Hypertens. (Greenwich), 2006, 8, 17-29. 32. Z. Kucekova, J. Mlcek, P. Humpolicek, O. Rop, P. Valasek and P. Saha, Molecules, 2011, 16, 9207-9217. 33. R. Edenharder, P. Kurz, K. John, S. Burgard and K. Seeger, Food Chem.

Toxicol., 1994, 32, 443-459. 34. X. Tang and R. Edenharder, Food Chem. Toxicol., 1997, 35, 373-378. 35. F. Bianchini and H. Vainio, Environ. Health Perspect., 2001, 109, 893-902. 36. T. Takezaki, C.-M. Gao, J.-H. Ding, T.-K. Liu, M.-S. Li and K. Tajima, J. Epidemiol., 1999, 9, 297-305. 37. W.-C. You, W. J. Blot, Y.-S. Chang, A. Ershow, Z. T. Yang, Q. An, B. E. Henderson, J. F. Fraumeni and T.-G. Wang, J. Natl. Cancer Inst., 1989, 81, 162-164. 38. C. Gao, T. Takezaki, J. Ding, M. Li and K. Tajima, Jpn. J. Cancer Res., 1999, 90, 614-621. 39. A. W. Hsing, CancerSpectrum Knowl. Environ., 2002, 94, 1648-1651. 40. Y. Zhou, W. Zhuang, W. Hu, G.-J. Liu, T.-X. Wu and X.-T. Wu, Gastroenterology, 2011, 141, 80-89. 41. J. Hu, Y. Liu, Y. Yu, T. Zhao, S. Liu and Q. Wang, Int. J. Epidemiol., 1991, 20, 362-367. 42. I. Kuriyama, K. Musumi, Y. Yonezawa, M. Takemura, N. Maeda, H. Iijima, T. Hada, H. Yoshida and Y. Mizushina, J. Nutr. Biochem., 2005, 16, 594-601. 43. K.-R. Park, J.-H. Lee, C. Choi, K.-H. Liu, D.-H. Seog, Y.-H. Kim, D.-E. Kim, C.-H. Yun and S. S. Yea, Int. Immunopharmacol., 2007, 7, 1251-1258. 44. J.-H. Lee, H.-S. Yang, K.-W. Park, J.-Y. Kim, M.-K. Lee, I.-Y. Jeong, K.-H. Shim, Y.-S. Kim, K. Yamada and K.-I. Seo, Toxicol. Lett., 2009, 188, 142-147. 45. C. N. Huhtanen, J. Food Prot., 1980, 43, 195-196. 46. P. Rattanachaikunsopon and P. Phumkhachorn, Biosci., Biotechnol., Biochem., 2008, 72, 2987-2991. 47. M. Pârvu, I. Rusu and O. Rosca-Casian, Contrib. Bot., 2013, 48, 75-82. 48. S. Klimpel, F. Abdel-Ghaffar, K. A. S. Al-Rasheid, G. Aksu, K. Fischer, B. Strassen and H. Mehlhorn, Parasitol. Res., 2011, 108, 1047-1054. 49. J. E. Klementowicz, M. A. Travis and R. K. Grencis, Semin. Immunopathol., 2012, 34, 815-828. 50. WebMD, Chive, https://www.webmd.com/vitamins/ai/ingredientmono403/chive, accessed 23 April 2020. 51. D. A. Moneret-Vautrin, M. Morisset, P. Lemerdy, A. Croizier and G. Kanny, Allerg. Immunol. (Paris), 2002, 34, 135-140.

CHAPTER 9

Cinnamon: Cinnamomum verum (syn Cinnamomum zeylanicum), Cinnamomum cassia (syn Cinnamomum aromaticum), Cinnamomum burmanni, Cinnamomum loureiroi 9.1

Names

English: Cinnamon (Ceylon Cinnamon), true cinnamon Basqu: Kanela, Kanelondo Mongolian: Shantsaj Chinese: Rou gui French: Cannelle Malay: kayu manis,1 kaṟuvappaṭṭa Portuguese: canelleira-da-India Spanish: Canela Tigrinya (spoken in Ethiopia and Eritrea): Qerfe Urdu: Dar chini and Dal chini Cinnamon, the word, comes from the late Middle English, which is from the Old French word cinnamome, which is itself from the Greek word kinnamōmon, and from the Latin word cinnamon which is kinnamon in Greek, which comes from a Semitic language and possibly based on Malay.2

9.2

Taxonomy

Order: Laurales Family: Lauraceae Genus: Cinnamomum Species: Cinnamomum zeylanicum, synonym Cinnamomum verum

9.3

Origin, Description and Adulteration

Cinnamon spice is the curled (quills) sun-dried inner bark of evergreen trees of the

genus, Cinnamomum. It is reddish brown in colour with a sweet and pungent aroma characterised by a woody, musty and earthy flavour, and is warming to taste.3 Approximately 250 species of cinnamon have been defined; the most utilized commercially today are Cinnamomum verum (C. verum; synonym C. zeylanicum), “the true cinnamon”, and C. cassia, also referred to as Chinese cassia or cassia bark tree.4 Cinnamon (C. verum) is indigenous to Sri Lanka and south India and is now widely cultivated in Sri Lanka, Java, Seychelles, Madagascar, South West Indies, Brazil, Martinique, and Jamaica.5 It is an important economic plant and is sometimes referred to as true cinnamon to distinguish it from the cheaper spice Cassia. True cinnamon grows in wet tropical regions, it is an evergreen tree (10–15 m high), with glossy leaves and small white flowers.5 Four or five years after planting, its branches reach 1.5–2 cm thickness, and it can be harvested every second year. The outer bark is scraped off, and sections of the inner bark (1.67 m, or 42 inches) are peeled off, and are then stretched, layered, hand-rolled (into quills), trimmed and dried. By-products of quills include quillings (5–20 cm long), featherings (small twisted pieces), chips (trimmings of bark or quills) and powder (from different grades of bark). Cinnamomum burmannii is the most common bark imported from Indonesia. Vietnam produces Cinnamomum loureirii, referred to as Saigon Cinnamon, which is considered the finest Cinnamon available. Cinnamomum verum is grown in Sri Lanka, but due to its specific flavour it is not commonly imported into the United States. Cinnamon is sold ground (in powdered form) or as a rolled ‘quill’ of the bark in Europe, Mexico, Australia and New Zealand.3 The Food and Agriculture Organization (FAO) shows a world production of cinnamon at 224 144 tonnes, 98.5% of which is from Asia, with Indonesia and China as the main producers. Sri Lanka is the primary source of C. verum.6 The US Food, Drug and Cosmetic Act of 1938 defined “cinnamon” as C. verum, C. cassia, and other species of cassia. Europe refers only to C. verum. The bark of C. verum is thinner than that of C. cassia, and has a weaker taste.4 Cinnamon (C. verum) powder (and oil) are often adulterated with another inferior form of cinnamon known as cassia cinnamon (Cinnamomum aromaticum). Yasmin et al.7 used Fourier transform near-infrared (FT-NIR) and Fourier transform infrared (FT-IR) spectroscopic analysis to determine adulterants in C. verum with success.

9.4

Historical and Current Uses

The first recorded use of cinnamon (species not specified (spp.)) was in approximately 2800 BCE by Shen Nung (the father of traditional Chinese medicine). Since then it has been used in many different cultures as a folk medicine, a culinary spice, and a food preservative, and it is consumed throughout the world. There is evidence of uses of cinnamon throughout recorded history.4 In Egypt, cinnamon was used in the mummification process called quinnamon by the Phoenicians and Hebrews, it is mentioned in the Book of Exodus (Chapter 30; verse 23).4 Cinnamon arrived in Europe in the first century CE, where it was highly

sought after – costing 15 times more than silver. Arab traders controlled the early trade in cinnamon to the Romans and Greeks by keeping the source a secret. The Greek authors Herodotus (5th century BCE) and Theophrastus (4th century BCE) both thought it came from Arabia. The Romans believed cinnamon was sacred and burned it at funerals. Ethnobotanical records show that burning cinnamon in incense was believed to aid in healing, improve spirituality and stimulate the male passion.8 Cinnamon was one of the first spices coveted in 15th century European explorations, and it may have indirectly led to the discovery of America.3 During the 13th and 14th centuries Venetian traders controlled the cinnamon trade in Europe until the Portuguese broke their monopoly when they arrived in what was called Ceylon (now Sri Lanka) in the early 1500s. Cinnamon became one of the most highly valued spices in Europe, and locating the source became a mission of 15th and 16th century European explorers.5 In the 17th century, the Dutch expelled the Portuguese from Ceylon, monopolised the trade and kept the spice rare and expensive by not allowing commercial farming until the East India Company obtained the monopoly in 1796, and it was not until 1833 that the cinnamon trade was opened up. It was not brought into cultivation until 1776.9,10 Nowadays, Sri Lanka is the main producing country, though cinnamon also comes from India, Malaysia, Madagascar, and the Seychelles.10 Cinnamon features in the Book of Herbs by Rosalind Northcote (1903) in a recipe for mustard “balls” (it was custom in Italy to store mustard in balls until needed) with a recipe for a pot pourri as quoted: “1/2 lb bay salt, 1/4 lb salt-petre and common salt, all to be bruised and put on six baskets of rose-leaves, 24 bay leaves torn to bits, a handful of sweet myrtle leaves, 6 handfuls of lavender blossom, a handful of orange or syringa blossoms, the same of sweet violets, and the same of the red of clove carnations. After having well stirred every day for a week, add 1oz cloves, 4oz orris root, 7oz cinnamon, and two nutmegs all pounded; put on the roses, kept well covered up in a china jar.”11 In the book of Ancient Herbs (1982) D'Andrea states: “Herbs in the ancient world are closely linked to the prowess of the Greek and Roman gods, the whims and wisdom of emperors, and the innovations of physicians and philosophers. Nero kicked Poppaea to death and then used a year's supply of Rome's cinnamon to bury her, and Hippocrates stressed herbal cures when he drafted the ground rules for modern medicine.”12 Cinnamon is mentioned several times in the famous Apicius Roman cookbook.13 White sauce for hare, for example, contained cinnamon. Cinnamon was also added to pickled beans or beans and pears as quoted: “pickled beans with peeled fresh pears, sugar, lemon peel cut thin, cinnamon, “English” mixed spices, and at last the roux, thinned with broth. This dish must be sweet and very fat”. The editors note that pumpkin pie was then made with stewed mashed pumpkin flesh with cumin essence (no cinnamon), an ancestor of the more palatable modern American dish which contains eggs, cinnamon, nutmeg, and ginger. The 14th and 15th centuries' Medieval cookbook, Le Viandier de Taillevent, mentions cinnamon extensively, for example, the list of “fine épices and poudre fine”, which were added to sauces, includes cinnamon with ginger, grain of paradise and either saffron or black pepper. Cameline is a sauce made with cinnamon and vinegar which is used for meat such as venison. Cinnamon was also used to flavour

galantine (de-boned shaped, stuffed meat).14 Cinnamon is strongly associated with a festive scent. In Europe it is mainly used in confectionery, desserts, baked goods, mulled wine, and pot pourri, whilst in the Middle East it is more common in meat dishes (for Moroccan tagines). It is also a constituent of Garam Masala (masala meaning spice mix) with cumin, coriander, cardamom, pepper, cloves, and nutmeg (this spice mix can vary in constituents and amounts of constituentsbetween Indian, Pakistani, Nepalese, Bangladeshi, Sri Lankan and Afghan recipes), and of the Middle Eastern Baharat spice blend (allspice, black pepper, chili peppers, cardamom, cinnamon, cloves, coriander, cumin, nutmeg). In the 2011 ethnobotanical leaflet by Pittman entitled “Cinnamon: It's not just for making cinnamon rolls”, the author lists cinnamon as an excellent spice in Indian, Moroccan and Greek dishes, and also in spaghetti sauce, beef stew, chili, lentils, rice dishes and fish, chicken, ham and hot chocolate. Cinnamon flavour is used in mints, chewing gums and toothpaste, however adverse effects have been reported (see section on Safety and Adverse Effects). The United States Department of Agriculture (USDA) granted Cinnamon, Ceylon (Cinnamomum zeylanicum Nees), Cinnamon, Chinese (Cinnamomum cassia Blume), and Cinnamon, Saigon (Cinnamomum loureirii Nees), as well as Cassia Chinese (Cinnamomum cassia Blume), and Cassia Padang or Patavia (cinnamomum burmannii Blume), Generally Recognized as Safe (GRAS) certifications when used as food.15 Cinnamon bark has been used for a thousand years in both Eastern and Western traditional medicines to treat anorexia and conditions of the gastrointestinal tract as a component of compounds used in traditional Greco-European medicines and traditional Indian Ayurvedic medicine.10 The European Commission E monographs approves cinnamon based on a combination of factors including its long history of traditional use in well established systems of traditional medicine. Dried bark of cinnamon (C. verum) is used for loss of appetite, bloating, dyspepsia, flatulence and spastic condition of the gastrointestinal tract. Sensitivity and allergy to cinnamon is possible and affects the mucosa and causes dermatitis, and it should not be used in pregnancy (see section on Safety and Adverse Effects). At doses of 2–4 g of bark or 0.05–0.2 g of essential oil or cut or ground bark for teas and essential oil, as well as for other galenical (for medical use) preparations, cinnamon is used for internal use as an antibacterial, fungistatic and to promote motility.10 The monograph for cinnamon flowers is on the list of herbs not approved, due to possible sensitisation to, and the frequent allergic reactions in the skin and mucosa caused, by the flowers. The British Herbal Pharmacopoeia reported that cinnamon essential oil showed strong antibacterial, antifungal, antiviral, and larvicidal activity, and its constituents eugenol, eugenol acetate, and methyl eugenol have been reported to enhance trypsin activity in vitro. Cinnamon bark has also shown to possess a strong lipolytic (fat breakdown) action.10 In the United States and Germany, cinnamon is used as a carminative (to relieve flatulence) and stomachic (promotes appetite and assists with digestion). It is also a component of multi-herb cough, cold, and fever formulations. Pharmacopeial grade cinnamon bark must contain no less than 1.2% volatile oil. Heart, kidney, liver and spleen meridians are treated with cinnamon in traditional Chinese medicine, where it is considered warming, and used for an array of

ailments linked to cold, such as weak back, poor digestion, pain/cold in the extremities.16

9.5

Chemistry, Nutrition and Food Science

Phenol Explorer shows that cinnamon (C. verum) contains hydroxycinnamic acids, mainly caffeic acid and some p-coumaric acid, and hydroxybenzoic acids 2hydroxybenzoic, protocatechuic and syringic acids.17 The expanded monograph from the Commission E for cinnamon states that it contains 1–4% essential oils of which cinnamaldehyde makes 60–80%, eugenol up to 10% and trans-cinnamic acid 5–10%. Phenolic compounds make up 4–10%, and the rest are condensed tannins, catechins, proanthocyanidins, monoterpenes and sesquiterpenes, as well as calcium-monoterpenes oxalate, gum, mucilage, resin, starch, sugars, and traces of coumarin.10 Cinnamon bark oil owes its flavour to the cinnamaldehyde content, and cinnamon leaf oil's clove-like aroma is due to its high eugenol content. Cinnamon essence, which is used in cooking and to flavour medicines, is made from cinnamon bark oil.5 The UK and US databases provide similar nutrient values for cinnamon (C. spp. species was not specified in UK data, and US data refer to C. aromaticum). With regards the nutritional quality of cinnamon, it is, overall, poor in a number of nutrients, especially in the context of the amount used in cooking, which is small. Nevertheless, it is high in dietary fibre, calcium, provitamin A and vitamin K1, and contains a small amount of phytosterols, and thus can contribute to the overall 2 g per day of dietary phytosterol recommended for the prevention of cardiovascular diseases if consumed regularly (see Table 9.1).18,20 Table 9.1

Nutrition composition of cinnamon.18,19 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0

Cinnamon (100 g)

UK data

US data

Energy/cal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Iron/mg Copper/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg

Na Na 53.1 1.2 (0.35) 4 10.6 26 1002 8.32 0.34 60 17.47 64 431 3 10

247 80.59 53.1 1.24 (0.345) 3.99 10.58 26 1002 8.32 0.339 60 17.446 64 431 3.1 10

Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg Iodine/µg

1.8 30 0.02 0.04 1.3 0.16 4 6 Na 31.2 0.36 Na

1.83 15 0.022 0.041 1.332 0.158 3.8 6 2.32 31.2 0.358 —b

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. The effects of cooking on cinnamon's phytochemical composition has been investigated. A study compared the antioxidant capacity of cinnamon tea (1 g dried herbs in 100 mL boiled water), mulled wine with (1 g) and without cinnamon, and a mixture of distilled water (100 mL) and Merlot wine (200 mL). Antioxidant capacity was measured via the Trolox equivalent antioxidant capacity assay (TEAC). The mixture was brought to the boil, then covered and left to simmer for 30 min. The antioxidant capacity for mulled wine (with cinnamon) was almost 4 times greater than that of the mulled wine control (no cinnamon) and 55 times greater than that of the cinnamon tea.21 Baker et al.22 compared the antioxidant capacity of cooked and uncooked cinnamon, using the TEAC assay (expressed in TEAC) and the total phenolic content (TPC) assay (expressed as gallic acid equivalents – GAE). Uncooked extracts were prepared by covering cinnamon (1 g) with boiled water (25 mL) stirred for 2 minutes, and cooking was carried out by adding cinnamon (1 g) to distilled water (25 mL) and leaving it to simmer for 60 minutes at 50 °C. The antioxidant capacity of the uncooked samples was not significantly different to that of cooked cinnamon, but the total phenolic content of cooked samples was significantly higher than that of the uncooked cinnamon. The potential for cinnamon and its derivatives (extracted constituents) to be used as functional food ingredients was reviewed in 2017, and the authors concluded that cinnamon essential oil was a strong candidate for use as a food preservative (specifically as an anti-microbial for the prevention of microbial spoilage) and thus could contribute to food safety by preventing food borne illness. The addition of cinnamon directly to the food matrix, and incorporating cinnamon oil into packaging material, were feasible strategies for extending the shelf life of food without impacting on sensory properties negatively. The antioxidant capacity of cinnamon and its derivatives (conferred by phenolic constituents) can also contribute to extending the shelf life of foods.23

9.6

Bioactive Properties, Purported Health

Benefits and Therapeutic Potential: Current and Emerging Research 9.6.1

Antioxidant Properties

The essential oils, dried fruit and bark extracts of cinnamon have been shown to possess antioxidant properties in vitro.22,24,25 In a study of the antioxidant content of over 1000 foods, ground cinnamon (C. spp. species was not specified) was 4th on the list of 50 foods with the highest antioxidant content, behind ground cloves, dried leaf Meditarranean oregano, ground ginger, and just above turmeric powder; on the list the top five foods were culinary herbs and spices.26 Dragland et al. 27 ranked cinnamon (C. spp.) third for antioxidant content behind clove and allspice out of 38 dried commercial culinary herbs and spices. Khatun et al. 25 also reported a high antioxidant capacity for C. verum in relation to other culinary spices. Shan et al. 28 also reported relatively high antioxidant capacities for both C. verum and C. cassia, with the former reported as possessing a higher antioxidant capacity likely due to its higher polyphenolic content. Both eugenol and cinnamaldehyde, which are present in cinnamon, possess antioxidant activity.29 There is a small amount of evidence that the antioxidant properties of cinnamon may confer some degree of protection on the liver in animal models of liver injury and liver disease (specifically acute alcohol induced fatty liver disease). Cinnamon (C. spp.) extracts (both aqueous and ethanol) resolved lipid peroxidation and liver injury via normalization of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT); the ethanol extract appeared to be more potent than the water extract based on its effect on malondialdehye (MDA) a reactive aldehyde and a marker of oxidative stress, MDA, SOD and CAT.30,31 In a murine model of acute alcohol induced fatty liver disease, a commercially available ethanol extract of cinnamon bark (C. spp.) was shown to have a protective effect against the accumulation of fat in the liver and the production of inducible nitric oxide synthase (iNOS), an enzyme required for the formation of nitric oxide (NO) – a free radical and pro-inflammatory mediator which plays a key role in the development of alcoholic liver disease.31 Human studies have also been used to investigate the significance of the antioxidant properties of cinnamon. Cinnamon (0.5 g in ground form – C. spp.), in combination with other herbs and spices (black pepper (0.7 g), cloves (0.5 g) Mediterranean oregano (3 g), rosemary (0.5 g), ginger (1.2 g), paprika (3.4 g) and garlic (1.5 g)), when added as a herb and spice blend to hamburger meat, resulted in a decrease in the levels of MDA in the plasma and urine of the healthy subjects. The findings of the study suggest that such a blend could protect against disease processes that result from oxidative stress, specifically carcinogenesis and atherogenesis.32 Interestingly however, a similar herb and spice blend with a slightly higher amount of cinnamon (C. spp.) (0.61 g) (in combination with black pepper (0.91 g) cloves (0.61 g), garlic powder (1.181 g), ginger (1.51 g), Mediterranean oregano (2.26 g), paprika (2.85 g), rosemary (0.61 g) and also including turmeric (2.79 g)) affected some but not all the markers of antioxidant status measured in healthy, overweight subjects. Although the findings of this study

support the role of an antioxidant rich herb and spice blend improving antioxidant status, the inconsistency of outcome raises questions about the usefulness of antioxidant assays when used to ascertain antioxidant activity in vivo.33,34 In subjects with type 2 diabetes (T2D), cinnamon (C. spp.) (0.45 g) consumed as part of a herb and spice blend consisting of black pepper (0.79 g), cloves (0.45 g), Mediterranean oregano (2.925 g), rosemary (0.45 g), ginger (1.2375 g), paprika (3.375 g) and garlic powder (1.4625 g) added to ground beef caused a reduction in MDA alongside an improvement in endothelial vascular function. As endothelial dysfunction can increase the risk of cardiovascular disease, it is tempting to surmise that the improvement may be due to the ability of the herbs and spices used, including cinnamon, to confer some degree of protection.35 Although whether this protection is due to its antioxidant properties is unclear. Human studies have reported the significant antioxidant effect of cinnamon on its own. Ranjbar et al. 36 reported that healthy subjects who consumed 100 mg per 30 mL of cinnamon (C. verum) with tea every day for 2 weeks had significantly decreased and increased plasma MDA and total antioxidant power (capacity), respectively, compared to subjects who consumed tea only. The total plasma thiol was also greater for those who consumed the tea plus cinnamon. In another study by Ranjbar et al.,37 they reported significant decreases in lipid peroxidation in the plasma of operating room staff who consumed 100 mg per 30 mL per day of cinnamon (C. verum) tea, made using commercially available cinnamon powder and boiling water, for 10 days. These subjects were chosen due to their exposure to anaesthetic gases which may result in oxidative stress. However, no significant changes were reported for other markers of oxidative stress, namely total antioxidant power and total thiol molecules. Roussel et al. 38 reported similar inconsistencies regarding the effect of cinnamon (250 mg of a dried aqueous extract (referred to in the study as Cinnulin PF)) given twice daily for 12 weeks to prediabetic overweight and obese subjects. Furthermore, Mashhadi et al. 39 reported no change in MDA in female athletes who consumed 3 g per day of cinnamon (C. spp.). In contrast, Borzoei et al. 40 reported a decrease in MDA levels in women with polycystic ovary syndrome (PCOS) – see below for more about this condition – following cinnamon ((C. spp.) although the article does refer to C. verum in the introduction) supplementation (1500 mg per day for 8 weeks) compared to those who received the placebo. Although some markers of antioxidant status, namely ferric reducing antioxidant power (FRAP) and plasma thiol, increased and oxidative stress decreased compared to those for the placebo group, there was no change in antioxidant enzymes glutathione peroxidase (GPx) and SOD. Percival et al. 24 reported that cinnamon (Cinnamomum loureiroi, C. loureiroi) consumed by healthy humans at 1.7 g per day (administered in capsule form) for 7 days (11.9 g in total) did not result in any detectable increase in antioxidant activity in the serum of these subjects. Furthermore, the serum of subjects who consumed the cinnamon capsules did not protect against hydrogen peroxide induced DNA damage. Some of the findings summarised above appear to suggest that in humans cinnamon confers some degree of protection via its antioxidant properties, but the inconsistencies observed in its impact on antioxidant status make the beneficial significance of these properties unclear. This lack of clarity may, as stated above, be due to the biomarkers used, as they may be affected by any compound that

possesses reducing power (essentially the ability of a compound to act as an antioxidant).41,42 In addition, the differences in subjects between the studies might also be an influencing factor. Despite the disparities, some studies suggest that cinnamon's antioxidant properties may be linked to its effects on insulin sensitivity and the control of glucose levels in those with T2D, as well as its wound healing, anti-cancer and neuroprotective properties, which are reviewed below.

9.6.2

Anti-inflammatory Properties

Both the bark and essential oil of cinnamon have been demonstrated to possess antiinflammatory properties in vitro and/or also in vivo using animal models.43,46 Inhibition of pro-inflammatory markers, including cyclooxygenase 2 (COX-2) and monocyte chemoattractant protein-1, and of anti-inflammatory activity induced by cotton pellet granuloma which gives rise to chronic inflammation in rodents, by cinnamon have been reported in the literature.47 Evidence indicates that the antiinflammatory activity of this spice is conferred on it by its major bioactive constituents namely eugenol, cinnamaldehyde and linalool.48,51 Regarding its anti-inflammatory activity in humans, Percival et al. 24 reported that C. loureiroi 1.7 g per day (administered in capsule form) for 7 days (11.9 g in total) did not affect the expression of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-α) and interleukin-6 (IL-6) in stimulated human monocytes. A recent systematic review and meta-analysis noted that evidence from clinical trials, in particular randomized control trials (RCTs), is limited and does not report consistent outcomes.52 The meta-analysis identified six RCTs which investigated the effect of cinnamon supplementation (all studies used C. verum) on C-reactive protein (CRP), a key mediator and marker of inflammation, in a number of conditions associated with chronic inflammation, specifically non-alcoholic fatty liver disease (NAFLD), T2D, metabolic syndrome (MetS), rheumatoid arthritis (RA), overweight or obese pre-diabetes, as well as in healthy subjects. Dosage and duration across these studies ranged from 1200 mg per day to 3000 mg per day and 8–24 weeks respectively. The formulations of cinnamon also varied, with studies using cinnamon capsules, sticks or extracts in powder form, either administered on their own or with co-supplements or drugs. Of the six RCTs, four reported significant reductions in CRP following cinnamon supplementation in subjects with NAFLD, MetS, overweight or obese pre-diabetes and RA.53,56 The authors of the meta-analysis concluded that the reductions reported in these studies were of clinical importance with respect to the risk of having a cardiovascular event, and that the anti-inflammatory action of cinnamon via its lowering of CRP was most evident in the RCTs in which the basal levels of CRP were greater than 3 mg L−1, the duration of the supplementation was greater than 12 weeks and the dosage was 1500 mg per day. However, they also noted that their conclusions were based on a very limited number of RCTs that had very different study designs, not only with regards to the subjects used but also the formulation and dosage of cinnamon supplementation, and the duration of the supplementation. The authors, therefore, made it clear that further research using well designed studies is required for their conclusions to be confirmed.

Singletary57 in an informative review on the potential health benefits of cinnamon (C. verum, C. cassia/C. aromaticum and C. burmanni and (C. spp.)) identified a study on healthy human subjects (female athletes) in which 3 g per day of cinnamon powder taken for 6 weeks improved muscle soreness but had no effect on IL-6.39

9.6.3

Antinociceptive/Analgesic and Wound Healing Properties

The anti-nociceptive/analgesic and wound healing properties of cinnamon, particularly C. verum, have been reported in vitro.43 However, the bulk of the literature comes from animal studies in which extracts of cinnamon and its leaf oil were used.44,47 Wound healing properties, specifically via an increase in a process called epithelialization, which involves the migration and proliferation of epithelial cells across the edges of a skin wound, and an increase in the breaking strength of the wound have also been demonstrated for this spice in vivo using animal models when administered topically and orally.58,59 A small number of studies have also investigated these properties in humans. The analgesic effect of a herbal ointment which contained cinnamon (C. spp.), ginger, mastic (a resin obtained from the mastic tree, which is used for its wound healing and anti-microbial properties) and sesame seed oil, has been reported in a double blind RCT involving patients with knee osteoarthritis (the amounts of these constituents were not provided in the study). The ointment was massaged over the knee for one minute three times a day for six weeks (no additional information was provided about the ointment formulation). The study found that although it was not better at providing pain relief, morning stiffness and limited motion, the effects of the cinnamon ointment were comparable to that of a salicylate ointment (salicylate is a salt of salicylic acid from which aspirin is derived).60 Mohammadi et al. 61 assessed the efficacy of cinnamon (C. verum), specifically a 2% cinnamon extract ointment on perineal pain (pelvic pain) and healing of episiotomy wounds (which result from a surgical incision made to enlarge the opening for a baby to pass through during labour) in an RCT. The authors reported that for those that received the ointment, which was administered for 10 days, the pain and healing scores were significantly better than for those who received the placebo. A recent RCT by Zareie et al. 62 reported a significant decrease in the frequency, severity and duration of pain alongside significant decreases in markers of inflammation– IL-6 and NO – in migraine sufferers who took cinnamon powder in capsule form (600 mg per capsule; three capsules taken once a day for 2 months). Cinnamon's pain relief effects are believed to be linked to the anti-inflammatory properties of its major constituents eugenol, cinnamaldehyde and linalool, with evidence also suggesting that the effect of the latter constituent may be mediated by NO and cholinergic and glutamatergic compounds (i.e. compounds that mimic the neurotransmitter acetylcholine and modulate the amino acid neurotransmitter glutamate, respectively, and are involved in contributing to endogenous pain controlling systems).49,50,63,64 As oxidative stress that results from injury may damage or impair epithelialization as well as collagen synthesis, it has been

postulated that the antioxidants in cinnamon might be responsible for promoting wound healing.58,59 Cinnamon's (C. verum) anti-inflammatory activity might also contribute to its wound healing properties.58 However, additional research is required to establish whether cinnamon can be used in the development of novel analgesic and wound healing treatments. The effect of cinnamon in women with primary dysmenorrhea, which results in painful cramps that are cyclical as they occur just before or during menstruation (the condition can also cause nausea), has also been a focus of the potential benefit of this spice due to its traditional use in the treatment of abdominal cramps and nausea. Three double blind RCTs reported decreases in menstrual bleeding, the severity scores for nausea and pain, and the frequency of vomiting in women given cinnamon (the species used was not specified although it is assumed that it was C. verum as this species was mentioned in both studies) compared to those given the placebo. The dosages and durations were 1260 mg per day for the first 72 h of the women's menstrual cycle65,66 and 1000 mg three times a day for the first 72 h of the menstrual cycle for two cycles continuously.67 However, when compared to the non-steroidal anti-inflammatory drug ibuprofen, cinnamon was not more effective.66

9.6.4

Glucose Lowering and Anti-diabetic Properties

The potential of cinnamon to maintain glucose homeostasis (the tight regulation of blood glucose levels) and/or improve glycaemic control is well established using non-human studies.68,69 In vitro, C. verum has been shown to inhibit the activity of enzymes involved in glucose digestion, namely pancreatic α-amylase and αglucosidase. Such activity suggests that this spice could reduce the intestinal absorption of glucose post ingestion. C. verum has also been shown in vitro to possess insulin-like effects that are involved in maintaining glucose homeostasis, specifically the stimulation of glucose uptake, gluconeogenesis (glucose synthesis from non-carbohydrate precursors) and glycogen synthesis. Research indicates that cinnamon may also be able to stimulate insulin release and activate insulin receptor activity.68 Cinnamon is also reported to inhibit haemoglobin glycation (a biomarker of diabetes which can lead to the vascular complications that result from this disease) in vitro.70 In animal studies, C. verum is reported to reduce fasting blood glucose (FBG) levels (which is used to identify those who are pre-diabetic and diabetic) and glycated haemoglobin (HbA1c) and increase insulin levels. C. verum has also been shown to be of benefit in animal models of diabetic neuropathy.68 Clinical trials, systematic reviews and also narrative reviews have investigated or evaluated the efficacy of cinnamon supplementation in improving glycaemic control in non-diabetic, pre-diabetic and diabetic subjects.57,71,72 In a recent narrative review, Singletary57 provides an informative qualitative analysis of cinnamon's effects on glycaemic control. Beginning with non-diabetics, Singletary identified five RCTs which demonstrated the effect of cinnamon on insulin resistance and glycaemic control in women with PCOS. This condition is an endocrine disorder that gives rise to a number of conditions in women of

reproductive/child bearing age, including hyperandrogenism (excess androgen (male hormone) levels), irregular menstrual cycles and/or polycystic ovaries (ovaries that form small fluid filled sacs, also called follicles, which may fail to release eggs). The dosage of cinnamon in these RCTs ranged from 999 mg per day to 1500 mg per day; in fact for the majority of the RCTs (4 out of 5) the dosage was 1500 mg per day. Cinnamon was taken as a powder in capsule form for all studies. The duration ranged from 8 weeks to 6 months and the sample size ranged from 6 to 42 subjects. The species of cinnamon used was not identified in any of the studies. The effect of cinnamon on insulin resistance was reported in 4 of the RCTs, for which 3 reported an improvement when compared to the placebo, and in less than half of the studies FBG levels decreased as a result of the cinnamon intervention compared to the placebo group.55,73,75 Singletary57 also identified a larger number of RCTs carried out on healthy and obese subjects and those with NAFLD, but the reported findings are not consistent for blood glucose and insulin. Of the RCTs identified, about 12, approximately 25%, reported a significant decrease in postprandial glucose area under the curve following cinnamon supplementation (postprandial blood glucose area under the curve is used widely to determine if glucose tolerance – the ability to metabolize/process glucose – is impaired).76,78 Supplementation in these subjects ranged from a 1 g single dose to 3 g per day for 14 days; in fact most involved single doses of cinnamon powder in capsule form. Others provided cinnamon in the form of aqueous or ethanol extracts or tea.77,79 C. verum, C. cassia, C. burmanni and C. aromaticum were used in this set of studies. Cinnamon was reported to decrease insulin resistance and/or improve insulin sensitivity in only 3 out of the 12 studies identified.78,80,81 A number of these studies also investigated the effect of cinnamon on gastric emptying as this process is delayed by hyperglycemia. However, there was no change in gastric emptying following cinnamon supplementation in two out of the three studies in which it was investigated.80,82,83 One study reported that increasing dosages of C. verum (85–500 mg per day) over 12 weeks resulted in no change in FBG in healthy subjects.84 In contrast, a recent study by Ezzat-Zadeh et al. 85 reported that consumption of cinnamon (C. spp.) – 6 g of cinnamon added to oatmeal – by healthy subjects who typically consumed a diet low in fibre and polyphenols resulted in a decrease in the rate of change of glucose and plasma insulin and C-peptide (a protein produced and released by the pancreas alongside insulin; it is an indicator of how much insulin is produced and can be used to differentiate between type 1 and type 2 diabetes as there is little to none in the type 1 form). Another study, on subjects with NAFLD, reported that powdered cinnamon given in capsule form (1.5 g per day for 12 weeks) resulted in lower levels of FBG and a decrease in insulin resistance compared to those receiving the placebo.53 The inconsistencies reported highlight the need to interpret these findings with caution. Evaluation of RCTs on the effectiveness of cinnamon on glycaemic control in subjects with poor glucose homeostasis as a result of impaired glucose tolerance (subjects with types 1 and 2 diabetes and subjects with MetS) revealed inconsistencies in outcomes, which resulted in no more than cautious suggestions regarding the efficacy of cinnamon and the need for further studies.57,71,72 Singletary57 identified 27 RCTs carried out between 2003 and 2018. The outcomes

of the trials varied due to the use of different statistical analyses, cinnamon species and cinnamon formulations (cinnamon powder or aqueous extract in capsule form). Regarding subjects with T2D, some studies used subjects with controlled glucose levels and others did not. The issue of gender-based responses was also raised. Dosages and durations varied (120 mg per day to 6 g per day and 6 weeks to 12 weeks) with one study using a single dose. Although just over half of the studies reported some degree of improvement in blood glucose control, there were inconsistencies in how individual indicators of this control responded to cinnamon. For example, in some studies improvements in FBG were reported but not in others. The same applied to HbA1c. (The majority of these RCTs (20) reported inconsistencies in the effect of cinnamon on FBG and HbA1c.) Furthermore, it was not possible to establish a dosage and a duration that were associated with the positive changes reported, which was likely due to the wide range of dosages and durations used. Other issues highlighted by Singletary57 as contributing to the inconsistencies reported include differences in ethnicity, culture (subjects were from Pakistan, India, US, Germany, the Netherlands, Thailand, UK, Israel, Sweden, China, Iran and Iraq)71,72,86 and also diet, including the test meals used and the different amounts and forms of carbohydrate used which could have influenced efficacy.78,82,87 Regarding the clinical significance of the findings related to diabetic patients, it is unclear what they are. Making reference to analysis carried out by Santos and da Silva86 on the significance of cinnamon's effect on glycaemic control, and also lipid profiles, Singletary57 concluded that “in only a few studies” did the modest benefits provided by cinnamon in the RCTs meet the American Diabetes Association's goals for decreasing FBG and HbA1c. Going a step further, Santos and da Silva86 and Costello et al. 72 concluded that the decreases in glucose, and also triglyceride (TG) levels, due to cinnamon, despite being significant, are not of clinical importance particularly in those with the severest forms of T2D in which both FBG and lipid levels are extremely high. Finally, Namazi et al. 71 in a recent systematic review and meta-analysis of the efficacy of cinnamon on glycaemic control in T2D came to similar conclusions because of the high heterogeneity between studies. They acknowledged that although there is evidence of an effect, this is limited to blood glucose levels and no other parameters of glycaemic control including HbA1c were changed/improved. They therefore stressed the need for a cautious interpretation of the positive effects reported and the need for new high quality trials. A study in which cinnamon was combined with other herbs and spices, and consumed as part of a meal, has generated results that suggest that in a ‘real-world’ context, this spice may contribute to conferring protection against chronic noncommunicable diseases, specifically T2D. Haldar et al. 88 have reported that cinnamon (0.25 g and 0.5 g) in combination with a number of other herbs and spices known to be polyphenol rich namely cayenne pepper (0.5 g and 1 g), clove powder (0.25 g and 0.5 g), coriander seeds (powder) (1 g and 2 g), cumin seeds (powder) (1 g and 2 g), garlic (fresh) (10 g and 20 g), ginger (fresh) (10 g and 20 g), Indian gooseberry (‘amla’ powder) (1 g and 2 g) and turmeric (2 g and 4 g) and consumed as part of a vegetable curry that included eggplant, improved postprandial glucose homeostasis in a dose-dependent manner in men with BMIs in the healthy and overweight ranges. This effect may be due to a dose-dependent

increase in the levels of the hormone glucagon-like peptide-1 (GLP-1), which plays a key role in improving glucose homeostasis.89,90 Interestingly, this spice blend increased postprandial TG levels, which contrasts with other findings (see section below on Lipid Lowering Properties). However, Haldar et al. 88 suggest that the decrease in eggplant with the increase in the amounts of the spices added to the curry might explain this increase, as this food is reported to possess lipid lowering effects (albeit in rats).

9.6.5

Lipid Lowering Properties

Numerous in vitro and in vivo (animal) studies have demonstrated the lipid lowering effects of cinnamon,29,69,91 with mechanisms of action linked to increasing fatty acid oxidation and the activation of peroxisome proliferatoractivated receptors (PPARs) – activation of these receptors results in the decrease in TG levels and total cholesterol.92,93 Human studies involving cinnamon (C. spp.) (0.61 g and 1.11 g) consumed as part of a herb and spice blend have reported a lowering of TG levels in healthy overweight subjects following the consumption of the blend in conjunction with a meal.33,94 Although one study only reported the reduction in postprandial TG levels when the period after the consumption of the meal included a rest period. When the postprandial period included a series of tasks that gave rise to stress (referred to as stressor tasks) there was no evidence of the reduction in postprandial TG, which suggested to the authors that psychological stress may lessen any protective effect of the blend on cardiovascular disease risk. The study also suggested that the herb and spice blend inhibits lipid digestion in vivo, as enzymes involved in this process, namely pancreatic lipase and phospholipase A2, were inhibited in vitro by the blend in a dose-dependent manner. Li et al.,35 in another culinary herb and spice blend study which included cinnamon (C. spp.) (0.45 g), did not report a reduction in TG levels post consumption of hamburger meat seasoned with the blend. It was suggested that this finding could be due to the small impact the hamburger meat on its own had on postprandial TG. Cinnamon's lipid lowering capacity on its own has been reviewed by Maierean et al. 95 The authors identified 13 RCTs, mainly involving subjects with T2D, with a minority of subjects with impaired glucose tolerance and NAFLD. A number of the studies included were also used in the reviews by Yazdanpanah et al.96 and Mousavi et al.,97 and again as with the other systematic reviews, dosage (1–10 g per day), formulation (capsules of Cinnulin PF, powder and extract, and cinnamon given in combination with dietary polyphenols (procyanidins or cellulose)) and duration (60 days–4 months) varied. Furthermore, the species of cinnamon used was not the same and in some studies the species was not specified.98,108 The review concluded that cinnamon supplementation was effective in lowering blood TG, total cholesterol (TC), although it had no effects on low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). The authors argued that T2D may have confounded the findings thus making it difficult to apply them to other groups. Furthermore, not all the studies provided information as to whether subjects were also taking lipid-lowering medication, which could have also influenced the findings. Thus, the authors concluded that although the findings

suggest possible benefit of cinnamon in those with T2D and impaired glucose intolerance, the findings' clinical significance need to be confirmed. An RCT published in the same year (2017)56 confirmed the conclusions of the systematic review in relation to the lipid lowering effects of cinnamon in subjects with impaired glucose tolerance (the subjects had MetS for which impaired glucose tolerance can sometimes be a feature109) and obesity. The subjects took capsules each containing 500 mg of cinnamon (prepared from cinnamon bark, which the authors referred to as Dalchini (which is C. verum)) at a dosage of 3 g per day for 16 weeks. This intervention, compared to the placebo group, resulted in significant decreases in TG, TC, LDL-C and their LDL/HDL ratio; their HDL-C increased significantly. The authors acknowledged these findings as promising but again noted that they could not as yet be extrapolated beyond the subjects used. The lipid lowering effect of cinnamon in women with PCOS, for which insulin resistance and dyslipidemia are common features, has also been investigated. Two double blind RCTs reported that cinnamon supplementation (C. spp.) (cinnamon powder in capsules at 1.5 g, in three divided amounts, per day for 12 weeks or three cinnamon capsules each containing 500 mg a day for 8 weeks) significantly decreased LDL-C compared to placebo and/or baseline levels. However, the effects of these interventions on other lipids, namely TG, TC and HDL-C, were not consistent.40,75,110 In one study, TC and TG were significantly decreased and HDL-C significantly increased compared to placebo and/or baseline levels but in another no significant changes in these lipids were reported.75,110

9.6.6

Anti-obesity Properties

Studies on the anti-obesity properties of cinnamon have generated mixed and inconsistent results. For example, some studies have reported that cinnamon supplementation (water soluble cinnamon extract (Cinnulin PF®) and fresh cinnamon bark (C. spp.)) had beneficial effects on body composition, by increasing lean mass in pre-diabetic subjects with features of MetS, decreasing body mass index (BMI), body weight, percentage body fat and visceral fat, and increasing percentage skeletal muscle, in subjects with T2D.111,112 However, other studies, in which either fresh cinnamon bark (C. spp.) or C. cassia (powdered and in capsules) were used, have reported no significant changes in body composition (body weight, BMI and waist circumference (WC)) following cinnamon supplementation compared to placebo in women with PCOS.75 Another study has reported significant decreases in BMI and WC after 12 weeks compared to baseline, but there were no significant changes in these body composition measures compared to the placebo group.103 Two recent systematic reviews with meta-analyses by Yazdanpanak et al. 96 and Mousavi et al. 97 have been carried out on RCTs on the effect of cinnamon on body composition to ascertain, based on current evidence, what the position is regarding the efficacy of this spice in the management of obesity. Both reviews included the same studies, which were focussed on subjects who were pre-diabetic, overweight or had T2D, MetS, PCOS and RA. Both reviews concluded from their analyses that cinnamon is effective in reducing body weight, BMI, waist hip ratio (WHR), WC

and/or fat mass. From their analysis, Yazdanpanak et al. 96 concluded that cinnamon supplementation appears to be at its most effective on BMI and body weight at a dosage of 2000–3000 mg per day but they did not find a relationship between dosage and effect. Mouvasi et al. 97 reported an effective dosage on fat mass of equal to or greater than 2000 mg per day when administered for at least 12 weeks. They also found that the effects were greater on body weight in subjects under 50 and those with a baseline BMI of at least 30 kg m−2 (which is in the obese range113). As with the systematic reviews discussed above, study design heterogeneity is a limitation. For example, the type of subjects used differed between studies, and some studies used mixed groups of male and female subjects, which may give rise to different responses.57 Dosages also varied (336 mg per day to 10 g per day), and the formulations used also differed − capsules of cinnamon in the form of Cinnulin PF®, powder or extract were used as well as cinnamon given in combination with metformin, which is used to treat T2D, cinnamon given in combination with tea, and cinnamon combined with exercise, and durations ranged from 6 to 16 weeks. Furthermore, the species of cinnamon used differed and some studies did not specify the species used. Yazdanpanak et al.,96 therefore, interpreted their findings with caution and they highlighted the need for further well designed studies in overweight and obese subjects who are metabolically healthy (that is without conditions such as T2D and MetS) to establish cinnamon's effectiveness in reducing body weight. In contrast, Mousavi et al. 97 stated that cinnamon “could be recommended as a weight-reducing supplement”. However, they also stated the need for further studies in light of the heterogeneity issues. A number of mechanisms of action have been postulated to explain some of the effects of cinnamon on body composition. These include the action of its bioactive constituent cinnamaldehyde on gastro-intestinal function, energy expenditure, appetite, visceral fat deposition and fatty acid oxidation.96 Other mechanisms are suggested to involve cinnamon's polyphenols.96

9.6.7

Efficacy in the Treatment of Non-insulin/Non Lipidaemic Symptoms of Polycystic Ovarian Syndrome (PCOS)

In addition to investigating the effect of cinnamon on insulin resistance and glycaemic control in women with PCOS, the spice's effect on hormone levels, menstruation and ovarian cysts has also been investigated. Again, across the small number of RCTs (which are the same as those discussed above), dosages ranged from 999 mg per day to 1500 mg per day. None of the studies reported changes in the serum levels of the oestrogen hormone oestradiol, and the androgens, or ovarian volume, which is a measure of reproductive potential.57

9.6.8

Anti-hypertensive Properties

Findings from some studies concerning the effect of cinnamon on blood pressure suggest that this spice may possess cardioprotective properties linked to blood pressure. However, results, particularly from human studies, are mixed.

The lowering of blood pressure by cinnamon (C. verum) has been demonstrated in normotensive and hypertensive rats using aqueous and ethanol extracts, which caused significant drops in mean arterial blood pressure and systolic blood pressure (SBP).114,115 More recently, the effect of cinnamon on blood pressure has been investigated in humans with a focus on subjects who were pre-diabetic or had T2D. Wainstein et al. 116 reported that in subjects with T2D, cinnamon (C. cassia) supplementation (1200 mg per day of powdered cinnamon in capsules for 12 weeks), decreased SBP. However, no significant change was reported for diastolic blood pressure (DBP) but it did decrease at the end of the supplementation period. When cinnamon (C. verum) (3 g daily) was given with three glasses of black tea for 8 weeks to subjects who had T2D, no reduction in blood pressure (SBP) was reported.117 However, Akilen et al. 103 reported significant decreases in both SBP and DBP after 12 weeks of cinnamon supplementation (C. cassia) (2000 mg per day of capsules of cinnamon powder) compared to the placebo group for subjects with T2D. Ziegenfuss et al.,111 reported that capsules of cinnamon extract (C. spp.) (500 mg per day) given for 12 weeks resulted in a significant decrease in SBP compared to the placebo group, but there were no changes in DBP. In a systematic review and meta-analysis of these three RCTs, Akilen et al. 118 concluded that short term (no more than 12 weeks) consumption of cinnamon had a significant anti-hypertensive effect in diabetic and prediabetic subjects. However, as with the systematic reviews and meta-analyses discussed above, they advised caution in interpreting what the authors acknowledge to be promising findings due to study design heterogeneity, the limited number of studies and their small sample sizes. A more recent systematic review and meta-analysis carried out by Mousavi et al. 119 included a larger number of RCTs (9), as their analysis was not limited to subjects with diabetes or prediabetes. Their analyses identified that greater effects on the lowering of SBP occurred at amounts equal to or greater than 2 g of cinnamon for interventions that lasted at least 12 weeks for participants who were under 50 years of age. For DBP, they found that it was decreased using lower amounts. However, they did not find any significant relationship between dosage and duration for both SBP and DBP. Regarding possible mechanisms of action, researchers have put forward the antioxidant properties of cinnamon, due to the role that oxidative stress plays in the development of T2D.38,120 Other mechanisms that have been proposed include activation by cinnamon of PPARs. Cinnamon might also elicit the lowering of blood pressure via its inhibition of advanced glycation end (AGE) products, for example glycated proteins, such as glycated haemoglobin (HbA1c), and LDL-C.116

9.6.9

Neuroprotective Properties

The interest in the possible use of cinnamon as a novel treatment for degenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is based in part on the antioxidant and anti-inflammatory properties of cinnamon and some of its bioactive constituents, as both oxidative stress and chronic inflammation contribute to both AD and PD.121,122 However, there is a paucity of studies on the

neuroprotective effects of this spice. Constituents of different species of cinnamon, and also sodium benzoate – a metabolite of cinnamaldehyde,123 have been shown to possess some potential in rodent models of ischaemic brain damage (in which blood flow to the brain is restricted), and murine and human neural (brain) cells (astroglia and neurons) in vitro.124 In addition, Frydman-Marom et al. 125 reported that feeding aqueous extract of cinnamon (C. spp.) bark powder (referred to as CEppt in the study) to a fly (Drosophila melanogaster) model of AD resulted in improved longevity, full recovery of locomotion defects and inhibition of the formation of plaques of β-amyloid fibrils, which characterize AD and are neurotoxic as they destroy connections between neurons. They also investigated the effect of the same preparation in a murine model of AD and reported a decrease in plaques and an improvement in cognitive function. The extract also protected rat neural cells in vitro from the toxic effect of β-amyloid fibrils.125,126 Peterson et al. 127 reported that cinnamon (C. verum) extract decreased tau aggregation, which is another main feature of AD; the tau protein, when it accumulates in the brain, is toxic. However, despite this reported potential, no human studies have been carried out.

9.6.10

Chemopreventive/Anti-cancer Properties

Investigation into the chemopreventive/anti-cancer properties of cinnamon (focussed on C. verum and C. cassia) and its bioactive constituents are limited to in vitro and animal studies.29 In vitro, cinnamon, an aqueous extract as well as a procyanidins fraction isolated using high performance liquid chromatography (HPLC), has been shown to inhibit the enzyme vascular endothelial growth factor subtype 2 (VEGFR2) kinase, which is involved in angiogenesis (the formation of new blood vessels which plays a key role in carcinogenesis).128 This effect may be due to bioactive constituents of cinnamon, which have been shown to inhibit angiogenesis, tumour growth via cell cycle arrest and tumour invasiveness, and to promote apoptosis.129,131 However, the actions of cinnamon and its constituents on cancer cell growth do not appear to always be the same. For example, Lackova et al. 132 reported that extracts (methanolic) of cinnamon promoted the growth of human prostate cancer cells. Yet its constituents were reported to inhibit the growth of these and other human cancer cells, including those of the breast and lung.133,134 In vivo, aqueous extracts of cinnamon have been shown to enhance the activity of the phase 2 enzyme glutathione S-transferase (GST) and decrease lipid peroxidation in a murine model of colon cancer. Enhancement of GST activity is linked to cancer prevention via the deactivation of chemical carcinogens.135 Cinnamon may therefore elicit a chemopreventive/anti-cancer effect via activation of GST, resulting in detoxification and/or a suppression of oxidative stress. Evidence of cinnamon preventing or inhibiting the cancer process via its antioxidant properties is supported by Chou et al.136 who reported that cinnamon, specifically the essential oil of C. cassia and its bioactive compound cinnamaldehyde, inhibited alpha-melanocyte stimulating hormone induced melanin synthesis and thiobarbituric acid-reactive substance (TBARS) levels (a marker of oxidative stress) in murine melanoma cells in vitro. The inhibition of oxidative

stress in these cells by cinnamon and its constituent was further supported by the normalisation of the levels of the antioxidant enzyme CAT. An in vivo study by Bhattacharjee et al. 137 investigated the effect of cinnamon in combination with cardamom in a murine model of colon carcinogenesis (see chapter on Cardamom for details). They reported that the combination enhanced GST activity and reduced oxidative stress by lowering lipid peroxidation; thus providing evidence in vivo of the spices' ability to induce the phase 2 detoxification enzyme in a model of carcinogenesis.

9.6.11

Anti-microbial Properties

The anti-microbial activity of cinnamon (both extracts of the bark and leaves and also its essential oil) against bacteria and fungi pathogenic to humans is well established.29,69,138,140

9.6.11.1 Anti-bacterial Properties Ranasinghe et al. 69 identified 30 studies (carried out in Africa, Asia, Europe, the UK and the US) reporting the anti-bacterial activity of C. verum covering a wide range of clinically significant bacterial species including the gram-negative Helicobacter pylori, Klebsiella pneumoniae, and Pseudomonas aeruginosa, and the gram-positive Clostridium difficile, Listeria monocytogenes, and Staphylococcus aureus. Some of these studies reported the effectiveness of C. verum against multidrug resistant strains of Escherichia coli and Klebsiella pneumonia.139,141 Although the majority of studies are in vitro, a small number of human studies have been carried out. Rosti and Gastaldi reported the effectiveness of cinnamon bark (from C. verum) in the successful treatment of enteric (gut) infections, specifically due to Salmonella enteritidis, and E. coli 0157:H7, following consumption of ground cinnamon bark 3 to 4 times a day for 10 days or ground bark and cinnamon flavoured tea for 2–3 times a day for a week.142,143

9.6.11.2 Anti-fungal Properties C. verum also acts against pathogenic and toxigenic (toxin producing) fungal species Candida, including multi-drug resistant strains of Candida albicans, and Aspergillus, respectively.141 Furthermore, a commercially available form of C. verum is reported to work effectively against fluconazole resistant and susceptible Candida species in some HIV patients with oral thrush following cinnamon's administration for one week (fluconazole is an anti-fungal medication used to treat candidiasis (oral thrush)).144 Natural flavours from C. verum and/or cinnamic aldehyde, which gives cinnamon its flavour, when added to gum were effective in killing bacteria that contribute to halitosis.145

9.6.12

Prebiotic Potential

Studies in vitro and in vivo (in humans) have demonstrated the prebiotic potential of

cinnamon (C. spp.) via its ability, on its own and in combination with other herbs and spices (for details of the combination go to the chapter on Black Pepper) to modify human gut microbiota.146,147 However, larger, longer term and diet controlled (as diet influences the profile of gut microbiota) studies are required to better establish the prebiotic potential of cinnamon. With the role of a diverse microbiome being linked to protection against the development of chronic non communicable diseases,148 this is an exciting area of research.

9.6.13

Anti-parasitic Properties

Regarding cinnamon's anti-parasitic activity, the essential oil of its bark and leaf of C. verum have been shown to be effective against species of mosquito that transmit malaria, which is caused by the parasite Plasmodium, and the human head louse parasite Pediculus humanus capitis.69,149,150

9.7

Safety and Adverse Effects

Although cinnamon is generally regarded to be safe when used in the preparation of food, it is noted that one of its polyphenolic constituents, coumarin, is known to be mildly hepatotoxic in humans. Thus, concerns have been raised about the heavy consumption of foods that have cinnamon as an ingredient.151,152 The levels of coumarin vary between species of cinnamon, with C. verum reported to contain less than 0.01 g kg−1 but C. cassia reported to contain 3.6 g kg−1.153 Therefore knowledge of which species of cinnamon is being used is important with regards to safety. In a recent, quite detailed and comprehensive systematic review, Hajimonfarednejad et al. 154 reported on the safety and adverse effects of cinnamon across 38 RCTs, 20 case reports, 7 case series and data collected by the World Health Organization (WHO), the UK Medicines Control Agency, the US Food and Drug Administration (FDA), the Australian Database of Adverse Event Notification (DAEN), the Canadian Vigilance Adverse Reaction Online Database and the German Bundesinstitut Fur Arzneimittel Und Medizinprodukte (BfARM). No combination, animal and in vitro studies were included. For the RCTs, only 5 reported adverse effects (in subjects with PCOS, T2D, seasonal allergic rhinitis). It did not appear that symptoms were specific to species. Fourteen RCTs reported no adverse effects (in subjects with T2D, PCOS, dysmenorrhea, and who were post episiotomy, overweight, obese, pre-diabetic or healthy) and 19 did not include any information about adverse effects. The symptoms reported in the 5 RCTs were nausea, heartburn and stomach ache, which were the most common, headache, rash and hives, cough, irritation of the throat, menstrual cramps, fever, body aches and hypoglycaemic seizure in a subject with T2D. The duration of the cinnamon interventions in these studies ranged from 4 weeks to 6 months, and the dosage from 200 µg per day to 1.5 g per day; the lower dosage, which was for C. verum, was administered in the form of a nasal spray, the higher dosage, which was for C. casia, was administered orally in capsule form. Dosages of 80 mg per day (ethanol extract of cinnamon, C. spp.), 1 g per day of powdered cinnamon (C. spp.) in pill

form, and 1 g per day of powdered cinnamon (C. cassia) in capsule form also caused adverse effects. Although adverse effects occurred at these dosages and durations, it must not be assumed that these will give rise to adverse effects in all, including healthy, subjects, as not all subjects in the RCTs reported the symptoms listed above. Of the 141 subjects randomized to receive a cinnamon intervention 17 (approximately 12%) reported adverse effects. Furthermore, in the 14 RCTs for which no adverse effects were reported, there was overlap in the ranges for duration and dosage with those that did report adverse effects. Regarding the case reports and case series, which concerned mainly healthy subjects although a small number were about subjects with conditions including T2D, coronary heart disease, hypertension, hyperlipidemia, depression, rheumatism, obesity and fibromyalgia, adverse effects were more significant than those reported in the RCTs and included acute hepatitis, oral and allergic contact stomatitis, which results in inflammation of the mouth and lips, allergic contact dermatitis, exacerbation of rosacea (a chronic skin condition that results in flushing and facial redness) and oral mucosal reactions. No information regarding the dosages was provided mainly because the subjects took cinnamon in the form of cinnamon flavoured food and products including chewing and bubble gum, toothpaste, mints, bread pudding, sugar and coffee. Cinnamon was also taken in the form of supplements, vaginal suppositories, containing 3% cinnamon, cinnamon oil and cinnamon oil pills, and cinnamon essential oil. Following intervention or removal or elimination of cinnamon/cinnamon products these symptoms disappeared. Information obtained by Hajimonfarednejad et al. 154 from the organizations listed above indicated that the number of cases of reported cases of adverse reactions to cinnamon were and are low. The WHO registered a total of 44 cases of predominantly gastrointestinal adverse reactions to cinnamon over a 43 year period (1973–2016), and reports of 58 adverse effects were received by the UK Medicines Control Agency over a 52 year period (1963–2016). Reported symptoms were mainly associated with headaches, amnesia and dizziness but there was one case of liver failure which was fatal. The FDA noted 91 reports of adverse effects including gastrointestinal, cardiac, hepatic, renal, respiratory, skin, vaginal (bleeding), psychiatric (for example panic attack), nervous system (for example dizziness, migraine and tremor) and muscular (for example muscle spasms) disorders. For the remaining organizations, 11 adverse effects, including gastrointestinal, throat, skin and liver disorders, in six cases, were reported. It must be stressed that even with the most prevalent adverse effects, the total number is low. For example, from data obtained by Hajimonfarednejad et al. 154 from these organizations, the gastrointestinal disorders totalled 30. The authors concluded from the data obtained that cinnamon as a spice or as a flavouring agent is safe to use as part of one's diet, it is tolerated well in RCTs but in large amounts and/or for long durations it may, as shown in the RCTs, give rise to adverse effects.

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CHAPTER 10

Clove (Syzygium aromaticum, Eugenia aomaticum, Eugenia caryophyllata) 10.1 Names English: Cloves Bulgarian: Karamfil Chinese: Ding Heung (Cantonese), Ding Xiang, Gong Ding Xiang (Mandarin) French: Clous de girofle Spanish: Clavos de olor Welsh: Clawlys and Clof The name clove comes from Middle English and from the old French “clou” meaning nail “de girofle” of gillyflower (gillyglower was the original name of the spice).1

10.2 Taxonomy Order: Myrtales Family: Myrtaceae Genus: Syzygium Species: Syzygium aromaticum (L.) Merrill et L. M. Perry.

10.3 Origin, Description and Adulteration Native to the Maluku Islands in East Indonesia, clove is a medium size tree (8–12 m) often cultivated in coastal areas, no higher than 200 m above sea level. The flower buds start producing 4 years after planting. The spice is the dried, handpicked, closed nail-shaped flower bud (and seed) of the evergreen plant Syzygium aromaticum L. Merrill et L. M. Perry (syn. Jambosa caryophyllus (Sprengel) Niedenzu and Eugenia caryophyllata Thunberg) of the Myrtaceae family. These buds are dark red to brown with a strong, penetrating pungent sweet, warm, acrid flavour, which leaves a numbing sensation in the mouth.2 Clove is a popular ornamental plant due to its unique fragrance and elegant red flowers. The essential oil of clove is used in cosmetics, toothpaste, soaps and perfumes. According to the Food and Agriculture Organization (FAO), 166 065 ktonnes of clove were produced in 2017, 91.5% from Asia (mainly Indonesia and Madagascar).3 The essential oil of clove, extracted from buds, leaves and stems, is in high demand, and is therefore of high commercial importance so adulteration cannot be

ruled out and methods have been developed for the detection of potential adulterants.4 Possible adulterants of the spice are the use of exhausted clove (the volatile oil has been extracted), the stem and fruits of clove as well as magnesium salt, sand and earth.5

10.4 Historical and Current Uses Clove was used as a spice, a food, in religious practices associated with love and protection and even to make jewellery.6 Clove has been found in ceramic vessels in Syria dating from 1721 BCE and early references to clove can be found in the Han Dynasty period (300 BCE) in China under the name “chicken-tongue spice”;7 it was used as a breath freshener. Clove became a very important, and expensive, spice in European commerce at the beginning of the 8th century, after large forests were first discovered in Indonesia, in the Moluccas (the Spice Islands2), where parents planted a clove tree for every newborn child. It was considered a bad sign if the tree did not thrive.8 Clove was used in folk spells to win friendships or attract positive attention. Candles studded with cloves were lit to prevent gossip and lies. Guan9 quotes an example of a lavish wedding from Freedman:10 “The marriage of Duke George of Bavaria and Princess Jadwiga of Poland in 1476 involved the purchase of “386 pounds of pepper, 286 of ginger, 207 of saffron, 205 of cinnamon, 105 of cloves, and a mere 85 pounds of nutmeg,” furnishing a series of banquets over a number of days”.9,10 The 13th century Venicien explorer, Marco Polo, described vast crops of cloves and other spices in Java and in the islands of the Chinese Sea during the 13th and 14th centuries. In 1501, large quantities of Indian spices such as nutmeg, mace, and cloves made their way to Portugal. In the 17th century the Dutch East India Company gained the monopoly on clove, as they did with nutmeg. Clove is mentioned in the Apicius Roman cookbook as an ingredient for the cooking of beets and boiled chicken, and as part of a mixture to “keep meat fresh and without too much salt”, with honey, whole black pepper, bay leaves, onions, root vegetables and wine. Cloves were also included in a recipe for a summer fruit compote.11 Today clove is still used in both savoury and sweet dishes. It is present in Mexican cuisine “clavos de olor,” often combined with cumin and cinnamon, and is also popular in Peruvian cuisine. In many cultures and cuisines, clove is often blended with other spices. The Chinese five spices mix contains fennel, cassia, black pepper, ginger and clove. In Sri Lanka and North India, cloves are added to biryanis (rice mixed with vegetables or meat), and pickles and Garam Masala (masala meaning spice mix) with cumin, coriander, cardamom, pepper, cinnamon, cloves, and nutmeg (this spice mix varies in constituents and amounts of constituents in Indian, Pakistani, Nepalese, Bangladeshi, Sri Lankan and Afghan recipes). The Middle Eastern Baharat spice blend contains allspice, black pepper, chili peppers, cardamom, cinnamon, cloves, coriander, cumin, nutmeg. In the West, cloves are used in meat dishes (curries), dressings, deserts and sauces. Clove is a contributor to both ketchup and Worcester sauces, traditionally added to flavour apple and rhubarb desserts and pumpkin pie, and is often used in winter dishes and

festive drinks. The United States Department of Agriculture (USDA) granted clove Generally Recognized as Safe (GRAS) certification when used as food, and granted clove essential oil GRAS certification when used as a food additive.12 Clove has antiseptic and antimicrobial activities, and has been used in Indian Ayurvedic, Chinese and Western medicine for similar applications for dentistry preparations and topical anesthetics.8 Clove oil is used in mouthwash and helps to treat tooth pain. In dental emergencies cloves are applied to the area of pain, providing a numbing effect which is due to eugenol. In dentistry, eugenol is mixed with zinc oxide, and this mix forms a cement that is used as a temporary filling for a tooth cavity. The Commission E monographs warn that clove essential oil may irritate mucosal tissues but there are no known interactions with drugs. It is used in mouthwash (corresponding to 1-5% essential oil) (see section on Safety and Adverse Effects). Clove features in the Online Encyclopaedia of Traditional Chinese Medicine,13 and is described as warm and pungent. An online source suggests that clove is used for the meridians of the kidney, spleen, stomach, and lung.14 Clove is used to help relieve colds and nausea, and aids in digestion, hiccups, vomiting, diarrhoea, cold sensations in the stomach, the management of premature ejaculation and vaginal discharge, as well as in dentistry as described above.

10.5 Chemistry, Nutrition and Food Science Phenol Explorer15 shows that clove is rich in phytochemicals, including the flavonols (kaempferol and quercetin), the phenolic acids (gallic, syringic protocatechuic and p-coumaric acids) and the hydroxyphenylpropenes (acetyl eugenol and eugenol). Studies confirmed that gallic acid (estimated by highperformance liquid chromatography, HPLC) was the most abundant constituent in cloves, with other gallic acid derivatives and hydrolyzable tannins present in high concentrations. Caffeic, ferulic, ellagic and salicylic acids have also been identified in clove. Eugenol is the main bioactive compound of clove, and α-humulen has also been identified with β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone and ethyl hexanoate.16 The essential oil fraction of clove is normally extracted via steam distillation and studies report that its composition is approximately 95% eugenol with βcaryophytine, carvacrol, and thymol making up the rest of the essential oil. It is effective against fungi, including Mycotoxigenic Aspergillus, and bacteria.17 Various other extraction methods have been used for the extraction of eugenol, including solvent extraction, hydro-distillation, microwave-assisted extraction, supercritical carbon dioxide extraction and ultrasound-based extraction.18 Regarding the nutritional composition of clove, UK data are the same as for US data for dried samples but with some additional information in the latter (see Table 10.1).19,20 With regards to the nutritional quality of clove, it is generally considered to be poor in the energy yielding nutrients (carbohydrate, fat, protein); however it is rich in fibre, iron, selenium, and phytochemicals. The phytosterol level in clove is high (2.56 mg g−1, see Table 10.1), and although the amount used in cooking is

normally low, cloves could make some contribution to the 2 g per day of dietary phytosterol recommended for the prevention of cardiovascular disease, if consumed regularly.21 Table 10.1 Nutrition composition of ground cloves.19,20 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Per 100 g Cloves

Dried/Ground UK data

Dried/Ground US data

Energy/Kcal Carbohydrates/g Dietary Fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

Na Na Na 20.1 (4.40) 6 6.9 256 730 0.49 Na 5.6 260 8.5 110 1100 Na 240 2.2 53 0.11 0.27 1.5 Na 0 0 Na —b Na

274 65.53 33.9 13 (3.952) 5.97 9.87 256 632 0.368 —b 11.83 259 60.127 104 1020 7.2 277 2.32 8 0.158 0.22 1.56 0.391 0.2 25 8.82 141.8 0.509

a N: Present in significant amounts but not determined. b —: Not assessed or not present.

The United States Department of Agriculture (USDA) granted a Generally Recognized as Safe (GRAS) certification to essential oils of clove for use in traditional food packaging. However, the European Commission authorised the use of linalool, thymol, eugenol, carvone, cinnamaldehyde, vanillin, carvacrol, citral, and limonene in food products but not the essential oils of herbs and spices (except for rosemary which is an approved additive).22 Innovative food research and development does however include clove essential oil in studies from Europe. For example, a collaboration between a Spanish and an Argentinian institution investigated the incorporation of sunflower protein films with clove essential oil in biodegradable and edible films for the preservation of

sardine patties.23 The results showed increased antioxidant properties, reduction of the fish samples' lipid auto-oxidation and delayed the growth of mesophiles.23 Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. Cooking has been shown to affect the antioxidant capacity of clove. A study compared the antioxidant capacity of clove tea (0.1 g dried herbs in 100 mL boiled water), to that of clove stewed (0.1 g) in 100 mL water (clove was first boiled for 10 minutes and then simmered for 60 minutes). Antioxidant capacity was measured via the Trolox equivalent antioxidant capacity assay (TEAC). The antioxidant capacity of stewed clove, was 6.5-fold, and significantly, higher than that of the tea.24 The cooking water of the stew likely contained biologically active compounds that leached out of the spice which would then either be ingested directly or through other foods that absorbed cooking water, or discarded. The increased liberation of biologically active compounds from the softening of the spice post exposure to heat seemed a logical explanation for the effects observed. Baker et al. 25 compared the antioxidant capacity (using the TEAC assay) and the total phenolic content (TPC) assay (measured by the Folin Assay) of uncooked clove compared to cooked cloves. Uncooked clove (0.1 g) was covered with boiled water (25 mL) and stirred for 2 minutes, and cooked cloves (0.1 g) were added to distilled water (25 mL) and left to simmer for 60 minutes at 50 °C. The antioxidant capacity of cooked cloves was 2.3-fold lower than that of the uncooked cloves. The total phenolic content of cooked cloves was 3.3-fold lower than that of uncooked cloves. These results suggest that clove's antioxidant capacity was greatly reduced by cooking.

10.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 10.6.1

Antioxidant Properties

Clove, including its essential oil, possesses antioxidant properties.25,39 It is noted in the literature that, of the most common culinary herbs and spices, its antioxidant capacity, regardless of the assay used or the type of extract, is one of, if not, the highest. For example, Dragland et al. 26 reported that commercially available dried cloves had the highest antioxidant capacity of the culinary herbs and spices investigated; its antioxidant capacity was approximately 4 times higher than those of the second and third ranked, allspice and cinnamon, respectively. In addition, Shan et al. 28 reported that extract (methanol) of dried clove had an antioxidant capacity that was approximately 1.5 times higher than those of the second and third ranked cinnamon and oregano, respectively. Abid et al. 29 reported antioxidant capacities for clove extracted in different solvents (water, ethanol, and water and ethanol) that were the highest out of a list of culinary spices that included coriander, fennel and paprika. Halvorsen et al.,27 Bamdad et al. 30 and Baker et al. 25 also

reported antioxidant capacities for clove (ground or aqueous extract) that were much higher than those of other common culinary herbs and spices, including nutmeg, black pepper, caraway, parsley, basil, cinnamon, ginger, and Mediterranean oregano. The main contributors to clove's antioxidant capacity are its phenolic compounds eugenol and also thymol and quercetin.35,36,38,40 Clove's antioxidant properties have also been demonstrated via its ability to inhibit lipid peroxidation and protein oxidation, both markers of oxidative stress.32,35,37,39 Regarding the beneficial/therapeutic significance of clove's antioxidant capacity, evidence suggests that it may in part contribute to its hepatoprotective ability, which has been identified using a rat model of paracetamol induced liver damage (see section on Hepatoprotective Properties). The antioxidant properties of clove are also reported to be linked to its memory enhancing abilities. Halder et al. 41 reported that clove oil, in addition to increasing the levels of the antioxidant reduced glutathione (GSH), decreased memory deficit (both for short and long term memory) induced in mice. The potential health and therapeutic benefits of clove's antioxidant property via its phenolic constituents, has also been demonstrated in humans. Clovinol, a polyphenolic extract of clove buds, has been shown to improve antioxidant status and decrease lipid peroxidation in healthy human subjects.42 In a randomized double-blind cross-over study, the same preparation given in capsule form (250 mg per capsule once a day for 2 weeks) to social drinkers, who consumed 1 g kg−1 of body weight of alcohol per day for 2 weeks,43 decreased oxidative stress and improved the subjects' antioxidant status, as indicated by increases in the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). These improvements occurred alongside a faster elimination of acetaldehyde, a metabolite of alcohol (ethanol), which causes liver injury, inflammation and also hangovers in heavy drinkers, and a decrease in hangover severity. The anti-inflammatory properties are explored in the next section. There is also some evidence that clove may act as a chemopreventive agent via its antioxidant properties (see section on Chemopreventive/Anti-cancer Properties).

10.6.2

Anti-inflammatory Properties

Clove extract and its essential oil have also been identified as possessing antiinflammatory properties primarily in vitro, but also in vivo, in animals and humans. Clove oil is reported to inhibit the production of markers of inflammation in an in vitro model of chronic inflammation and fibrosis (scarring that occurs during wound healing due to excess tissue remodelling) in which skin fibroblasts were used. Markers of inflammation that were decreased were vascular cell adhesion molecule-1 (VCAM-1), interferon gamma inducible T-cell alpha chemoattractant (1-TAC), a monokine induced by interferon gamma, and interferon gamma-induced protein 10. However, there was no decrease in the production of the proinflammatory cytokine, interleukin-8.44 Bachiega et al. 45 reported that clove essential oil both prevented and inhibited the release of interleukin 1-beta (IL-1β) and IL-6, both pro-inflammatory cytokines, from stimulated murine macrophages in vitro. Interestingly, the oil also inhibited IL-10, which is a key anti-inflammatory cytokine. Rodrigues et al. 50 also reported the ability of clove (both the oil and

hydroalcoholic clove bud extract) to inhibit the release of IL-1β and IL-6. The oil inhibited the release of these cytokines from stimulated murine macrophages, and from macrophages taken from mice given the extract. Baker et al. 25 provided evidence of clove's ability to inhibit the activity of another pro-inflammatory mediator, cyclooxygenase 2 (COX-2). Aqueous extract of clove, plus cooked, and cooked and digested (in vitro) clove, significantly inhibited the activity of this enzyme and the production of prostaglandin E2. Despite studies identifying the anti-inflammatory properties of clove, there is little regarding its beneficial and/or therapeutic significance. In their 2015 review, Pulikkotil and Nath46 proposed that in addition to its antioxidant and anti-microbial properties, clove's anti-inflammatory properties provide the basis for its use in the treatment of periodontal disease (gum disease), the treatment of which clove is used in traditional medicine in parts of Asia.47 However, to date, no clinical trials investigating the efficacy of clove in the treatment of this disease have been carried out. The potential health and therapeutic benefits of clove's anti-inflammatory activity have also been highlighted in drinkers. In their randomized double-blind cross-over study on the effects of the polyphenol rich extract of clove (Clovinol), Mammen et al. 43 reported that after taking this formulation for 2 weeks there was a significant decrease in the pro-inflammatory markers C-reactive protein (CRP) and IL-6 (alongside improvements in antioxidant status, the faster elimination of acetaldehyde and decreased hangover severity in the social drinkers (see section on Antioxidant Properties)). This formulation of clove was also reported to decrease oedema in rats; the effect of the highest dosage was comparable to that of the nonsteroidal anti-inflammatory drug diclofenac.48 Evidence indicates that the antiinflammatory properties of clove reported are due to its main constituent eugenol, which has been shown to suppress inflammation both in vitro and in vivo, the latter in animal studies.45,48,50

10.6.3

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

Evidence from in vitro, animal and human studies provides some support for clove's potential use in the prevention and/or management of type 2 diabetes (T2D), cardiovascular disease, and/or metabolic syndrome (MetS) via its glucose lowering, anti-diabetic and/or lipid lowering properties. Studies carried out in vitro and in vivo (the latter including human studies) have demonstrated cloves' potential glucose lowering and anti-diabetic activity. Clove extracted in ammonium hydroxide was reported to be one of the most effective of a long list of culinary herbs and spices at increasing insulin dependent glucose oxidation in rat adipocytes in vitro.51 In addition, clove extract (ethanol) was the top ranked culinary herb/spice inhibitor of protein glycation, a biomarker of diabetes that can lead to the vascular complications that result from this disease, in vitro. Its inhibitory capacity was 2-fold that of other culinary herb/spices known for their anti-diabetic activity including cinnamon (Cinnamomum burmanni),52 and 6fold and almost 10-fold higher than those for turmeric and ginger, respectively. Skukri et al.,53 reported that clove oil significantly lowered blood glucose in a rat

model of diabetes. The effect of the oil was comparable to that of glibenclamide, which is used to treat T2D. The decrease in blood glucose was associated with some degree of reduction in oxidative stress, which is induced by hyperglycemia,54,55 and a trend towards an improvement in antioxidant status. In addition, clove significantly decreased the number of necrotic cells in the liver and hearts of the diabetic rats; it was noted that this protective effect was not observed in the hearts of diabetic rats given glibenclamide. Clove, and glibenclamide, also minimised considerably the degree of cataracts in their (the rats') lenses. The possible use of clove as a functional food in the prevention of T2D was supported further by the findings of Kuroda et al.,56 who reported that ethanol extract of clove given to diabetic mice lowered their blood glucose levels; the effect of the extract was comparable to that of pioglitazone, which is used to treat T2D. Alshammari57 investigated the effect of clove added to Arabic coffee (also referred to as Coffee Arabica/Turkish Coffee/Saudi Coffee) in mice in which diabetes was induced by the consumption of a high fat diet. The authors included Arabic coffee in the investigation as its consumption in rats has been linked to lowering lipid levels and liver damage.58 Furthermore, coffee may protect against the development of chronic non-communicable diseases including T2D.59 The clove/Arabic coffee combination, as well as Arabic coffee, significantly decreased blood glucose, along with insulin, and glycated haemoglobin. The clove/Arabic coffee combination, and Arabic coffee, also affected the activities of enzymes involved in regulating blood glucose levels, namely glucokinase, glucose 6 phosphatase and fructose 1,6 bisphosphatase. Glycogen levels were also increased in the liver by the combination. The effects on the glycaemic markers (blood glucose and glycated haemoglobin), the glucose metabolising enzymes and glycogen indicated that Arabic coffee and clove promote glucose storage as a way of lowering blood glucose in this animal model via an increase in insulin sensitivity. The clove/Arabic coffee combination, and also Arabic coffee, also significantly decreased total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C). They also increased/normalised high density lipoprotein cholesterol (HDL-C) levels. Constituents isolated from an ethanol extract of clove, namely dehydrodieugenol and dehydrodieugenol B, were shown to possess peroxisome proliferator activated receptor gamma (PPAR-γ) ligand binding activity. This receptor has been identified as a major target for the action of insulin-sensitizing drugs such as pioglitazone so it is possible that the glucose lowering effect of clove could in part be mediated via this receptor.60,61 There is evidence that non-eugenol constituents may also have a role to play in clove's ability to lower blood glucose via another mechanism of action.62 Eugenol reduced clove extract inhibited, in vitro, activities that contribute to raising blood glucose levels, specifically glycogen phosphorylase b activity and glucagon stimulated glucose production in rat hepatocytes (liver cells). In addition, the constituent eugenlin, but not eugenol, was found to inhibit both activities also. When fed to diabetic mice, the eugenol reduced extract significantly decreased blood glucose and the levels of glycated haemoglobin. A study in which clove was combined with other herbs and spices has generated results that suggest that in a ‘real-world’ context, this spice may contribute to the conferring of protection against chronic non-communicable diseases, specifically T2D. Haldar et al. 63 have reported that clove powder (0.25 g and 0.5 g) in

combination with a number of other herbs and spices known to be polyphenol rich (namely cayenne pepper (0.5 g and 1 g), cinnamon powder (0.25 g and 0.5 g), coriander seeds (powder) (1 g and 2 g), cumin seeds (powder) (1 g and 2 g), garlic (fresh) (10 g and 20 g), ginger (fresh) (10 g and 20 g), Indian gooseberry (‘amla’ powder) (1 g and 2 g) and turmeric (2 g and 4 g)) and consumed as part of a vegetable curry improved postprandial glucose homeostasis in a dose-dependent manner in men with BMIs in the healthy and overweight ranges. This effect was possibly via a dose-dependent increase in the levels of the hormone glucagon-like peptide-1 (GLP-1) which plays a key role in improving glucose homeostasis.64,65 Interestingly, this spice blend increased postprandial TG levels, which contrasts with the findings of another study in which a herb and spice blend was used.66 However, Haldar et al. suggested that the decrease in eggplant with the increase in the amounts of the spices added to the curry might explain this increase as this food is reported to possess lipid lowering effects (albeit in rats).63 On its own, clove has also been shown to maintain glucose homeostasis in healthy subjects.67 A polyphenolic clove extract (a hydroalcoholic extract of dried clove buds) when given once a day in capsule form (250 mg per capsule) for 30 days (subjects consumed a meal which consisted of rice, a vegetable curry, meat or fish, and water within 30 minutes and were then given the clove supplement every day for 30 days) significantly decreased postprandial glucose; the first significant drop was noted at day 12 of clove supplementation. The authors also investigated the effect of clove on the subjects' preprandial ‘pre-lunch’ glucose daily and noted that a significant decrease was observed only in subjects who had a ‘pre-lunch’ plasma glucose of between 101 and 125 mg dL−1. For those with a ‘pre-lunch’ plasma glucose of ≤100 mg dL−1 there was no change. Furthermore, the postprandial glucose lowering effect was greater in the higher ‘pre-lunch’ plasma glucose group. Such findings suggest that clove may have a role to play in preventing the development of T2D. Based on in vitro work which formed part of the study, the glucose lowering action of clove may be mediated via an increase in glucose uptake into skeletal muscle, an inhibition of hepatic glucose production and inhibition of enzymes involved in carbohydrate digestion namely alpha-amylase and alpha-glucosidase. With a focus on clove's lipid lowering properties in conditions caused by abnormal or elevated lipid profiles, Jung et al. 68 reported that in mice fed a high fat diet supplemented with clove extracts (ethanol extracts of dried flower buds) there was a significant decrease in white adipose tissue (fat) mass, TC, TG, leptin (a hormone produced mainly by adipose tissue which is involved in the control of energy balance (energy homeostasis) via appetite regulation), glucose and insulin compared to the high fat fed controls. In addition, HDL-C levels decreased slightly compared to the high fat diet controls. The extract inhibited the differentiation of pre-adipocytes in vitro, and in vivo decreased the expression of proteins linked to lipid metabolism including PPAR-γ. However, the reported effect on PPAR-γ is in contrast to the findings of Kuroda et al.,56 which are summarised above, as they reported the activation of PPAR-γ by constituents isolated from clove. They also reported that clove stimulated, in vitro, the differentiation of pre-adipocytes via PPAR-γ activation. The lipid lowering effects may involve constituents other than eugenol, as Sanae et al.,62 in addition to reporting clove's glucose lowering effects,

which are summarised above, reported that eugenol reduced extract of clove significantly lowered triglyceride (TG) and fatty acid levels in diabetic mice compared to the diabetic controls. Clove oil is also reported to lower lipid levels. Rats fed a high fructose diet supplemented with butter, which acted as a source of saturated fat, developed dyslipidemia (abnormal lipid profile), fatty liver, oxidative stress, inflammation, and liver dysfunction as indicated by significant increases in TC, TG, and LDL-C, and a significant decrease in HDL-C. Oxidative stress and levels of the proinflammatory cytokine, tumour necrosis factor alpha (TNF-α), and the liver function enzymes ALT and AST were increased in these dyslipidemic rats. When two different formulations of clove oil – a conventional emulsion or a microemulsion of clove oil (the latter was given to determine if it was more effective as a result of better delivery) – or a micro-emulsion of eugenol were given, the lipid profiles of the rats improved, although they were not normalised, as did liver function. In addition, oxidative stress and inflammation decreased. The magnitude of the effect of the three treatments were similar indicating that the micro-emulsion resulted in no improvement in efficacy.69

10.6.4

Chemopreventive/Anti-cancer Properties

In contrast to its constituent eugenol, there is relatively little published research on the chemopreventive/anti-cancer activity of clove (extract of the bud/plant and essential oil). Furthermore, the chemopreventive/anti-cancer and anti-mutagenic effects of clove reported in the literature are limited to in vitro studies. Evidence also suggests that there is no single mechanism of action by which clove is cytotoxic to cancer cells. Clove (aqueous and ethanolic extracts and its essential oil) has a cytotoxic effect on human breast cancer cells (MCF-7) with the essential oil being the most potent.70 Kouidhi et al. 71 reported on the cytotoxic effect of clove essential oil on human colorectal cancer cells (HT29), human lung cancer cells (A549) and human epidermoid/squamous cancer cells (cells that form on the surface of the skin and on the epithelium/lining of the respiratory and digestive tracts). However, the level of potency of the oil was lower for the latter two cell lines. The mechanism of action of clove may involve eugenol's ability to induce apoptosis and cell cycle arrest.72,73 In addition, there is evidence that this constituent could exert a chemopreventive/chemotherapeutic effect via its anti-inflammatory activity.74 Eugenol is also reported to inhibit the expression of matrix metalloproteinase (MMP) in HT1080 cells (fibrosarcoma (cancerous fibroblast) cells). The protein MMP is involved in tumour metastasis. This effect (on MMP) has only been shown in vitro.75 There is also evidence that clove could act as a chemopreventive agent via its antioxidant properties. Miyazawa and Hisama76 suggested that the suppression of mutagen activation by clove extract (methanol extract and methanol extract reextracted with hexane) might occur via the antioxidant action of its constituents eugenol and trans-isoeugenol. Such a suggestion is strengthened by the inhibition of peroxynitrite (an oxidant) induced DNA damage by a methanol extract of clove.39 In fact clove was the most potent inhibitor of this damage compared to the

other culinary herbs and spices investigated, including greater cardamom, cinnamon, cumin, paprika, nutmeg, rosemary and turmeric. Clove may also prevent DNA damage via attenuation of the inhibitory effect of mutagens on phase 2 detoxification enzymes, such as glutathione S-transferase (GST). However, this effect was for clove in combination with other culinary spices, namely cardamom, cinnamon, cumin and pepper.77

10.6.5

Hepatoprotective Properties

Animal studies using different formulations of clove indicate that this spice may confer benefit against the development of liver damage arising from oxidative stress, fatty liver and hepatic inflammation. Ethanol extract of dried and powdered clove given prior to the induction of liver damage resulted in the normalisation of the liver function enzymes ALT, AST and ALP.78 Aboelnaga reported clove's protective effect against liver damage in rats. Consumption of diets containing clove led to significant improvements (a decrease) in AST, ALT and ALP. Glucose levels and lipid (TC, TG, LDL-C, VLDL C and HDL-C) profiles also improved significantly. This study also investigated the effects of cardamom and star anise, both of which led to the same improvements (see the chapter on Cardamom for more on its hepatoprotective properties).79 When clove oil was consumed by rats with the hepatotoxin carbon tetrachloride, similar improvements in liver function and lipid profile were reported alongside a decrease in hepatic oxidative stress and an improvement in antioxidant status.80 The polyphenol rich extract of clove bud (Clovinol) was also shown to protect against liver damage in rats via the normalisation of liver function enzymes, decreased oxidative stress and improved antioxidant status. This preparation also suppressed inflammation by decreasing levels of CRP and the expression of IL-6 and TNF-α.81

10.6.6

Gastroprotective Properties

The gastroprotective effect of clove has been reported in a small number of studies.82 Animal studies by Magaji et al. 83 and Okasha et al. 84 reported on the anti-ulcerative effect of clove bud extract. The extract also minimized gut mucosal damage. Issac et al. 48 reported that both pre-treatment and simultaneous administration of Clovinol significantly inhibited gastric ulcer production in rats. There were also improvements in gastric morphology with evidence of protection against disruption of the gastric mucosa. It was noted that the effect of the highest dosage used (100 mg kg−1 body weight), when given as a pre-treatment, was higher than that of the drug ranitidine (also known as Zantac) which is used to treat gastric conditions including gastric ulcers; this drug acts by decreasing the production of stomach acid. Pre-treatment with, and simultaneous administration of, Clovinol also resulted in significant increases in antioxidant enzymes (CAT, SOD and GPx) and GSH, and decreases in oxidative stress, in the gastric mucosa of the animals.

10.6.7

Analgesic, Wound Healing, Anti-convulsive, Anxiolytic, Anti-allergic and Aphrodisiac

Properties Clove's analgesic effect, to which eugenol has been shown to be a major contributor,49,85,87 has been reported in a small number of human studies. When compared to the topical anaesthetic benzocaine, the analgesic effect of 2 g of homemade clove gel (a mixture of ground commercially available clove and liquid glycerine at a ratio of 2:3) applied to the lining of the mouth above the gums of subjects who subsequently received two needle sticks, was comparable.88 Elwakeel et al. 89 reported that clove oil cream (1%) when applied 3 times daily for 6 weeks provided pain relief (based on subjective improvement in pain levels) in subjects suffering from anal fissures (small tears in the lining of the anus). These subjects required no additional analgesics. The number and percentage of subjects who reported improvements in pain levels were greater than for those receiving lignocaine, which is used as a local anaesthetic. Furthermore, there was a marked difference, between the clove group and the lignocaine group, in those for whom there was complete healing of the fissure. As stated above, clove oil is traditionally used to treat periodontal conditions47,90 (see section on Anti-inflammatory Properties) so in addition to its antiinflammatory and anti-microbial (see section below on Anti-microbial Properties) effects, its use in this capacity may also be due to its pain relief properties. Clove is also traditionally used as a calming agent and a recent study reported that aromatherapy using clove essential oil decreased anxiety during the first stages of labour with an efficacy that was greater than that of peppermint oil91 (see the chapter on Mint for studies on mood and behaviour). Clove is also traditionally used in Iranian folk medicine to treat epilepsy, and a study by Pourgholami et al. 92 reported that its essential oil prevented convulsions in mice. The constituents eugenol and carvacrol may be responsible for clove oils anti-convulsant effects.87,93,94 Hot water extract of clove given intravenously or orally was reported to inhibit IgE mediated (type 1) allergic reactions in vivo in rats and in vitro using IgE sensitized mast cells.95 Finally, ethanolic extracts of clove bud were reported to increase the sexual activity of male rats.96

10.6.8

Anti-microbial Properties

Clove (extract and essential oil) possesses anti-bacterial, anti-fungal and/or antiviral properties, with evidence suggesting that eugenol and also carvacrol are the main contributors to these activities.46,82,97,105

10.6.8.1 Anti-bacterial Activity Antibacterial activity, in vitro, for clove (extract and essential oil) has been reported against a range of pathogenic (including methicillin resistant and oral) bacteria. These include the gram-negative Shigella flexneri, Shigella sonnei Pseudomonas aeruginosa, Proteus vulgaris, Serratia marcescens, Salmonella typhimurium and other species of Salmonella, Streptococcus mutans and Porphyromonas gingivalis,

and the gram-positive Actinomyces viscoses, Bacillus cereus, Clostridium botulinum, Listeria monocytogenes, Prevotella intermedia, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus suis.35,71,104,106,121 Clove essential oil was reported to have no activity against Klebsiella pneumoniae.108 However, studies in vitro and in vivo report that the oil protects against colonization by these bacteria.122,123

10.6.8.2 Anti-fungal Activity Early work on the anti-fungal activity of clove was reported by Hitokoto et al. 98 They reported that compared to thyme, caraway seeds, sage leaves, dill seeds, turmeric, sweet marjoram, basil leaves, anise, cumin and coriander seeds, powdered cloves had a relatively minor effect on the growth of the toxigenic (toxin producing) Aspergillus fungi Aspergillus flavus (A. flavus), A. ochraceus and A. versicolor, and their respective mycotoxins aflatoxin B1, sterigmato-cystin and ochratoxin A. Clove essential oil is reported to inhibit the growth of oral fungi including Candida albicans (C. albicans), C. guilliermondii and Geotricum capitatum, with its activity against Candida fungi shown to be comparable to that of the anti-fungal agent amphoterecin B.71,124

10.6.8.3 Anti-viral Activity The anti-viral activity of clove oil has been shown against the herpes simplex virus (HSV-1 and HSV-2) and against HSV-2 for an ethanolic extract of clove. However, when compared to the anti-viral medication acyclovir, which is used to treat HSV infections as well as chicken pox and shingles, clove was far less potent.97,105,125

10.6.9

Anti-parasitic Activity

A small body of work has reported on the anti-parasitic activity of clove extract (methanol and ethyl acetate) and clove essential oil against the Gardia lamblia parasite (also known as Gardia giardiasis and Gardia intestinalis) which causes giardiasis (a diarrheal condition) and the malaria parasite Plasmodium falciparum (specifically a chloroquine resistant strain).126,127 Again as with many if not all of clove's other bioactive activities, eugenol was noted as being responsible for this activity.

10.7 Safety and Adverse Effects When used as a food or food additive clove and clove oil are recognised as safe. However, there are concerns about the latter when used for medicinal purposes due to its main constituent eugenol.90 Clove essential oil is reported to be highly cytotoxic to human fibroblasts and endothelial cells at a low concentration (0.03% (v/v)).128 Based on animal studies, clove oil was reported to be slightly hazardous and have a lethal dose for 50% of

the test sample (LD50) value of 3597.5 mg kg−1 of body weight. Both the oil and Clovinol are reported to be safe based on a no observed adverse effect level of 1000 mg kg−1 of body weight per day.48,129,130 Shalaby et al.129 reported that with regular dosing of clove oil at a 10th of its LD50 there was an increase in the activities of liver function enzymes, which is indicative of some disruption of liver function. Investigations of its effect on liver tissue provided no evidence of hepatocyte (liver cell) damage. However, there was obstruction of hepatic blood vessels with infiltrating inflammatory cells. In this study, there was also evidence that clove oil caused a moderate amount of kidney damage. However, the amounts used in these studies were far higher than those used in human studies in which the efficacy of clove, its essential oil or Clovinol was investigated.43,67,88,89 Of these, only some reported on adverse effects, which were not serious. Alqareer et al. 88 reported that a small number of subjects formed small ulcers after application of 2 g of homemade clove gel to the lining of the mouth. Elwakeel et al. 89 noted that two subjects reported itching when clove oil cream was applied to the skin, specifically to anal fissures. There are case reports of adverse, including allergic, reactions to clove extract, clove essential oil and clove cigarettes in the literature.90 Symptoms included blisters of the fingers and palm, erythema (redness of the skin), severe respiratory problems – including pulmonary oedema and pneumonia, which in one case resulted in death (after smoking a clove cigarette), burning and inflammation of the lips and cheeks, reduction in sweat production and/or a local anaesthetic effect.90,131,135 Overdoses of clove oil in small children have also been reported with levels of 5 to 10 mL causing drowsiness, unconsciousness, deep coma, severe acidosis, cramps, impaired liver function, and coagulation, (the latter may be linked to clove's ability to inhibit platelet activation which has been reported in the literature136), convulsions, a lack of awareness of one's environment despite being awake due to the weakening of the central nervous system, leukocytosis (a marked increase in the number of whole blood cells), proteinuria (excess protein in urine) and ketonuria (ketone bodies in urine). In all cases the children were successfully treated.137,139 There are no data available about the use of clove oil by women during pregnancy and lactation. In animal studies, clove oil (0.25% which is equivalent to 375 mg kg−1 of body weight per day) was reported to increase significantly the number of dead cells compared to controls in mouse pre-implantation embryos in vivo.140 When given to female mice, rats, rabbits and golden hamsters from day 6 to day 15 of gestation, no toxic effects on the survival or implantation were apparent. In this study, clove oil was given orally and the dosages were 2.2 to 215 mg kg−1 of body weight (mice), 2.8–280 mg kg−1 of body weight (rats), 1.72–172 mg kg−1 of body weight (rabbits) and 1.8–177 mg kg−1 of body weight (golden hamsters).90

References 1. Oxford Advanced Learner's Dictionary, Clove_1 Noun – Definition, Pictures,

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CHAPTER 11

Coriander or Cilantro Coriander/Chinese Parsley (Coriandrum sativum) 11.1 Names English: Coriander, cilantro, Chinese parsley (herb) and Indian parsley (herb) Catalan: Celiàdria and Coriandre Chinese: Hu Sui Ye (leaves), Xiang Cai (seeds) French: Coriandre Spanish: Cilantro Tagalog (spoken in the Philippines): Kulantro, Unsuey, Wansuey and Uan-soi (herb) The name coriander comes from the old French coriandre, which is from Latin coriandrum, and from the Greek name koriannon.1

11.2 Taxonomy Order: Apiales Family: Apiaceae Genus: Coriandrum Species: Coriandrum sativum

11.3 Origin, Description and Adulteration Coriander is native to the Mediterranean region and West Asia. It grows upright (0.1–0.5 m high) and is an annual plant with pinnately divided (lobes arranged on either side of a central axis like a feather) linear segments in the upper leaves, and aromatic foliage, with umbels (flower cluster with an umbrella-like shape) of small white or purplish flowers that bloom in between summer and early autumn, spreading to 0.1–0.5 m wide, which are followed by aromatic spherical fruits.2 The plant seeds (dried coriander fruit), leaves and roots are all edible and Coriandrum sativum L. var. vulgare (synonym var. macrocarpum) Alefeld and C. sativum L. var. microcarpum de Candolle are commonly used. Coriander grows well in fertile, well drained soil and full sun is best for the seeds, whilst partial shade is more productive for the leaves. Coriander can suffer from aphid (small sap-suckling insects) infestation. It also suffers from a fungal

disease called powdery mildew.2 According to the World Spice Congress report (2012) coriander (leaf) is cultivated in Beni Swife (Egypt) and cut three times starting from December to mid-March. The delicate leaves can be heavily contaminated with herbicides. Ninety percent of the production is exported to the United States where herbicides and pesticide residues are not seen as an issue as much as in Europe.3 India is the largest producer of coriander seeds globally. Most European commerce is produced from India, Bulgaria, Russian Federation, Ukraine, Romania, Morocco and Egypt. The main importers of coriander seeds are the UK, Germany, Poland, Netherlands, France and Austria.4 Evidence of adulteration of dried powdered coriander and coriander seeds has been reported in Indian studies, namely with plant debris, starch and salt.5

11.4 Historical and Current Uses Coriander herb and seed usage has been recorded back to the Neolithic age, or over 7000 years BCE. It is mentioned in ancient Indian Sanskrit texts, and in the Old Testament, such as in the Book of Exodus 16:31: “And the house of Israel called the name thereof Manna: and it was like coriander seed, white; and the taste of it was like wafers made with honey. It is also mentioned in the Book of Numbers 11:7: “And the manna was as coriander seed, and the colour thereof as the colour of bdellium.”6 Coriander fruit was found in ancient Egyptian papyrus scrolls in Tutankhamun's and other Pharaohs' graves.7 Most of Hippocrates' (the ancient Greek's physician born 460 BCE) systematic enumeration of medicine materials used at the time came from the plant world, with a list of several hundreds from which fifteen are still in general use today, including the culinary and medicinal herbs sage, coriander, garlic, mint and rosemary.8 Pliny the Elder, the Roman physician (23–79 CE) was the first to use the genus name Coriandrum, from koros, referring to the fetid bed bug smell of the leaves. It was used as a medicine and an aphrodisiac, and also in perfumes. Coriander is sometimes referred to as Chinese parsley, it was introduced to Chinese medicine around 600 CE.9 Coriander was introduced to Europe and Great Britain by the Romans, and grew readily in gardens.9 Before toothpaste was commonly used, coriander seeds were chewed on to reduce bad breath. In the Apicius Roman cookbook,11 coriander is mentioned in over a hundred recipes, to flavour mushroom, cheese, pumpkin, cabbage and beet recipes, lentils, beans, peas, cereal, such as gruel, as well as recipes for chicken, hen, duck, pigeons, flamengo, parrots, goose. It was also used in meat, game, fish and sea foods, as well as sauces, including wine sauce for truffles. Coriander was also used in the making of Mortaria, a ready made preparation, which also consisted of mint, rue (Ruta graveolens - a herb commonly used then) and fennel seeds. After being crushed finely, lovage pepper, honey, broth and vinegar were added. Mortaria was principally used to make cold green sauce.10 Coriander is mentioned in the Book of Herbs by Northcote (1903) and she states: “It (coriander) was originally introduced from the East, but is now naturalised in

Essex and other places, where it has long been cultivated for druggists and confectioners. The seeds are quite round, like tiny balls, and Hogg remarks that they become fragrant by drying, and the longer they are kept the more fragrant they become”.11 Today coriander's fresh leaves are used as a garnish and added at the end of the preparation of a warm dish or in salads, so its use is very much as it was traditionally. Dried leaves and dried seeds are used in dishes all over the globe – curries, faridas, tacos, migas, vietnamese dishes, to flavour appetisers such as bajis, hummus, and meat and vegetable dishes, as well as soups, lentil dishes and noodles. Garam Masala (masala meaning spice mix) includes cumin, coriander, cardamom, pepper, cinnamon, cloves, and nutmeg, and varies in its constituents and their amounts between Indian, Pakistani, Nepalese, Bangladeshi, Sri Lankan and Afghan recipes. The Middle Eastern Baharat spice blend includes allspice, black pepper, chili peppers, cardamom, cinnamon, cloves, coriander, cumin and nutmeg.12 The seeds are also used to flavour alcoholic drinks, for example cucumber and coriander gin and tonic, and they are an essential component of the French liqueurs Benedictine and Chartreuse. Coriander seed preparations have been used as a carminative (to relieve flatulence), to aid digestion and stomachic (to improve gastric activity) in many traditional medicine systems and are still used today. Coriander seeds are combined with caraway and cardamom seeds in Ayurvedic medicine, and they, with caraway, fennel, and anise, are used in European medicine. In Iran, coriander seeds are used to treat anxiety and insomnia. The Commission E monographs approve coriander seed use for the lack of appetite and also for dyspepsia. The approved use of coriander is based on its long history of use in well-established systems of traditional medicine, research and pharmacological studies in animals.9 No contraindications or side effects have been reported, and there are no restrictions on its use during pregnancy or lactation in the monographs, however readers are also referred to the section on Safety and Adverse Effects. Amounts of coriander normally used in medicinal preparations equal 3 g per day of crushed seeds or powdered fruit or dry extract, for example infusions 3 g in 150 mL water.13 In the United States coriander is sometimes used in laxative preparations to alleviate their stomach-upsetting effects. The British Herbal Pharmacopoeia noted the carminative and stimulant action of coriander fruit, but the Commission E does not. In Ayurvedic medicine, the leaves are considered bitter, astringent, cooling and cleansing, whilst in traditional Chinese medicine (TCM) the leaves are considered bitter, aromatic, and warming.14 In traditional Chinese medicine both the leaves and the seeds are used for the meridians of the spleen, stomach, lung and large intestine to attain different effects.15 The leaves strengthen the spleen and promote digestion, they are nutritive and can be used in a tonic to treat anemia, nausea, hernia and vomiting. The leaves are also useful for menstrual cramps, as well as stomach and intestinal cramping, and constipation, and are used to treat measles, coughs and bronchitis. The seeds are used to soothe gastrointestinal disorders, indigestion, vomiting and diarrhoea, as well as to treat dysentery, bronchitis and coughs. The seeds are also useful in treating restlessness, joint and muscle pains, anxiety, and high blood pressure.

11.5 Chemistry, Nutrition and Food Science Phenol Explorer16 provides the list of phytochemicals in coriander. In fresh leaves, these include the flavonol quercetin and the phenolic acids gallic and protocatechuic acids (which are hydroxybenzoic acids) and 5-caffeoylquinic, caffeic and ferulic acids (which are hydroxycinnamic acids). Coriander dried leaves contain quercetin, as well as vanillic acid, which is a phenolic acid. There are no data for the seeds. Food preparation and cooking are known to impact the composition of foods, and may affect their phytochemical constituents. The impact of different boiling times (0, 1, 5, 10, 20 and 30 minutes) were tested on coriander leaves by measuring the total carotenoid content, total antioxidant capacity (using the trolox equivalent antioxidant capacity assay – TEAC) and total phenolic content (TPC). The total carotenoid content reached a maximum at 10 minutes of boiling, then decreased at and above 20 minutes. The TPC and TEAC were highly correlated. Boiling significantly decreased TPC and TEAC. Leaves and seeds extracts of coriander and coriander oil were assessed for their antioxidant capacities using the scavenging of the diphenylpicrylhydrazyl (DPPH) radical, inhibition of 15-lipoxygenase (15-LO), inhibition of phospholipid peroxidation. Coriander leaves had a higher antioxidant capacity than the seeds. The authors suggested that coriander (specifically its extracts) could be of potential use as a natural antioxidant.17 Coriander leaf contains the polyunsaturated fatty acid linoleic and also the furanocoumarins coriandrine and dihydrocoriandrine.18 Coriander seeds contain about 1% essential oil composed of 55–74% linalool, 20% monoterpene hydrocarbons (α- and β-pinene and limonene), anethole and camphor, with up to 26% being fatty acid (oleic, petroselinic and linolenic acids). Coriander oil is often obtained from solvent extraction of the ground seeds9 and contains over 80% aldehydes. To the majority of the population, the herb has a pleasant light and fresh lemon-lime flavour, but for those with a genetic variation of the olfactory (smell) receptor 6A2 (OR6A2), which absorbs the odour of aldehyde chemicals (in this case the aldehydes are mannitol, n‐acetaldehyde, furfural and linalool), who describe the smell as soapy and unpleasant.20 The dried coriander seeds are high in fibre and fat, and the dried leaf makes dietary contributions towards the following micronutrients: calcium, potassium, sodium and provitamin A (see Table 11.1). Coriander fresh leaves contain αtocopherol (vitamin E) as well as vitamin K, while the seeds are richer in polyphenols and essential oils than the leaves.18,19 Table 11.1 Nutrition composition of coriander.19 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Coriander (100 g) – UK data

Fresh leaf

Dried leaf

Dried seed

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g)

18 1.2 N 0.5

279 41.7 N 4.8

Na Na 41.9 17.8 (0.99)

Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

2.1 92.2 —b 67 0.23 Na 1.77 26 0.43 48 521 Na 46 0.5 675 0.07 0.12 1.1 0.15 27 62 2.5 310 0.57

21.8 7.3 —b 1250 1.24 Na 8 690 1.8 480 4470 Na 210 2.9 1310 1.25 1.5 10.7 Na 0 0 Na —b Na

12.4 —b 46 709 0.97 Na 16.32 330 1.9 409 1270 26 35 4.7 0 0.24 0.29 2.1 Na 21 0 Na —b Na

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

The use of herbs and spices as natural antioxidants in processed foods has become more widespread. These (natural antioxidants) work by reducing the oxidative degradation of constituents (normally lipids) and therefore preserve the nutritional composition of foods for longer. A study investigated the potential preservative effect of coriander essential oil added to vacuum packed ground beef (the highest concentration used was 0.02% (v/w)) and tested total viable counts of a selection of microorganisms (bacteria from the Enterobacteriaceae family, lactic acid bacteria, yeasts, and Brochothrix thermosphacta). Sensory acceptability was assessed by measuring amino nitrogen levels, protease activity, the proportions of meat pigments, pH levels, and protein characteristics were evaluated by electrophoresis. Sensory acceptability was also assessed by a panel of 7 trained assessors. The meat was stored at 0.5 ± 0.5 °C and 6 ± 1 °C for 15 days. Inhibition of undesirable sensory changes was reported. Coriander oil extended sensory acceptability by up to 3 days, and significantly decreased Enterobacteriaceae compared to the controls but there were no differences for the other microorganisms. Coriander oil had no effect on amino nitrogen levels, protease activity, the proportions of meat pigments, pH levels or protein electropherograms. The authors concluded that coriander essential oil at the concentrations used had limited benefits overall.21 However, a systematic review published in 2017 showed that coriander seed oil was one of the world's most commercially relevant essential oils, with antimicrobial activity against gram-positive and gram-negative bacteria, some yeasts, dermatophytes and filamentous fungi, making it a good candidate as a food preservative and concluded that future research was warranted.22 Due to the rapid deterioration of fresh coriander leaves at room temperature (a deterioration

that is only delayed by 2–3 days when fresh leaves are refrigerated), methods to preserve their aroma and flavour have been sought. One approach has been the development of a coriander fresh leaf paste, which was found to be microbiologically safe and sensorily acceptable following storage for 7 days at room temperature, despite some loss of colour, chlorophyll and carotenoid levels, flavour and antioxidant capacity.23

11.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 11.6.1

Antioxidant Properties

There is a considerable amount of literature reporting that extracts of whole coriander, its leaf, seed, roots and its essential oil all possess antioxidant capacity in vitro.17,24 ,39 The antioxidant capacities for the whole plant and/or dried leaf, have been shown to be low in comparison to those of other culinary herbs and spices including clove, cinnamon (C. verum) and Mediterranean oregano. Although the actual values vary depending on the antioxidant capacity assay used.24,25 The relatively low capacity is likely due to the polyphenol content of coriander, which is reported to be low compared to that of the other listed culinary herbs and spices.25 The nature of the coriander preparation also influences its antioxidant capacity. Leaf (including aqueous, ethanol and ethyl acetate) extracts of coriander are reported to have higher antioxidant capacities than those of its seeds, and this is likely due to the higher polyphenol content of the former.17 Coriander seeds have also been shown to inhibit lipid peroxidation in vitro.32 Evidence, from animal studies, suggests that coriander's antioxidant capacity may contribute to decreasing oxidative stress, which may have some significance in vivo in protecting the liver and kidney from oxidative damage (see section on Hepatoand Renal Protective Properties below).40 In addition, it has been argued that coriander's antioxidant properties could contribute to its glucose lowering, antidiabetic, lipid lowering, chemopreventive/anti-cancer, and neuroprotective, and other central nervous system (CNS), activities (see the relevant sections below).

11.6.2

Anti-inflammatory Properties

The anti-inflammatory activity of coriander, the aerial parts, specifically the stem and leaves, seed and essential oil, has been demonstrated in vitro and in vivo with evidence suggesting that its polyphenolic, specifically its flavonoids,41 and nonpolyphenolic constituents, including the chlorophyll derivative chlorophyllin,42,43 and its unsaturated fatty acids,44 contribute to this action. Ethanol extracts of aerial parts of coriander decreased the expression of proinflammatory mediators, including nitric oxide (NO), inducible nitric oxide

synthase (iNOS), prostaglandin E2 (PGE-2), and pro-interleukin 1 beta (pro-IL-1β) in simulated murine macrophages in vitro.43 Animal studies on the in vivo anti-inflammatory effect of coriander showed that oral administration of whole powdered seeds and hydroalcoholic extracts of coriander seeds significantly inhibited oedema.44,46 When compared to the effect of the non-steroidal anti-inflammatory drugs diclofenac and indomethacin, the drugs were found to be either more effective (diclofenac) or comparable or less potent (indomethacin) than coriander.45 However, potency depended on the amount used.46 Extracts of coriander seeds (hydroalcoholic) have also been shown to inhibit granuloma formation (granulomas form as the result of infection or inflammation; they are a collection of macrophages) in animal models of inflammation.18,46 Nair et al. 46 also investigated the effect of coriander (hydroalcoholic extracts of its seeds) in an animal model of arthritis and reported that the efficacy of its anti-inflammatory activity (based on decreases in joint swelling and the expression of pro-inflammatory mediators) compared to indomethacin was dependent on dose. Decreases in the levels and/or expression of pro-inflammatory cytokines interleukins 1 and 6 (IL-1 and IL-6) and tumour necrosis factor alpha (TNF-α) have also been reported in vivo in animal models of inflammation as a result of coriander extracts.43 The polyherbal formulation Sharangahara Samhita, which includes ripe seeds of coriander, unripe fruits (seeds) of Bilwa (Aegle marmelos), rhizomes of Musta (Cyperus rotundus) and roots of vala (Vetiveria Zizanioides) (all the herbal constituents make up the formulation in equal amounts) is used by practitioners of Ayurvedic medicine to treat inflammatory bowel disease (IBD) with some success, and it has been shown to have a protective effect in animal models of IBD. The effect of the formulation was comparable to that of prednisolone, a steroid drug used to treat inflammatory conditions.47 In a double blind randomized controlled trial (RCT), Reuter et al. 48 reported that 0.5% coriander essential oil significantly decreased ultraviolet induced erythema, which is an inflammatory skin disease. It was found not to be as effective as hydrocortisone, which was used as a positive control, but the authors concluded that it had the potential to be used alongside other treatments to manage this condition.

11.6.3

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

The glucose lowering effect, anti-diabetic potential, and the lipid lowering effect of coriander, its seeds especially, in animal and human studies have been reported, with results suggesting coriander may be of benefit in the prevention of type 2 diabetes (T2D) and cardiovascular disease, and could be used alongside drugs used to manage T2D. Aissaoui et al. 49 investigated the effect of coriander seed extract (aqueous) in normal and obese hyperglycaemic/hyperlipidamic rats. When given as a single dose, blood glucose was lowered in both groups but the hypoglycaemic effect was not as strong in the normal rats. Insulin resistance decreased significantly. However, there was no effect on lipid levels – triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol

(HDL-C). For the 30 day daily dose, blood glucose was lowered to normal levels in both the normal and hyperglycaemic and hyperlipidemic rats, and insulin resistance also decreased. However, in contrast to the single dose study, lipid levels (TG, TC and LDL-C) were significantly lowered. The effect of the daily dose on TC, LDL-C and HDL-C indicated that the coriander extract had a cardioprotective effect. Furthermore, the effects of both the single and daily dose of coriander on blood glucose and insulin resistance were comparable to that of the T2D drug glibenclamide, providing further support for coriander’s therapeutic potential in the management of T2D. Das et al. 50 in an animal model of T2D and dyslipidemia (abnormal lipid levels/profile) reported similar results to that of Aissaoui et al. concerning lipid levels. Coriander seed extract (aqueous) decreased TC, the LDL-C : HDL-C ratio and also the TC : HDL ratio; the direction of the changes in the ratios indicated that the extract decreased cardiovascular risk and thus had a cardioprotective effect. However, HDL-C was not increased significantly so this effect appeared to be focused on the effect of the extract on LDL-C and TC. The lipid lowering effects were comparable to that of another drug used to treat T2D – metformin. Other animal studies, using models of T2D, have also reported the glucose lowering and/or anti-diabetic ability of extracts of coriander seeds (aqueous, ethanolic and petroleum ether), and also coriander powder, given orally or intraperitoneally (i.p.).40,51,54 Reported effects include: the significant lowering of blood glucose, TC, and/or the formation of advanced glycation end products (which are markers of the progression of diabetes); and/or increasing pancreatic beta–cell activity; decreasing pancreatic damage via inhibition of inflammation, tissue degeneration and fat accumulation; and/or improving antioxidant status, based on increases in antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and increases in reduced glutathione (GSH) as well as vitamin C and E status; and/or decreasing oxidative stress, based on decreases in the level of lipid peroxidation. Again, effects reported were comparable to drugs used to manage T2D. Although carried out in animals, these studies provide some evidence of the potential use of coriander, in this case its seeds, for the prevention of, and as an adjuvant for the management, of T2D and its complications. A study by Abou El-Soud et al. 55 investigated the effect of coriander essential oil in an animal model of T2D. The essential oil significantly decreased blood glucose and also improved antioxidant status based on an increase in the enzyme GPx. The essential oil also appeared to protect against tissue damage, specifically of the pancreas and kidneys. Other animal studies have focussed solely on the lipid lowering potential of coriander with a focus on its potential use to protect against the development of cardiovascular disease,56,57 which has already been touched on above with regards to some of the T2D studies. Studies using animal models of hyperlipidemia have reported that coriander seeds (mainly in powdered form, although some studies also

used coriander seed extracts, one in combination with vitamin B6 and seed oil) have a lipid lowering effect, which included the lowering of TC, TG, LDL-C, VLDL-C and/or free fatty acid levels, the raising of HDL-C, and/or increases in the faecal excretion of cholesterol, and/or the reduced formation of aortic plaques, and/or improvements in other atherogenic markers. Coriander seed was also reported to decrease the content of saturated fatty acids, but increase mono- and polyunsaturated content, in the carcass and muscle of quails. As with its glucose lowering effect, its lipid lowering properties are reported to be associated with improved antioxidant status and a decrease in oxidative stress.40,58,63 A small number of human studies have been carried out which strengthen the potential use of coriander in the management of T2D. Waheed et al.64 carried out a clinical trial (it is not made clear if it was a blinded RCT) in which coriander seeds (powdered, aqueous extract and alcoholic extract) were taken by patients with T2D (not taking medication to control their blood glucose levels or who were taking hypoglycemic drugs but had a history of poorly controlled blood glucose) who were given either a low or high amount (2.5 g or 4.5 g) twice a day. Each preparation of coriander seed was taken for 14 days beginning with the powdered seed preparation after which blood glucose was determined. A week later the aqueous extract was taken for 14 days after which blood glucose was determined. A week later the alcoholic extract was taken for 14 days after which blood glucose was determined. All the preparations at both the high and low amount lowered blood glucose in both groups with the effect of the higher amount being significant. The therapeutic potential of coriander seed in the management of T2D is further supported by a more recent study (it is not made clear if it was a blinded RCT) by Rajeswari et al. 65 in which powdered seed, given in two equal doses totalling 5 g per day for 60 days, reversed hyperglycaemia and hyperlipidemia, based on significant decreases in fasting blood glucose, TC and TG. These changes were associated with a significant decrease in the level of oxidative stress. There was also a significant improvement in antioxidant status. However, the activity of CAT decreased. This enzyme converts the reactive oxygen species hydrogen peroxide to water so a decrease in the activity of this enzyme suggests an accumulation of hydrogen peroxide although the authors appeared to present an opposing argument. Haldar et al. 66 reported that coriander seeds (powder) (1 g and 2 g) in combination with a number of other spices (namely cayenne pepper (0.5 g and 1 g), cinnamon (powder 0.25 g and 0.5 g), clove powder (0.25 g and 0.5 g), cumin seeds (powder) (1 g and 2 g), garlic (fresh) (10 g and 20 g), ginger (fresh) (10 g and 20 g), Indian gooseberry ‘amla’ powder (1 g and 2 g) and turmeric (2 g and 4 g)) and consumed as part of a vegetable curry, improved postprandial glucose homeostasis in a dose-dependent manner in men with BMIs in the healthy and overweight ranges. This effect was possibly via a dose-dependent increase in the levels of the hormone glucagon-like peptide-1 (GLP-1) which plays a key role in improving glucose homeostasis.67,68 Interestingly, this spice blend increased postprandial TG levels. However, Haldar et al. 66 suggested that the decrease in eggplant with the increase in the amounts of the spices added to the curry might explain the increase as this food is reported to possess lipid lowering effects (albeit in rats). The proposed mechanism of action of the glucose lowering/anti-diabetic effect of coriander includes its pro-insulin effect as it is reported to increase insulin secretion, as well as glucose uptake, by liver and skeletal muscle, and hepatic glycogen

synthesis. Coriander is also reported to decrease glucose synthesis and release, and decrease the activity of enzymes involved in carbohydrate digestion namely intestinal alpha-glucosidase and alpha-amylase.49,69,72 Regarding its lipid lowering effects, there is evidence that coriander seeds inhibit cholesterol synthesis and also promote the conversion of cholesterol to bile acids and neutral sterols,61 which are then excreted. The polyphenolic constituents of coriander are believed to be involved in contributing to coriander's glucose and lipid lowering effects. The ability of coriander to inhibit the formation of plaques is suggested to be due to the action of coriander's polyphenols on lowering the oxidation of LDL-C.63 For the effect of coriander essential oil, linalool may have a role to play in its glucose lowering effect.57 The association between improved antioxidant status and suppression of inflammation in the T2D studies provides some evidence of a possible role for these properties in coriander's hypoglycaemic/anti-diabetic activities, particularly as hyperglycaemia can give rise to oxidative stress.73,74

11.6.4

Hypotensive Properties

In addition to its lipid lowering effects contributing to evidence of coriander's cardioprotective properties is its ability to lower blood pressure, and act as a diuretic and a vasorelaxant. However, these properties have only been demonstrated in vitro and also in animal studies. Jabeen et al. 75 demonstrated, in vivo, that crude seed extracts (aqueous and methanolic) lowered both systolic and diastolic blood pressure in a dose-dependent manner in normotensive rats. The hypotensive effect of the extract is believed to involve an action mediated by muscarinic receptors, which mediate functions of the parasympathetic nervous system including slowing down heart rate. Furthermore, the extract had a diuretic effect comparable to that of furosemide, which is used to treat fluid retention as a result of heart failure. Using rabbit aorta in vitro, coriander extract was shown to have a vasorelaxant effect against induced contractions. This effect was reported to be comparable to that of the drug verapamil, which is used to treat high blood pressure as well as tachycardia (very fast heart rate) and angina (chest pain). The extract was also shown to have a cardio-depressant effect in vitro in preparations of atria (the upper chambers of the heart). Some literature suggests that linalool may be the key constituent responsible for these reported effects.57

11.6.5

Hepato- and Renal Protective Properties

Extracts (aqueous and ethanolic) of coriander leaf, stem and seed, and also its essential oil, have been shown to protect against and reduce liver and kidney damage in animal models of hepato- and renal toxicity.76,83 Coriander in these studies was reported to normalise or improve liver function, based on the activity of the liver function enzymes including aspartate transaminase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT), and renal function, based on bilirubin, urea and creatinine levels. Decreases in liver and kidney tissue damage were also reported, specifically a decrease in the deposition of fatty tissue in liver, and also a decrease in tissue necrosis and degeneration. The effect of coriander was reported to be comparable to that of silymarin, an extract of milk thistle which is

purported to be a potential treatment for liver toxicity and is traditionally used to treat hepatic disorders, although its efficacy has yet to be fully established.79,85 The hepato- and renal toxins used increased oxidative stress and the benefits of coriander were associated with improvements in antioxidant status and decreases in oxidative stress. These findings suggest that the improvements reported could in part be due to the decreases in oxidative stress.76,77,79,81,82

11.6.6

Chemopreventive/Anti-cancer Properties

Coriander's chemopreventive/anti-cancer properties have been demonstrated in vitro and also in vivo in animal models. Extracts of coriander leaf, seed, roots and stems are reported to inhibit the growth of lymphoma cells,86 human breast cancer cells (MCF-7),39 gastric carcinoma (AGS) cells, prostate cancer cell lines (DU-145 and LNCaP), colorectal cancer cells (HCT116 and HT29), and lung cancer cells (NCIH460). However, the activity against some of these cancer cells lines did not exceed 30–35% inhibition in cell proliferation/growth.31,32 In the study by Tang et al.,39 the most potent anti-cancer activity was associated with the highest phenolic and antioxidant capacity. Furthermore, in this study the anti-proliferative effect of extracts of coriander root, leaf and stem was shown to be MCF-7 cell specific, as they had a decreased or non anti-proliferative effect on a normal human breast cell line – 184B5 – a human mammary epithelial cell line. The coriander root was shown to possess chemopreventive potential with its induction of apoptosis and cell cycle arrest of MCF-7 cells. In addition, it inhibited hydrogen peroxide induced DNA damage in 3T3-L1 human fibroblast cells and also inhibited/prevented hydrogen peroxide induced MCF-7 breast cancer cell migration. The root extract had an unexpected effect on the antioxidant enzyme activities in this cell line. Superoxide dismutase (SOD) activity increased but that of CAT and GPx decreased. Due to the inhibition of hydrogen peroxide induced processes, the authors suggested that coriander could be acting via the action of its antioxidants. It was also suggested that an accumulation of hydrogen peroxide in cells exposed to coriander via an increase in SOD and a decrease in CAT and GPx, could have resulted in the death of the cells. In an in vivo study, in which an animal model of colon cancer was used, consumption of dried powdered coriander seeds resulted in a decrease in tumours in the colon and small intestine, a decrease in cholesterol levels and an increase in faecal sterols and bile acids compared to the controls (animals not fed coriander). The effect of coriander on cholesterol, faecal sterols and bile acids suggested to the authors of the study that coriander may elicit a protective effect via a decrease in cholesterol synthesis. As cholesterol is required for the production of bile in the liver and intestines, a decrease in its synthesis would result in a decrease in the level of bile acids. Bile acids are metabolised by gut bacteria to secondary bile acids, which may have a role to play in the development of colon cancer.87,88 Furthermore, the authors suggested that coriander may also inhibit the absorption of bile acids by the intestines resulting in a decrease in the levels of faecal bile acids. Regarding the constituents that may contribute to coriander's chemopreventive/anticancer activity, possible constituents of interest include coriander's polyphenols and also ascorbic acid.39

11.6.7

Neurological and Neuroprotective Properties

There is a not inconsiderable amount of literature on coriander's anxiolytic (antianxiety), anticonvulsant and analgesic effects, which, evidence suggests, is mediated via its action on the central nervous system (CNS). Coriander's anxiolytic effects have been reported in animal studies. Its seed extracts (aqueous, hydroalcoholic and n-butanol fraction of the hydroalcoholic extract) have been reported to have calming/anxiety reducing/sedative-like effects in models of stress and/or anxiety.89,93 In addition, studies reported that the anxiolytic effect of coriander was comparable to that of diazepam, which is used to treat anxiety. In an animal model of Alzheimer's disease (AD), essential oil again had anxiolytic and anti-depressant effects,94,95 which were comparable to those of diazepam and tramadol, which is a painkiller but is noted for its anti-depressant effects. Evidence indicates that coriander essential oil may be acting via gamma aminobutyric acid (GABA) receptors;89,93 GABA is an inhibitory neurotransmitter, which decreases CNS activity. It elicits an anxiolytic effect when it interacts with its receptors. Some literature puts linalool as the major contributor to coriander's anxiolytic properties.93 However, Sahoo and Brijesh89 who reported on the anxiolytic effect of coriander seed extracts (aqueous) did not detect any linalool in the extract. It was suggested that the absence of this compound and other volatile compounds could have been due to how the extract was dried (in an oven at 50 °C). However, they did detect polyphenols including the flavonoids kaempferol, rutin, resveratrol and quercetin, as well as the phenolic acids, chlorogenic acid and caffeic acid which are all reported to possess anxiolytic activity.96,99 In addition, some polyphenols including quercetin are reported to have a high affinity for receptors used by diazepam.100,101 Coriander seed extract (aqueous, ethanol, hydroalcoholic) and its essential oil have all been shown to have anticonvulsant effects in animal studies.102,103 The effect at higher doses, including 800 mg kg−1 of body weight, was comparable to diazepam and phenobarbital both of which are used to treat convulsions. Coriander's anticonvulsant effect has been linked to the lowering of oxidative stress, as during convulsions the levels of oxidants and antioxidants increase and decrease respectively.57 This association has been demonstrated in animal studies in which water and ethyl acetate fractions of hydroalcoholic extracts of the aerial parts of coriander (stem, twigs and leaves) elicited anticonvulsant effects and decreased oxidative stress in the brain, specifically in cortical and hippocampal tissue (convulsions begin in the cerebral cortex and affect the hippocampus104). Linalool and other volatile compounds – limonene and myrcene – as well as the flavonoids quercetin and rutin have been linked to coriander's anticonvulsant effects.57,105 Analgesic effects of coriander have also been reported in the literature. Coriander seed extracts (aqueous, ethanolic) and also extracts (aqueous, ethanolic and chloroform) of its aerial parts are reported, in animals, to relieve pain with effects reported to be dose-dependent and comparable to that of morphine.90,106,107 Coriander seeds' use to relieve headaches dates back to ancient Persia,57 and in a lone human study in which subjects who suffered from migraines were given a

coriander syrup (15 mL three times a day for one month) which contained evaporated ethanol seed extract (5 mL of syrup contained 100 mg of the evaporated extract plus sodium valproate, which is used to prevent migraines) the frequency of the occurrence of the migraines, their duration and also the level of pain the subjects suffered all decreased markedly compared to the control group, who were also migraine sufferers and received the sodium valproate and a placebo syrup.108 Although a promising finding, the authors acknowledged that as the study was for one month it was unclear whether these beneficial effects would continue after long term use. Linalool via interaction with opioid receptors may be responsible for coriander's analgesic effect, as naloxone, which is an opioid receptor antagonist, weakens and blocks the analgesic effect of coriander.106,107 Furthermore, it is suggested that linalool may act via glutaminergic receptors to elicit an analgesic effect as these receptors are located in areas of the brain, spinal cord and periphery that are involved in the pain response. Bhat et al. 106 suggested that the reason why aqueous extracts of coriander seeds had a faster but shorter-lasting analgesic effect compared to the ethanol extracts was due to the aqueous extracts containing more linalool. Other constituents that might be involved are terpinene, camphor, alphapinene and geraniol. The beneficial effects reported for migraine sufferers could also be due to the anti-inflammatory property of coriander, as migraine development is reported to be associated with the release of pro-inflammatory mediators.108 Coriander is also reported to possess neuroprotective properties. Using an animal model of AD, evidence indicates that coriander essential oil via inhalation for 1 h for 21 days resulted in improvement in memory. Improved antioxidant status and decreased oxidative stress in the hippocampal region suggested that the effect in part could have been mediated by coriander's antioxidant properties.109 The possible role of coriander's antioxidant properties in conferring its neuroprotective effects is also supported by an animal study by Velaga et al. 110 However, other actions may be involved, as coriander also decreased lactate dehydrogenase in the hippocampus, which is indicative of a decrease in tissue damage, and also decreased the formation of amyloid plaques, hallmarks of the development of AD. There is also evidence of inhibition of apoptosis in the same region of the brain due to coriander.109 Coriander may also confer a neuroprotective effect by preventing cerebral ischaemia commonly referred to as a stroke. This protective effect is again suggested to be linked to a decrease in oxidative stress to which the development of stroke is associated.111,112 Using PC12 cells, which have been used to investigate the impact of ischaemia as a result of hypoxia (decreased oxygen supply) and the limited delivery of nutrients to cells,113 Ghorbani et al. 114 reported that the water fraction of a hydroalcoholic extract of the aerial parts of coriander (stem, leaves and twigs) reduced the decrease in the viability of these cells when they were deprived of glucose and serum. Interestingly, the other fractions – n-butanol and hydroalcoholic – increased the toxicity induced by the deprivation of glucose and serum, thus suggesting to the authors that the water soluble constituents of coriander may be responsible for preventing cellular damage caused by the lack of glucose and serum. Linalool and also the terpenes have been put forward as the key contributors to coriander essential oil's neuroprotective properties.57

11.6.8

Gut Modulatory Properties

Coriander is used in traditional medicine to treat gut disorders including indigestion, flatulence, constipation and diarrhoea,57 and animal studies appear to support this use as they have shown that aqueous extract of coriander seed increases gastric secretion,115 and crude seed extract (aqueous-methanol) can have both a spasmolytic (decreased contraction of smooth muscle) and a spasmogenic (increased contraction of smooth muscle) in intestinal tissue in vitro in a dosedependent fashion.75 Evidence suggests that these gut modulatory effects are mediated via a cholinergic mechanism (a mechanism that mimics the action of the neurotransmitter acetylcholine).75,115

11.6.9

Detoxification Properties

There is a small amount of evidence, based on animal studies, that suggests that coriander could be used as a detoxification agent, specifically for the removal of heavy metals, via its chelating (metal binding) properties.116,118 For example, suspensions of aerial parts of coriander proved to be effective in the reduction of lead deposition in bone and lead induced renal injury. It is suggested that citric acid and phytic acid, constituents of coriander, which are chelating agents, may be responsible.117

11.6.10

Anti-microbial Properties

The anti-microbial, specifically anti-bacterial and anti-fungal, properties of coriander are well established. Much of the evidence concerns its essential oil but the anti-microbial effect of extracts of its seed has also been reported against microbes pathogenic to humans.57

11.6.10.1Anti-bacterial Activity Concerning its action against pathogenic bacteria, coriander (essential oil and/or seed extract) is reported to act against both gram-negative pathogenic bacteria including Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella typhimurium, and gram-positive pathogenic bacteria including Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus species (spp.) including methicillin resistant Staphylococcus aureus (MRSA), Streptococcus mutans, Campylobacter spp., including Campylobacter jejuni, Salmonella spp., including Salmonella enterica, and Listeria monocytogenes.119,121

11.6.10.2Anti-fungal Activity Coriander essential oil acts against pathogenic fungi, including Candida spp. and toxigenic (toxin producing) Aspergillus niger.119,122 For the former the essential oil is reported to work in synergy with the anti-fungal agent amphotericin B.122 Constituents of coriander believed to contribute to its anti-microbial activity

include linalool, and also unsaturated aldehydes, which are found predominantly in coriander leaf.27,123 Linalool is believed to be responsible for disruption of the bacterial cell wall,33,124 and with regards to fungi, evidence indicates that the essential oil causes cytoplasmic damage, which results in leakage of components from the cell including DNA.122

11.6.11

Anti-parasitic Activity

Extracts (ethanolic) of coriander seeds are reported to possess anti-parasitic activity, specifically against the intestinal parasite Hymenolepis nana, an intestinal parasite which causes hymenolepiasis – a disease associated with gastrointestinal symptoms including nausea and abdominal pain as well as loss of appetite and weakness. The anti-parasitic action of coriander was comparable to that of niclosamide, which is used to treat tapeworm infections, and may be due to its volatile fatty acids.125

11.7 Safety and Adverse Effects Coriander (the seed, leaf and essential oil) is considered to be safe when used in the preparation and flavouring of food, and/or when included in cosmetic products; very few adverse effects have been reported when it is used in these ways.126 However, coriander powder is reported to give rise to positive skin patch tests, and although the frequency of the positive test was very low (8 out of 25 subjects had a positive test), the possibility that such reactions to coriander do occur cannot be excluded.127 There is some evidence that coriander powder can cause allergic reactions. Niinimaki and Hannuksela128 and Niinimaki et al.129 reported that coriander gave rise to positive skin prick tests, elevated specific immunoglobulin E and itching and stinging localised to the mouth and lips; although these symptoms were mild and occurred in a small number of subjects. Positive skin prick tests to coriander have also been reported by Moneret-Vautrin et al. 130 However, allergies to spices including coriander are low. There was also evidence of cross reactivity with birch pollen and vegetables including celery, suggesting that those with an allergy to coriander could also be allergic to birch pollen, mugwort pollen and vegetables including celery.129,130 In relation to all food allergies, the prevalence of allergies to spices in general is low. Evidence also suggests that such allergies occur only in adults, and spice allergies are said to account for just over 6% of all food allergies in this group.130 Human studies involving coriander either did not provide any information on adverse effects or reported adverse effects primarily concerning the gastrointestinal system. In the study by Waheed et al. 64 coriander seed given at 4.5 g twice a day for 14 days caused mild adverse effects including nausea, diarrhoea, vomiting and abdominal discomfort in some of the subjects. In their study investigating the effect of coriander syrup on migraine sufferers, Kasmaei et al. 108 reported no adverse effects although the authors acknowledged that the syrup was given for one month only so it was not clear if adverse effects could have occurred after long term use.

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CHAPTER 12

Cumin (Cuminum cyminum) 12.1 Names English: Cumin Coptic: Tapen and thapen Hebrew: Kamon, kammon and kamoon French: Cumin Spanish: Comino Tulu (spoken in Southwestern India): Jirige The name cumin comes from the old English cymen, which is from the Latin word cuminum, which is from the Greek kuminon, which is related to the Hebrew kammōn and Arabic kammūn. 1

12.2 Taxonomy Order: Apiales Family: Apiaceae Genus: Cuminum Species: Cuminum cyminum

12.3 Origin, Description and Adulteration Cumin is the dried seed of Cuminum cyminum, a member of the Apiaceae family, as are parsley and coriander. It is a yellow to brown pungent aromatic spice characterized by a strong musty-earthy flavour with a green-grassy note (scent);2 used as a condiment as a seed or ground. Cumin is native to the Mediterranean area, possibly Egypt and Syria, and has been cultivated in the Middle East, India, China and Mediterranean countries for millennia. India, Syria, Pakistan and Turkey supply most of the commercially available cumin. Cumin is a glabrous annual plant (so it germinates, flowers, sets seed and dies in one season) that grows up to 10–50 cm high, with fine feather-like leaves with oblong-linear tips. The flowers are in umbels (flower clusters with an umbrella-like shape) radiating in groups of 3 to 5 with white or red oblong petals, bordered with a long indented tip. The fruit is a schizocarp (split in 2), about 6 mm long and 1.5 mm wide. Cumin oil is extracted from the ripe, dried fruit.3 Adulteration of cumin has been reported in the literature and may pose serious health concerns. In 2015, large global recalls of cumin seeds were carried out due to

the presence of peanut allergens in cumin samples. Cumin adulterants include peach, cherry, peanut shell, peanut, tree nuts, such as almond, and fennel seeds coated with mixed marble dust and dye.4,6 The essential oil has also been adulterated with synthetic cuminaldehyde.7

12.4 Historical and Current Uses Cumin seeds were excavated in Syria at the Tell ed-Der site, and cumin dates back to the second millennium BCE. Cumin was also identified from several archaeological sites dating back to the New Kingdom (a period of ancient Egyptian history from 16th century BCE to the 11th century BCE).8 Cumin is mentioned in both the Old Testament (Isaiah 28:27) and the New Testament (Matthew 23:23).8 Archaeological evidence exists for the presence of cumin with black pepper and nutmeg in Roman military camps and later in Roman Britain with coriander, celery, dill, fennel, summer savoury and sweet marjoram. Cumin was readily available (as was black pepper) at the dining table in ancient Greece to flavour foods, and this is still the case in Morocco today. During the Middle Ages the use of cumin as a spice declined in Europe (except in Spain and Malta), and it was used to keep chickens and lovers from wandering; a happy life awaited the bride and groom who carried cumin seed throughout the wedding ceremony. Cumin was introduced to the Americas by Spanish and Portuguese colonists.8 The Apicius Roman cookbook contains many mentions of cumin. Cumin was used as a preservative for olives and condiments, and cumin sauce was used for shellfish, minced dishes and mixed in sausage mix. It was also an essential ingredient of Oxiporum (meaning easy passage) and used as a laxative, as part of a mixture of ginger, dates, rue (a herb commonly used then, Ruta graveolens), pepper and honey. Cumin was also used in vegetable dinners (often added to pumpkin dishes) and was used in food with the purpose of being more easily digested.9 The Book of Herbs (1903) mentions cumin, stating it was good for eyes. Northcote mentioned a remedy made of boiled cumin seeds with wine and barley for a variety of ailments. She also pointed out that Germans added cumin seeds to bread.10 Cumin provides a popular flavour in cooking today and appears to be favoured in savoury dishes. Cumin is an essential component of curry powder, chili powder and other spice blends. In Mexican cuisine, Adobo is an all-purpose popular seasoning with salt, paprika, black pepper, onion powder, Mexican oregano, cumin, garlic granules and chilli powder. Garam Masala (masala meaning mixed) used in curries, contains cumin, coriander, cardamom, pepper, cinnamon, cloves, and nutmeg, and varies in constituents and the amounts of constituents between Indian, Pakistani, Nepalese, Bangladeshi, Sri Lankan and Afghan recipes. The Middle Eastern spice blend Baharat is made with allspice, black pepper, chili peppers, cardamom, cinnamon, cloves, coriander, cumin and nutmeg.3 Good Housekeeping11 lists recipes with cumin including roasted cumin shrimps and asparagus, carrots with cumin and thyme, and chicken curry. Indian traditional recipes besides curries include cumin tea, Jeera (cumin) water, which is used for weight loss, and salty

lassi drink (a blend of yoghurt, water, spices sometimes with fruits) containing cumin. The oil of cumin has been used in cosmetics, perfumes and food.12 Cumin seeds have been used in traditional medicine widely across the globe. The seeds were used to treat hoarseness, jaundice, dyspepsia and diarrhoea, and also used to stimulate appetite and for their carminative properties. In America, Africa and India, cumin is used as an abortifacient (causes abortion) and as an emmenagogue (which increases menstrual flow). Cumin based pastes were applied to the forehead for headaches in Indonesia, where it was also taken orally for rheumatoid pain and to ease bloody diarrhoea. In India, cumin was used for kidney and bladder stones, leprosy and eye disease. In Unani medicine (Perso (Persian)-Arabic traditional medicine) the fruits were used for coughs and inflammation, as well as ulcers and corneal opacities (an eye disorder which affect the cornea) and sties.3 There is no record of the use of cumin in traditional Chinese medicine. Cumin seeds and oil are Generally Recognized as Safe (GRAS)13 under the US regulatory system with no adverse effects being reported. The German Commission E monographs do not approve the use of cumin for medicinal purposes due to the lack of evidence of efficacy14 (see section on Safety and Adverse Effects).

12.5 Chemistry, Nutrition and Food Science The Phenol Explorer database15 provides data that ground cumin contains the flavonol kaempferol and the hydroxycinnamic acid caffeic acid. The main volatile compounds in cumin seeds and powder samples are β-pinene, m-cymene, γterpinene, cuminaldehyde and cuminic alcohol.16 The major constituents responsible for the rich flavour of cumin are the aldehydes.17 UK data are the same as US data for the nutrition composition of cumin seeds (see Table 12.1). With regards the nutritional quality of cumin, it is generally considered to be poor in the energy yielding nutrients (carbohydrate, fat, protein), however cumin may make important dietary contributions towards calcium 8.31 mg g−1 and iron 0.66 mg g−1.18,19 Table 12.1 Nutrition composition of cumin.18,19 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Cumin seeds (100 g)

UK data

US data

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg

Na

375 44.24 10.5 22.27 (1.54) 17.81 8.06 Na 931 0.867

Na 10.5 22.3 (1.54) 17.8 8.1 Na 931 0.87

Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

Na 66.36 366 3.33 499 1790 N 168 4.8 127 0.63 0.33 4.6 0.44 8 10 3.33 5.4 Na

—b 66.35 366 3.333 499 1788 5.2 168 4.8 64 0.628 0.327 4.479 0.435 7.7 10 3.33 5.4 —b

aN: Present in significant amounts but not determined. b—: Not assessed or not present.

Food preparation and cooking are known to impact the composition of foods and may affect the phytochemical constituents in aromatic plants. Microwaving is a popular household cooking method with large-scale food applications. A study subjected cumin seeds to microwave heating, using various power levels, and also to conventional roasting at different temperatures. Gas chromatography–mass spectrometry results indicated that the microwave-heated samples showed better retention of characteristic flavour compounds, such as the aldehydes, than did the conventionally roasted samples.17 With increasing demand from the manufacturers of foods for natural extracts, essential oils offer sought after functional properties; with good antifungal activity against human pathogenic fungi, cumin is of interest as a functional component in food science.12 Cumin and its essential oil have been investigated for use on food preservation due to its antimicrobial and antioxidant activities. A 2015 study looked into the effects of cumin seed extracts on shelf life preservation of rainbow trout (Oncorhynchus mykiss) fillets stored at 4 ± 1 °C. The results showed that lipid oxidation and spoilage of the samples were significantly reduced in extracts treated with cumin in comparison with the controls. Cumin extract (6%) scored better than the control and cumin (3%) but not as well as the mint leaves (3 and 6%) for antioxidant, antimicrobial and sensory results for up to 18 days of storage.20

12.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 12.6.1

Antioxidant Properties

Cumin seeds possess antioxidant capacity in vitro.21,24 A comparison of its antioxidant capacity with those of other culinary herbs and spices, by Shan et al., 22 shows that its capacity in vitro is much lower than for those of clove, cinnamon (C. verum) and Mediterranean oregano, although its antioxidant capacity varies due to the nature of the extract and the assay used.25 In addition, its polyphenolic content, which is the main contributor to its antioxidant properties, and its polyphenolic composition vary based on the level of maturation, which can influence its antioxidant capacity.26 Cumin's essential oil also possesses antioxidant capacity in vitro which is reported to be higher than those of the synthetic antioxidants butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).27,29 Cumin extract is reported to decrease oxidative stress alongside memory enhancement and inhibition of stress in animal models, suggesting that its antioxidant properties may be of therapeutic significance treating memory loss and stress.30 However, further studies are required to establish further such significance. Evidence also suggests that cumin's antioxidant properties may be of significance in the management of diabetes and conferring hepato- and cardio-protection but this is limited to animal studies (see sections below on Glucose Lowering, Anti-diabetic, Lipid Lowering, Cardioprotective and Hepatoprotective Properties).

12.6.2

Anti-inflammatory and Immunomodulatory Properties

Cumin seed extracts have been shown to possess significant anti-inflammatory activity both in vitro and in vivo, although the latter has been shown in animal studies only.31,34 The anti-inflammatory effect of the essential oil has not been consistently reported in the literature.35 The activity in vivo has been shown to be comparable to that of the non-steroidal anti-inflammatory drugs (NSAID) sodium diclofenac and aspirin.31,32 Its bioactive constituent cuminaldehyde is believed to contribute to cumin's anti-inflammatory activity.36 In addition, the compound 8(amino(4-isopropylphenyl)methyl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4oxo-4H-chromene-6-carboxylic acid extracted from cumin seed has been recently identified to be a potent inhibitor of the proinflammatory mediator cyclo-oxygenase 2, and also of lipoxygenase,33 an enzyme involved in the regulation of the inflammatory response via the production of pro-inflammatory mediators. Evidence also suggests that cumin's anti-inflammatory properties may be of significance in the management of diabetes and in conferring cardioprotection, but this is limited to animal studies (see sections below on Hypoglycaemic/Anti-diabetic and Cardioprotective Properties). Regarding its immunomodulatory effects, evidence suggests that cumin has an immunostimulatory effect, which was demonstrated in vivo in animals with normal and suppressed immune systems. Cumin seed extract increased T cell number and T cell responses in these models. A flavonoid glycoside (7-(1-O-β-dgalacturonide)-4′-(1-O-β-glucopyranosyl)-3′4′,5,7-tetrahydroxyflavone) isolated from the cumin extract, was identified as a major contributor to these effects as it also increased T cell number as well as thymus (where T cells mature) and spleen

(where immune cells are stored) weights in immunosuppressed animals.37

12.6.3

Antinociceptive/Analgesic Properties

A small number of animal studies have demonstrated the analgesic effect of cumin seed extract and cumin essential oil.32,35 The potency of this effect in vivo by the seed extract was comparable to, and greater than, those of the NSAIDs piroxicam and sodium diclofenac, respectively. In addition, this activity was reported to be dependent on the nature of the extract and the animal model used.32 Omidvar et al. 38 carried out a randomized controlled trial (RCT) in which women with primary dysmenorrhea were given cumin powder (1.5 g twice a day for 3 days during each menstrual cycle for 3 consecutive cycles). They reported that cumin had no analgesic effect although it did significantly decrease fatigue, cramp, cold sweats and backache.

12.6.4

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

Studies carried out in vitro and in vivo (both animal and human studies) provide compelling evidence that the glucose lowering and anti-diabetic properties of cumin may be of benefit in the prevention and/or treatment of diabetes, specifically type 2 diabetes (T2D). With regards to its lipid lowering properties, these have also been demonstrated in animal as well as human studies, and provide some evidence for its use in the prevention and management of T2D and other hyperlipidemic/hyperlipidemic-associated conditions, including obesity, hypercholesterolemia and non-alcoholic fatty liver disease (NAFLD). Animal studies reported that cumin seed extract decreased blood glucose levels and also the levels of glucose in urine, in vivo, decreased the formation of advanced glycation end products, which are a marker of diabetes progression, both in vitro and in vivo, decreased glycated haemoglobin levels (HbAc1) (which is an advanced glycation end product), and increased insulin levels as well as hepatic and skeletal muscle glycogen (both of which contribute to the lowering of blood glucose). Cumin seed extract was also reported to decrease oxidative stress and inhibit the infiltration of inflammatory cells in the pancreas in animal models of diabetes.39,41 Cumin's constituents cuminaldehyde and cuminol are believed to contribute to effects related to glycaemic control as they have been shown to be insulinotropic (stimulate the production of insulin) and to protect against pancreatic beta cell damage in vivo.42 Human studies including RCTs have been used to investigate cumin's efficacy in the management of T2D. Andallu and Ramya43 reported that powdered cumin seed (5 g per day for 60 days) improved glycaemic control in T2D patients based on the significant decrease in their fasting blood glucose levels; this effect was reported to be greater than for that of the anti-diabetic drug glipizide. Two double blind placebo RCTs provided additional evidence of cumin's antidiabetic properties. Dosages and durations were 25 mg per day of essential oil given in capsule form for 3 months to T2D patients, and 50 mg or 100 mg per day of essential oil, given in capsule form, for 2 months to T2D patients.44,45 These

interventions resulted in a decrease in blood glucose, fasting blood glucose, HbA1c and/or serum insulin. Insulin sensitivity was also increased but there was no change in insulin resistance. Serum levels of adiponectin – a hormone which is involved in regulating glucose levels – was increased in the 50 mg/100 mg essential oil study, which also reported significant decreases in the pro-inflammatory markers tumour necrosis factor alpha and C-reactive protein, suggesting that cumin's antiinflammatory effect might have contributed to the improvement of glycaemic control.44,45 In a double blind randomized placebo RCT, cumin extract (225 mg per day) given for 6 months had no significant effect on fasting blood glucose levels in subjects with NAFLD, which is prevalent in T2D.46 In another human study, cumin (powdered seed at 1 g and 2 g) formed part of a polyphenol rich meal (vegetable curry) that also consisted of cayenne pepper (0.5 g and 1 g), cinnamon (powder 0.25 g and 0.5 g), clove powder (0.25 g and 0.5 g), garlic (fresh) (10 g and 20 g), ginger (fresh) (10 g and 20 g), Indian gooseberry ‘amla’ powder (1 g and 2 g) and turmeric (2 g and 4 g). The meal significantly decreased blood glucose levels in healthy subjects with a mean body mass index (BMI) of 23, although the BMI range was from 18.5 to 27.5 so some were in the overweight range.47 This effect was possibly via a dose-dependent increase in the levels of the hormone glucagon-like peptide-1 (GLP-1) which plays a key role in improving glucose homeostasis. Interestingly, this spice blend increased postprandial triglyceride (TG) levels, which contrasts with other findings in which a herb and spice blend was used.48 However, Haldar et al. 47 suggested that the decrease in eggplant with the increase in the amounts of the spices added to the curry might explain the increase, as this food is reported to possess lipid lowering effects (albeit in rats). Although it is unclear what cumin's contribution was in lowering the blood glucose levels of these subjects, this study provides some support for cumin in conjunction with other foods in the prevention of poor glycaemic control and the development of T2D. Studies have also reported on the lipid lowering effects of cumin however the findings are mixed. Animal studies have reported the lipid lowering effect (on total cholesterol (TC), serum cholesterol and/or TG) of cumin seed extract in models of diabetes and elevated cholesterol levels.41,49 However, in another animal study in which normal and hypercholesterolemic rats were used, cumin was reported to have no effect on serum and hepatic cholesterol levels.50 Human studies also reported some inconsistencies regarding the lipid lowering effect of cumin. However, this may in part be due to the different subjects used. In their study on the effect of cumin (see above for details) on T2D patients, Andallu and Ramya43 also investigated the spice's effect on their lipid profile and reported that cumin (powdered cumin seed at 5 g per day for 60 days) significantly decreased plasma cholesterol, TG, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), and increased high density lipoprotein cholesterol (HDL-C). The lipid lowering effect of cumin in these patients was noticeably greater than that of the anti-diabetic drug glipizide. In addition, in light of the changes in lipid profile, there was a significant improvement in the atherogenic index (cholesterol/HDL-C ratio) thus providing evidence of the cardioprotective potential of cumin in T2D patients. In patients with hypercholesterolemia, Samani and Farrokhi51 reported that

cumin (3–5 drops added to the patients' diet 3 times a day for 45 ± 3 days – no additional details about the preparation or the amount given were provided) significantly decreased the levels of oxidized LDL, which is involved in the development of atherosclerotic plaques, and significantly increased paraoxonase 1 activity (this enzyme protects against the oxidation of LDL and decreases the levels of lipid peroxides (products of lipid peroxidation and markers of oxidative stress)). The addition of cumin also resulted in the significant lowering of fasting blood glucose levels. Although these findings suggest that cumin confers cardioprotection, which the authors of the study suggested may be in part due to its antioxidant properties, this intervention did not result in any significant changes in TC, TG, LDL-C and HDL-C. The BMI of these subjects was also unchanged. In a study using subjects who were either overweight or obese, Zare et al. 52 reported that cumin seed powder (at 3 g per day consumed with low fat yogurt – 1.5 g of cumin plus 150 mL of low fat yogurt at lunch and dinner) lowered fasting cholesterol, TG, LDL-C and increased HDL-C. In addition, BMI, body weight, waist circumference and body fat mass were significantly decreased. In a double blind RCT, cumin essential oil, given in capsule form (100 mg per capsule), three times a day for 8 weeks (300 mg per day) to subjects who were overweight gave rise to similar findings to those of Zare et al. 52 regarding BMI and body weight.53 In addition, the essential oil decreased serum insulin and insulin resistance and increased insulin sensitivity in these subjects. The effects of cumin essential oil were shown to be comparable to that of Orlistat (also known as Xenical) which is used in the management of obesity. Although the mechanism of action for these effects was not elucidated in these studies, Taghizadeh et al. 53 suggested that modulation of insulin metabolism might have a role to play with regards to cumin's lipid lowering properties. Double blind randomized RCTs on subjects with T2D and NAFLD,44,45,54 have also been carried out to ascertain cumin's lipid lowering action and its beneficial potential. The dosages and durations of the interventions were 25 mg per day of essential oil given in capsule form for 3 months to T2D patients,44 50 or 100 mg of essential oil given in capsule form for 2 month to T2D patients55 and 225 mg day of cumin extract, given in capsule form for 3 months to NAFLD patients.54 In one of the T2D studies there were significant decreases in TG alongside a significant decrease and increase in oxidized LDL and paraoxonase 1, respectively. However, there was no change in TC, LDL-C and HDL-C.44 In the other T2D study, there was a significant decrease in TC and LDL-C and a significant increase in HDL-C.55 For the NAFLD study there were no significant changes in lipid profile or BMI.54 A systematic review and meta-analysis of studies on the lipid lowering properties of cumin, which included the studies by Zare et al.,52 Taghizadeh et al.,53 Shavakhi et al.,54 Keihan et al. 44 and Jafari et al.,45 Hadi et al., 56 concluded from their analysis that cumin's effects on the control of plasma lipids is beneficial and that it can be considered a safe option for the treatment of abnormal lipid profiles in the place of other lipid lowering drugs such as statins, which are used to lower LDL-C. However, this conclusion should be treated cautiously as they go on to say that more RCTs, with bigger samples sizes and for longer durations, are needed to provide a basis for recommending cumin in the treatment of hyperlipidemia.

12.6.5

Cardioprotective/Hypotensive Properties

In addition to lowering lipid levels, cumin may confer cardioprotection via its antiplatelet and hypotensive properties although the number of studies is small. The anti-platelet properties of cumin seed extract have been demonstrated in vitro. Srivastava57 reported that cumin inhibited platelet aggregation (the clumping together of platelets plays an important role in the development of arterial thrombosis). Cumin also inhibited thromboxane production by platelets (thromboxane induces platelet aggregation and arterial constriction). Aqueous extracts of cumin seeds decreased systolic blood pressure (SBP) in hypertensive rats. It also increased plasma nitric oxide and upregulated the expression of endothelial nitric oxide synthase,58 both of which are important in conferring vasoprotection and thus cardioprotection.59 This effect was also associated with a decrease in inflammation and oxidative stress. Using an animal model of obesity, Nejatbakhsh et al. 60 reported that seed extract of cumin significantly decreased body weight, BMI and the hormone leptin, which is produced by adipocytes (fat cells) and may play a role in the regulation of energy metabolism.

12.6.6

Chemopreventive/Anti-cancer Properties

Cumin's anti-cancer effect has been demonstrated in vitro and in animal studies. Cumin oil has been shown to be cytotoxic to HeLa (human cervical cancer) cells in vitro,27 and cumin seed extracts are reported to protect against the development and progression of colon cancer, stomach cancer, cancer of the uterus and cervix, and liver cancer in animal studies.61,64 Evidence from the in vivo studies points to cumin seed conferring its chemopreventive effect via the modulation of carcinogen metabolism involving both phase 1 and phase 2 enzymes.

12.6.7

Hepatoprotective Properties

Animal studies provide evidence of the hepatoprotective potential of cumin seeds, some of which suggest that cumin's antioxidant property may have a role to play. Cumin decreased/normalised the activity of liver function enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gluatmic oxaloacetate transaminase and glutamic-pyruvic transaminase.3,65,70

12.6.8

Gastrointestinal-protective Properties

An animal study by Vasudevan et al. 71 provides evidence that cumin modulates gastrointestinal function and possesses gastroprotective properties. Aqueous extracts of cumin seeds are reported to have an antidiarrheal effect.72 It was suggested that cumin's gastroprotective properties may be due to increased production of mucin, a protein which provides protection of the stomach wall.

12.6.9

Neurological and Neuroprotective Properties

The neuropharmacological properties of cumin essential oil have been linked to protecting against the development of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, the development, and also protection against, epilepsy, and the treatment of opioid tolerance and dependence. However, these studies are small in number and limited to animal studies.3

12.6.10

Memory Enhancing and Antioxidant Properties

Cumin essential oil is reported to enhance memory and inhibit stress, alongside decreasing oxidative stress, suggesting that its antioxidant properties may be of therapeutic significance in treating memory loss.30 However, further studies are needed to support this reported property and to understand its preventive and therapeutic significance particularly in the context of dementia prevention and treatment.

12.6.11

Anti-epileptic Properties

An animal study by Janahmadi et al. 73 reported that cumin essential oil decreased epileptic seizures in a dose-dependent manner and may also protect against their (the seizures') development.

12.6.12

Effect on Opioid Tolerance and Dependence

Animal studies have reported on cumin essential oil's ability to decrease opioid (morphine) tolerance and dependence.74,75 Its effect on decreasing the rewarding properties of morphine was shown to be dose-dependent.75

12.6.13

Fertility Inhibitory and Promoting Properties

Current evidence suggests that cumin can act to promote male fertility and may also possess contraceptive properties. In an animal model of male infertility, cumin essential oil increased sperm count, sperm motility and sperm viability, and decreased the level of testicular tissue damage.76 In contrast, in male mice (of normal fertility), isolated fractions of cumin extract affected spermatogenesis resulting in decreased sperm motility, sperm density and sperm morphology, which resulted in a significant negative impact on fertility. Testosterone levels were also significantly decreased.77 Using an animal model of obesity Nejatbakhsh et al. 60 reported that extracts of cumin seed improved sperm quality, specifically sperm count, motility and decreased the number of abnormal sperm, however none of these changes were significant.

12.6.14

Anti-osteoporotic Properties

There is limited evidence of cumin's anti-osteoporotic properties in vivo, which may be of significance in those who are postmenopausal. Cumin seed extract, given to an animal ovariectomy (removal of one or both ovaries)-induced bone loss model,

decreased the urinary excretion of calcium, and increased the calcium bone content and mechanical bone strength. There was also greater bone density. The effect of cumin in the study was comparable to that of oestradiol, the main oestrogen hormone.78

12.6.15

Anti-microbial Properties

The anti-microbial activity of cumin, its seed extracts and especially its essential oil, covers a wide range of microbes, bacterial, fungal and viral, that are pathogenic to humans. Cumin's essential oil is more potent in its anti-microbial action than its seed extracts (aqueous, ethanolic, hydroalcoholic and methanolic).

12.6.15.1Anti-bacterial Activity For bacteria, cumin has been shown, in vitro, to act against pathogenic bacteria that are gram-negative including Campylobacter jejuni (C. jejuni) and C. coli, Klebsiella pneumonia, Neisseria gonorrhoeae, Salmonella typhimurium and Vibrio cholera, and gram-positive including Staphylococcus epidermidis (S. epidermidis), S. aureus, S. haemolyticus, Propionibacterium acnes, Corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, Bacillus cereus, Listeria monocytogenes, Clostridium tetani (C. tetani), C. difficile, and Enterococcus faecalis.3,27,79,86 Furthermore, cumin essential oil has been shown to be equally, or more, effective in its antibacterial action compared to standard antibiotics.87 The essential oil has also been shown to inhibit the formation of gingival bacterial biofilms (plaque formation) in vivo using human volunteers. The oil at 200, 400, 600 or 800 parts per million (ppm) was blended with toothpaste, with which the volunteers brushed their teeth. The oil was effective at inhibiting gingival biofilm formation at all concentrations and proved to be more effective than chlorhexidine, which is used in mouthwash.79 Evidence indicates that the antibacterial action of cumin is due mainly to its monoterpene constituents, which include pinene and cineole.88

12.6.15.2Anti-fungal Activity Cumin, specifically the essential oil, has been shown to act against toxigenic (toxin producing) fungi, Aspergillus niger (A. niger), A. flavus, A. ochraceus and A. parasiticus, and the production of the mycotoxins of some of these fungi,3,89,90 and also pathogenic fungi Candida albicans (C. albicans), C. dubliniensis, C. glabrata, C. krusei and C. parapsilosis.

12.6.15.3Anti-viral Activity The essential oil for cumin also possess anti-viral activity, specifically against herpes simplex virus.28

12.6.16

Antiparasitic Properties

Regarding its anti-parasitic activity, cumin essential oil has been shown to have irritant, repellant and toxic effects against the Anopheles gambiae complex which consists of a number of species of mosquitoes.91 These mosquitoes are major vectors for the transmission of the parasite Plasmodium falciparum, and other Plasmodium spp., which cause malaria. Evidence suggests that cumin may act via interactions between its constituents that are antagonistic, additive or synergistic depending on its action.92

12.7 Safety and Adverse Effects Cumin is safe when used and consumed for culinary purposes.56 From the small number of human studies involving its seed extract and essential oil that investigated safety, cumin use did not give rise to major or serious side effects.56 However, there are reports that chronic consumption of cumin can lead to bleeding, respiratory problems, liver cancer (at levels higher that those normally consumed for dietary purposes), hypoglycaemia and dermatitis. It is for this reason that the use of cumin by pregnant and breastfeeding women and those with respiratory disorders is cautioned.93,94 When used for medicinal purposes, and possibly due to many of the bioactive properties reported above, it is recommended in the literature that cumin must be prescribed by a physician as it is reported to interfere with a number of different types of medication, including antibiotics, anti-seizure, anti-diabetic and lipid lowering agents as well as estrogens and phyto-oestrogens (plant oestrogens), gastrointestinal agents, insecticides, iron, osteoporosis agents and painkillers.93

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CHAPTER 13

Dill (Anethum graveolens, Anethum foeniculum, Peucedanum graveolens, Anethum sowa) 13.1 Names English: Dill, dill weed, aneth Chinese: Shi luo Croatian: Kopar and mirodija Korean: Tir and inondu French: Aneth Spanish: Eneldo Russian: Ukrop The word dill comes from the old English dile, or dyle, which is a relative of the Dutch dille and German Dill but is of unknown origin.1 In Latin dill translates to “calm or soothe” most likely due to its ability to reduce colic, in infants, and stomach complaints. The combination of “Ano” and “theo” in the genus means “upwards I run”, describing its growth characteristics.

13.2 Taxonomy Order: Apiales Family: Apiaceae Genus: Anethum Species: Anethum graveolens (European dill) and Anethum graveolens var. sowa (Indian dill).

13.3 Origin, Description and Adulteration Dill is from the Apiaceae family like parsley, coriander and cumin. This plant can be annual (so it germinates, flowers, sets seed and die in one season) or biennial (it takes two years to complete its life cycle from the growth of its roots and stems to flowering, producing seeds and dying), with aniseed scented leaves 0.5–1 m in height that spread 0.1–0.5 m. Dill has finely dissected, aromatic blue-green and flat umbels (flower cluster with an umbrella-like shape) of very small yellow flowers that bloom in summer.2 The seed, which is light brown, oval shaped, sweet and citric with a slightly bitter taste, is used as a spice (which has a similar appearance

and taste to cumin seeds).3 Dill's flowers are edible and have an aniseed flavour. It is ideal for salads (which is a common practice in Sri Lanka), vegetables and fish, mayonnaise, white sauce and pickles.4 Dill grows easily in well-drained soil, in full sun but must be sheltered from strong winds. It is normally pest resistant and free of disease. Indigenous to the Mediterranean region, dill may have originated from Eurasia (perhaps southern Asia).5 Dill is cultivated worldwide in tropical and temperate climates. According to the World Spice Congress report6 dill is cultivated in Beni Swife (Egypt) and harvested three times from December to mid-March. The delicate leaves can be heavily contaminated by herbicides, and 90% of the production is exported to the United States where pesticide residues are not seen as an issue as much as in Europe. European dill (Anethum graveolens) can be subject to adulteration mainly with Indian dill (Anethum graveolens var. sowa) and with added terpenes.7 Indian dill grows in northern India and has a high content of the toxic compound dillapiole compared to European dill, which has none. Dill herb oil is often adulterated with dlimonene.5

13.4 Historical and Current Uses Records dating back 5000 years suggest ancient Egyptians used dill as a medicine.8,9 The Chinese have used the herb for thousands of years for digestion and also to help reduce fever and anxiety. Ebers Papyrus (an Egyptian medical knowledge record from 1550 BCE) included dill in a prescription for pain. Dill oil was burnt in homes, and the ancient Greek physician, Dioscorides (40–90 AD) prescribed mashed scorched dill seeds to help heal wounded soldiers by applying the mixture directly to wounds. It is also used for hiccups, sleeplessness, to increase milk flow in nursing mothers and to calm colicky babies. In ancient Rome, gladiators were fed meals containing dill for strength and courage.9,10 Dill seeds were chewed in church to keep members of the adult congregation awake and the children quiet. The King of France Charlemagne (742–814 CE) ordered dill oil to be available on banquet tables to help prevent indigestion in guests who had overeaten (and produced noises he was not fond of). In the Middle Ages, dill was thought to be used by magicians and witches, drunk in water or used in charms placed over the doorway or above a sleeping baby as a symbol of love and protection from curses. Thought to be an ingredient of love potions and aphrodisiacs, dill leaves were woven into household brooms to sweep away negative enchantments and curses.11 In Germany and Belgium, brides added a sprig of dill to their wedding gowns or in their bouquets for a prosperous marriage. A bride would add mustard and dill seeds to her wedding gown and repeat the words “I have you, mustard and dill, Husband, when I speak, you stay still!” to protect themselves against overpowering husbands.11 Dill means “good spirit” or “to lull” in flower language (symbolic meaning given to flowers to express feelings). However, European monks believed that dill could affect fertility and had the power to chase off incubus or male demons that preyed sexually on sleeping women. King Edward I of England (who reigned from 1272–1307), taxed dill that arrived by ship

to help pay for the repair of London Bridge.12 The 17th century botanist Nicolas Culpeper recommended dill as a tonic for the brain. Dill was a popular herb in 17th century England and was planted in many gardens. It was brought to America by the English puritan settlers of the 17th century.8 Dill features extensively in the Apicius Roman cookbook, to accompany meat dishes including crane, duck, flamingo, parrots, boar and sickling pig, and it is also found in various fish recipes. Amalatum was a popular dish, which consisted of chicken stewed with leeks, dill and salt. A dish called Minutal (small dish) of hare's livers was prepared with diced cooked pork shoulder, broth, wine and various herbs and spices including dill. Porridge gruel recipes also included dill, and it was often added to peas.13 Northcote mentions dill in the Book of Herbs (1903): “Dill is supposed to have been derived from a Norse word meaning “dull”, because the seeds were given to babies to make them sleep. Beyond this innocent employment it was a factor in working spells of the blackest magic! Dill is a graceful, umbelliferous plant,… the seeds resemble caraway seeds in flavour, but are smaller, flatter and lighter. There is something mysterious about it, because… besides being employed in spells by witches and wizards, it was used by other people to resist spells cast by traffickers in magic…. The leaves are used with fish, though too strong for everyone's taste, and if added to ‘pickled Cucumbers’ it gives the cold fruit a pretty, spicie taste.”14 Today dill herb is commonly paired with potato, pickling gherkins, lamb and fish dishes. Dill is a key ingredient in dill pickles, and can also be added to baked goods, mac and cheese, and soups such as Borscht (a beetroot soup). Dill is used in egg dishes, sauces such as yogurt and cucumber, as an ingredient or as a garnish. Dill, like other aromatic herbs, can also be used to flavour vinegar, salt and butter. Dill is a popular culinary herb all over the world. In the Herb Society of America's Essential Guide to Dill (2010), Wright gives examples of dill's culinary uses around the world and lists the Swedish salmon appetizer Gravlax, Greek madakis (grape vine leaves filled with dill, rice, garlic, pine nut), Turkish pureed beans dishes, Indian Dhansak (a type of chicken curry recipe), as well as middle Eastern rice, beans and meat dishes.9 The essential oil of dill is used to make liqueurs such as Green Witch gin. Dill has been used traditionally to support digestion. In the United States the regulatory status of Generally Recognized as Safe (GRAS) has been accorded to dill, dill herb oil and dill seed oil.15 The Commission E monographs report that dill seeds are antispasmodic (suppress muscle spasms) and bacteriostatic (prevent the growth of bacteria) and have been used traditionally for indigestion with a dosage of either 3 g of seeds or 0.1–0.3 g of essential oils a day. No contraindication, drug interactions or side effects were reported in the monographs, however dill weed is not approved16 (see section on Safety and Adverse Effects). Dill has been an important Ayurvedic medicine since ancient times, it is an essential ingredient in gripe water, given to relieve colic pain in babies, and used for urinary complaints, piles and mental disorders. The seed is aromatic, carminative (relieves flatulence), mildly diuretic, a galactagogue (promotes or increases the flow of breast milk), a stimulant and stomachic (stimulates gastric activity). The volatile oil is used to improve appetite, relieve gas and aid digestion, and the seeds chewed to improve bad breath.17 In Chinese traditional medicine, dill (weed and seed) has been used to support the

stomach, spleen and kidney meridians. It is prescribed for stomach and abdominal aches and pains, gas, bloating, constipation, poor appetite, menstrual cramps, colds and flu, and anxiety.18

13.5 Chemistry, Nutrition and Food Science The Phenol Explorer database19 provides information on the phytochemical, specifically the polyphenol, composition of dill. Fresh dill contains the flavonoids isorhamnetin, kaempferol, myricetin and quercetin. Dried dill contains the flavonoid quercetin and the phenolic acid vanillic acid. The main constituents reported in dill herb oil are 7-α-hydroxy manool (24.43%), l-carvone (14.28%), limonene (13.9%), epi-α-bisabolol (6.81%), α-terpinene (5.44%), and α-phellandrene (4.63%) with the minor constituents p-cymene (2.13%), sabinene (1.98%) and α-pinene (1.43%).20 According to the UK data, the nutritional quality of dill varies between the seed, fresh and dried samples (see Table 13.1). Generally considered poor in nutrients, fresh dill (dill weed) is high in water, riboflavin, vitamin C and folate. Dried dill is high in iron, potassium, sodium, pro vitamin A, vitamin E and vitamin B6. Dill seeds are high in fat, copper and zinc.21 Table 13.1 Nutrition composition of dill.21 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Dill (100 g) – UK data

Seeds

Dried

Fresh

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg

Na

253 42.2 13.6 4.4 (Na) 19.9 7.3 Na 1780 0.49 Na 48.8 450 3.9 540 3310 Na 210 3.3 5545 0.42 0.28 2.8 1.46 0

27 0.9 2.5 0.8 (Na) 3.7 83.9 Na 340 Na Na 3.2 44 Na 85 750 2 26 1.8 1015 0.18 0.58 2.1 Na 86

Na Na 14.5 (0.7) 16 7.7 Na 1520 0.78 Na 16.3 260 1.8 280 1190 Na 20 4.5 5 0.42 0.28 2.8 Na 0

Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

0 Na —b Na

0 9.27 —b Na

36 1.7 —b Na

a N: Present in significant amounts but not determined. b —: Not assessed or not present.

Food preparation and cooking can impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. The impact of dehydration techniques on the antioxidant capacity and phytochemical composition of fresh dill greens (aerial parts) was investigated.22 The dehydration processes used were hot air (HA) 50 °C, 58–63% relative humidity (RH), low humidity air (LHA), 50 °C, 28–30% RH, radiofrequency (RF), 50 °C and 56–60% RH. Aqueous methanolic extract of dill dehydrated by LHA contained the highest antioxidant capacity. Constituents, including polyphenols, carotenoids, ascorbic acid and minerals retained good acceptance levels that can contribute to improving shelf life of foods, thus dill may have the potential to be used as a food additive.23 The impact of microwaving dill leaves was assessed on their antioxidant capacity (measured via the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay) and their chlorophyll and carotenoid contents. Dill (3 g) was microwaved in water (50 mL) for 1, 2 and 3 minutes, and compared against a control (0 minutes) the overall antioxidant capacity of dill significantly increased from 48.14% to 50.71% after 1 min of heating, after which a gradual decrease in antioxidant capacity was observed after 2 and 3 min of heating, which totalled 30.3% loss. This loss was possibly via a leakage of bioactive constituents into the cooking water, followed by degradation by heat. Some loss of green colour and chlorophyll content was recorded after all heating times (the loss of colour was also due to the degradation of carotenoids presumed to be mainly lutein and β-carotene). The authors concluded that microwave heating causes significant loss in some bioactive components in dill, with the quality of appearance, brightness and greenness being significantly affected.24 In the food industry today, the use of synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) for preserving food has declined because they were not seen as acceptable components of food by consumers. The use of herbs and spices as natural antioxidants in processed foods has become more widespread. These (natural antioxidants) work by reducing the oxidative degradation of constituents (normally lipids) and therefore preserve the nutritional composition of foods for longer. Dill is high in phytochemicals with antioxidant capacity that could help improve the shelf life of food products. The antioxidant capacity of ethanolic extract of dill flowers was compared to the antioxidant capacities of dill leaf and seeds extracts using the 2,2-diphenyl-1picrylhydrazyl (DPPH) assay, reducing power, chelating power, and β-carotene content. The flower extract had higher antioxidant capacity than the leaf and seed extracts. Flavonoids and proanthocyanidins were the most abundant bioactive compounds followed by the phenolic acids and proanthocyanidins.23 Dill seed essential oil is an antimicrobial agent, and dill seed acetone extract and essential oil have a potential use as natural antioxidants in food preservation.25 A

study26 investigated the antifungal activity of dill seed essential oil on cherry tomatoes against Aspergillus flavus (A. flavus), A. oryzae, A. niger and Alternaria alternata. The cherry tomatoes exposed to essential oil vapour at 120 µL mL−1 and 100 µL mL−1 concentrations. Microstructure observations of A. niger, using light and scanning electron microscopy, revealed degenerative signs in the microorganisms after the essential oil treatment, suggesting the essential oil of dill could be used as a food preservative.

13.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 13.6.1

Antioxidant Properties

Dill (flower, seed and leaf and branch/weed, and the essential oil of the seed) possesses antioxidant capacity in vitro.23,27 ,38 A comparison of the antioxidant capacity of the herb with those of other culinary herbs and spices indicates that it is comparable to that of bay leaf, higher than those of basil, rosemary, parsley, caraway, chives and thyme, and lower than those for Mediterranean and Mexican oregano (Origanum vulgare and Poliomintha longiflora, respectively).27 Although the antioxidant capacity varies depending on the nature of the preparation as well as the cultivation conditions,17,34,37,39,40 both of which influence levels of the constituents that contribute to antioxidant capacity,23,32,33,39,41,42 and the assay used.29 Extracts of the flower are reported to possess higher antioxidant capacity in vitro than the seed and leaf.23 The constituents of dill flower that are believed to be major contributors to its antioxidant capacity are the polyphenols, specifically chlorogenic acid, myricetin, and 3,3′,4′,5,7-pentahydoxyflavan (4 → 8)-3,3′,4′,5,7pentahydoxyflavan. For the seed essential oil, the constituents that are reported to be major contributors to its antioxidant capacity are carveol and perillyl alcohol.28 Dill's antioxidant properties have also been demonstrated in vivo, using animals, and its antioxidant capacity has been shown to be comparable to that of the synthetic antioxidant BHT and also ascorbic acid.43 There is some evidence suggesting that dill's antioxidant properties may be of significance in the enhancement of memory of those with cognitive impairment and in protecting against liver damage (see sections below on Memory Enhancing and Hepatoprotective Properties).

13.6.2

Anti-inflammatory and Analgesic Properties

Dill leaves have been shown to possess anti-inflammatory activity in vitro which is influenced by the nature of the extract.37 Dill's, specifically its seed extract, oil, essential oil and aerial parts, anti-inflammatory and analgesic activities have been

demonstrated in animal studies, with dill oil and seed shown to have a greater or comparable effect to that of the non-steroid anti-inflammatory drugs (NSAIDs) sodium diclofenac and acetyl salicylic acid (aspirin).44,47 In contrast, extracts of dill seed and dill's aerial parts have been shown to increase sensitivity to pain. This variable effect appears to be due to the nature of the animal model used.46 Evidence from a randomized controlled trial (RCT), which was double blind, suggests that dill's anti-inflammatory effects may be of benefit in the management of type 2 diabetes (T2D) and other conditions in which insulin resistance occurs, including metabolic syndrome (MetS) and obesity. In these conditions, elevations in pro-inflammatory mediators are reported to affect insulin sensitivity.48,51 In this study dill powder, made from its leaf and stem, given at 3.3 g per day (dill was in capsule form and each capsule contained 1.1 g of dill so three capsules were taken a day) was given for 8 weeks to subjects with T2D. Compared to baseline data before and after adjusting for age, gender, the type of hypoglycaemic drug taken and the use of hypolipidemic drugs, the levels of the pro-inflammatory markers C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were significantly decreased. There was no change in the levels of these markers in the placebo group.52 Dill's anti-inflammatory activity may also contribute to its reported memory enhancing effect (see section below on Neuroprotective/Memory Enhancing Properties). Dill's analgesic effects have been investigated in women with primary dysmenorrhea. In a RCT, powdered seed of dill given in capsule form (500 mg per capsule, two capsules a day 12 hourly) for 5 days, from 2 days before the beginning of menstruation for 2 cycles, had a comparable analgesic effect to the NSAID mefenamic acid. Both provided significant pain relief in the first and second months after treatment; in the placebo group pain relief was only significant in the second month.53 In a systematic review of the effect of dietary supplements on this condition, Pattanittum et al. 54 concluded, based on this single RCT, that there was no consistent evidence of the efficacy of dill when compared to mefenamic acid. There were also issues concerning the risk of selection bias, the randomization process and the small sample size of the RCT that affected the usefulness of the findings of this study. A more recent RCT by Omidvar et al. 55 reported that in women with primary dysmenorrhea, powdered dill seed (1.5 g twice a day for 3 days during each menstrual cycle for three consecutive cycles) was the most effective at providing pain relief compared to ginger and cumin. The authors noted that the findings for dill agreed with that of an earlier study by Mohammadinia et al. 56 in which the effect of dill was compared to that of mefenamic acid. In addition, they suggested anethol and tannin as constituents of dill that may be responsible for the effect reported, based on reports of their sedative and contractile properties (see section below on Antispasmodic and Contractile Properties).

13.6.3

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

There is some evidence concerning the glucose lowering, anti-diabetic and lipid lowering effects of dill (its flowers, powder, seed extract, leaf extract, tablet, dill pearls and/or essential oil). The bulk of the evidence, however, comes from animal

studies.57,58 Dill is reported to lower blood glucose, fasting blood glucose (FBG) and insulin resistance, as well as inhibit protein glycation (protein glycation is a biomarker of diabetes and can lead to the vascular complications that result from this disease) and increase the secretion of insulin.43,57,59 Its glucose lowering effect is reported to be comparable to that of the anti-diabetic drug glibenclamide.60 In addition, dill is reported to lower lipid levels, including total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and increase high density lipoprotein cholesterol (HDL-C), although these changes were not observed consistently across studies. A large number of these effects have been shown in vitro or in animal studies, using models of diabetes and hyperlipidemia. However, a small number of RCTs provide some support for dill's potential in the prevention and management of T2D, MetS and hyperlipidemia. In an early study, Kojuri et al. 61 reported in a single blind RCT that dill (650 mg taken twice a day for 6 weeks; no information concerning the nature of the preparation was provided) increased TG and decreased TC and LDL-C, but these changes were not significant. Rashidlamir et al. 62 reported that T2D patients given dill in capsule form (3 capsules a day at 900 mg kg −1 body weight) in combination with aerobic training for 4 weeks significantly decreased FBG and the LDL-C/HDL-C ratio, which is indicative of an improvement in the atherogenic index (which is used as a marker of abnormal lipid levels and an indicator of risk of developing cardiovascular disease) compared to controls, who did not receive dill and aerobic training. In addition, although there was a decrease in LDL-C, TG and body mass index (BMI) these were not significant. Haidari et al. 63 reported that dill (powdered leaves) in capsule form (one capsule contained 1 g of dill, which was taken three times a day, so the total amount given per day was 3 g per day, for 8 weeks) significantly decreased serum insulin, insulin resistance, LDL-C, TC and malondialdehyde (MDA), which is a marker of oxidative stress, compared to baseline. The levels of HDL-C and total antioxidant capacity were also significantly increased compared to baseline. With the exception of insulin resistance, insulin, LDL-C, TC and MDA were also significantly lower than for the placebo group, and HDL-C significantly higher. Dill also improved gastrointestinal symptoms in this study. Randomized controlled trials by Sahib et al. 64 (500 mg of crude leaf powder in capsule form, taken twice a day for 4 weeks), Mansouri et al. 65 (600 mg per day of dill extract in capsule form for 3 months), Kazemi et al. 66 (dill pearl given for 1 month, additional details not available in English) and Mirhosseini et al. 67 (6 Dill tablets a day for 8 weeks – no information was provided concerning the amount of dill per tablet) all reported that dill significantly improved lipid profile in hyperlipidemic subjects, some with MetS, with one noting improvements in the atherogenic index and another noting that dill's effects were comparable to that of the lipid lowering drug lovastatin.64 However, there were some anomalies, for example, Sahib et al. 64 reported that dill lowered HDL-C, although this effect was not significant but Mirhosseini et al. 67 reported that dill did not affect HDL-C levels. Mirhosseini et al. 67 also noted that dill, which was given in tablet form (6 tablets a day but the amount of dill per tablet was not provided), was not as effective as the lipid lowering drug gemfibrozil with

regards to HDL-C and TG although dill had a greater lowering effect on TC. Evidence suggests that dill's glucose lowering and anti-diabetic effects may be due to its polyphenolic, specifically its flavonoid, constituents which are noted for their hypoglycaemic effect as well as their ability to inhibit glycation. However, other constituents, including carvone, may also have a role to play.57,58,68,70 With regards to its lipid lowering effect, a number of mechanisms are proposed which involve dill's flavonoids and also carvone, limonene and alpha-phellandrene. These include inhibition of intestinal cholesterol absorption, increased excretion of faecal bile acids and inhibition of key regulatory enzymes of fatty acid and cholesterol synthesis, specifically acyl CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase.30,71

13.6.4

Hepatoprotective Properties

There is some evidence of the hepatoprotective effect of dill (seed oil, dill extract, dill herb powder and extract of the powder, commercially available dill tablet and dill leaf extract). However, this evidence is based solely on animal studies.43,72,75 Dill was reported to protect against chemically induced hepatotoxicity, limit damage caused by hepatotoxicity and/or improve liver function affected by hepatotoxicity. Dill's effect is reported to be comparable to that of silymarin, an agent extracted from milk thistle with a history of use in protecting against liver damage although evidence regarding its efficacy in humans is limited.76 In the majority of these studies, antioxidant status was improved and/or oxidative stress decreased, suggesting that dill's hepatoprotective effect may involve its antioxidant properties.

13.6.5

Chemopreventive/Anti-cancer Properties

A small amount of research has been carried out demonstrating the chemopreventive/anti-cancer effects of dill in vitro. Dill seeds and its essential oil are reported to inhibit the growth/proliferation of human liver cancer cells (HepG2 cells) via apoptosis and cell cycle arrest.77,78 These preparations of dill are also reported to decrease the viability of HepG2, colon cancer (Colo205), embryonic kidney adenocarcinoma (2 9 3) and urinary bladder cancer (T24P) cells by between 55 and 60%.79 Interestingly, methanol extracts of dill seeds were reported to stimulate the proliferation of the human breast cancer cells (MCF-7) in vitro along with a number of other culinary herbs including dried parsley, rosemary leaf and fennel seed. Extracts of the aerial parts of these herbs were shown to possess potent estrogenic activity, which may explain the proliferative effect on the MCF-7 cells.80

13.6.6

Neuroprotective/Memory Enhancing Properties

Animal studies provide evidence that dill may possess memory enhancing properties via a number of mechanisms. Dill essence was reported to enhance memory using a mechanism that might be mediated via oestrogenic receptors in the brain.81,82 In addition, aerial parts of dill (the actual parts were not specified but

these are likely to have been the leaf, stem and flower) in combination with sticky black rice (Oryza sativa) which were both used based on their antioxidant and antiinflammatory properties in addition to their reported neuroprotective properties, were shown to enhance memory. The authors of this study suggested that the underlying mechanisms of this effect involved decreasing acetylcholinesterase (AChE) activity (AChE is an enzyme which hydrolyses, breaks down, the neurotransmitter acetylcholine and plays a role in the pathogenesis of Alzheimer's disease), oxidative stress and neuroinflammation based on lower levels of the proinflammatory mediators/cytokines TNF-α and IL-6 in the hippocampus.83

13.6.7

Anxiolytic/Calming Properties

The anti-anxiety effect of dill has been demonstrated in women in labour and is likely linked to its contractile properties, which are reviewed below. In an RCT, Hekmatzadeh et al. 84 reported that, compared to oxytocin (a hormone that stimulates contractions during labour which was given to stimulate contractions), boiled dill seed (10 g of seed boiled in 100 mL water for 10 minutes) given once at the beginning of active labour (when the cervix dilates and contractions become stronger) significantly lowered the level of anxiety (based on the level of state anxiety – current feeling of anxiety – and trait anxiety – tendency to express anxiety). Labour was also shorter in the dill group, although it was only significantly shorter during the first stage of labour.84 Although the study provides support for the use of dill during labour, larger clinical trials are required to ascertain more fully its benefit during labour.

13.6.8

Anti-epileptic Effect

There is evidence from animal studies that dill leaves and seed may be beneficial in the management of epilepsy, possibly as an adjuvant therapy, with evidence that dill leaves may act by protecting against damage to the hippocampus,85,86 which is considered to be the site of origin of epileptic seizures.87,88 Its flavonoids as well as linalool, carvone and limonene have been put forward as constituents in dill that contribute to this effect possibly via their antioxidant or anti-inflammatory properties.86,89

13.6.9

Antispasmodic and Contractile Properties

Dill's fruit/seeds antispasmodic (relaxatory) properties have been demonstrated in vitro using smooth muscle preparations. This action may be due to the blocking of calcium channels (increases in intracellular calcium lead to stimulation of muscle contractions).90 In contrast, dill has also been shown to possess contractile properties. These have also been demonstrated using smooth muscle preparations in vitro.91 Based on a small number human studies, specifically RCTs and retrospective cohort studies, dill's contractile properties, which may be due to increases in intracellular calcium ultimately leading to the stimulation of muscle contraction,92 have been shown to be of possible significance for women who are in

active labour although more studies are needed. Hekmatzadeh et al. 93 reported that boiled dill seeds (two tablespoons) given orally to women at the beginning of active labour significantly decreased the duration of the first stage of active labour compared to the controls (who received nothing). The level of labour pain was also significantly lower. Zagami et al. 94 also reported that dill, prepared by steeping 1 tablespoon of whole dill seed in boiling water (a full or half cup) for 3–4 minutes, increased contractions and decreased the duration of the first stage of active labour compared to controls (who received nothing). In this study, women consumed the dill seed preparation at the beginning of uterine contractions. These contractile properties may also be of significance following delivery. Akbari et al. 95 reported that dill seed extract (0.18 g kg−1) when given orally to women immediately after delivery, significantly decreased bleed time in the first hour after delivery, compared to the controls, who received oxytocin. The authors suggested that this effect may be due to the stronger contractile effect of dill on smooth muscle. The contractile effect of dill may be due to its tannins and also limonene.94

13.6.10

Fertility

Studies suggest that dill seed extract may be used as a contraceptive agent, and could also be used to regulate the menstrual cycle of women with irregular cycles. The main constituents of dill, including limonene and carvone, may contribute to the influence of dill on fertility in these studies.96,99 However, currently these studies are limited to in vitro and animal studies and so, as noted by the authors of these studies, more research is required in this area.

13.6.11

Impact on Skin/Dermal Properties

Limited evidence suggests that dill may be of use in the maintenance of the elasticity of skin and thus may possibly delay the ageing process and be of benefit in the treatment of premature ageing. Studies in vitro and/or ex vivo have reported that dill seed extract (1%) increased the expression of genes for the proteins elastin, collagen1A1 and lysyl-oxidase like extracellular enzyme, all of which are essential for skin elasticity.100,101 A double blind RCT by Sohm et al.100 backed up these properties as they reported that the extract, when applied to the whole face twice a day for 3 months by subjects in place of their usual product, improved skin elastic recovery compared to the placebo. Skin elasticity, based on clinical evaluation, was also improved and the majority of subjects (95%) reported noticeable improvements in skin elasticity. In contrast, in another more recent RCT which was triple blinded, Meza et al. 101 reported that the same extract had no effect on the elasticity of the skin of subjects suffering from premature aging due to repeated exposure to ultraviolet rays from the sun. However, when combined with blackberry leaf extract, which in vitro was shown to inhibit elastase activity (this enzyme breaks down elastin) and increase elastin gene expression and tropoelastin, which is a precursor of elastin, skin elasticity in these subjects was increased. This result is suggestive of a synergistic effect. Dill (seed extract) may also be of use in the treatment of hyperpigmentation via its umbelliprenin content, which in addition to its anti-inflammatory,

immunomodulatory, chemopreventive and apoptotic properties, has been shown to inhibit melanin synthesis.102,105 However, this effect is currently limited to an in vitro study in which murine cells were used.106

13.6.12

Anti-microbial Properties

A large number of in vitro studies highlight the anti-microbial potential of dill, which acts against a number of bacteria, both gram-positive and gram-negative, and fungi, which are pathogenic to humans. Evidence points to carvone, limonene and also camphor, alpha-phellandrene and p-cymene as the constituents that contribute to this activity. The mechanism of action of dill essential oil's antimicrobial activity is believed to involve compromising the cell membrane integrity of bacteria and the plasma membrane and mitochondria of fungi.38,107,108

13.6.12.1Anti-bacterial Activity Beginning with its anti-bacterial activity, dill, mainly its essential oils from its seeds, leaves and flowers, as well as seed extracts, have been shown to act against gram-negative bacteria pathogenic to humans including Klebsiella pneumonia, Campylobacter spp. including Campylobacter jejuni (C. jejuni), Salmonella typhimurium and Pseudomonas aeruginosa, and multi-drug resistant strains of some of these bacteria, and gram-positive bacteria pathogenic to humans including Staphylococcus epidermidis (S. epidermidis), S. aureus, methicillin resistant S. aureus (MRSA), Bacillus cereus and L. monocytogenes.38,108,112 In addition, dill essential oil prepared from aerial parts of the plant has been shown to accelerate the healing of wounds infected with MRSA.107 The beneficial/therapeutic significance of dill's anti-bacterial activity has been demonstrated in a double blind RCT involving dill seed oil mouthwash – the amount or percentage was not provided but subjects were instructed to rinse with the mouthwash once in the morning and once in the evening each time for 60 seconds. The trial was for 90 days and the effects of the dill seed oil on plaque build-up and gingivitis (gum disease) were compared to that of a standard mouthwash – chlorhexidine. The dill seed oil's ability to combat the build-up of plaque and the development of gingivitis was comparable to that of the standard mouthwash. Despite these promising results, the authors highlighted the importance of further investigating the reported effect by carrying out longer and larger clinical trials.113

13.6.12.2Anti-fungal Activity Dill is reported to act against pathogenic fungi including Candida albicans (C. albicans), C. glabrata, C. krusei, C. parapsilosis and C. tropicalis, toxigenic (toxin producing) fungi Aspergillus niger (A. niger), A. flavus and A. ochraceus, and the production of the mycotoxins of some of the toxigenic fungi.38,114,116 In an RCT, which was not blinded, dried dill seed extract in the form of vaginal suppositories (containing 2% dill) taken for 7 nights by women with vulvovaginal candidiasis, which is caused by species of Candida, especially C. albicans, successfully reduced

the infection and clinical symptoms caused by this condition. The effect was comparable to clotrimazole, which is used to treat vaginal fungal infections.117 As with the dill seed oil mouthwash study, the authors highlighted the need for larger studies to further establish the therapeutic significance of these findings.

13.7 Safety and Adverse Effects Dill (both the seed and leaf) when used for culinary purposes is considered safe.118 With regards to the clinical trials reviewed above, not all reported on adverse effects. Of those that did, Payahoo et al.,52 who used dill powder made from its leaf and stem, reported no side effects (see section on Anti-inflammatory and Analgesic Properties for details concerning the preparation, dosage and duration). This (no side effects) was also the case for studies carried out by Mansouri et al.,65 Rashidlamir et al.,62 Kojuri et al.,61 Kazemi et al. 66 and Mirhosseini et al. 67 (see section on Glucose Lowering, Anti-diabetic and Lipid Lowering Properties above for details of preparation and dosage (where available) and duration). In the clinical trial by Heidarifar et al. 53 in which dill powder was used (see section on Antiinflammatory and Analgesic Properties for details concerning the preparation, dosage and duration), out of 75 women, 2 reported increased menstrual bleeding and one reported gastrointestinal discomfort. In a single case study, fresh dill was reported to cause severe allergic reactions following ingestion and inhalation of food cooked/prepared with dill. Symptoms, which included oral pruritus (an unpleasant sensation in the mouth or itchy mouth), swelling of the tongue and throat, urticaria (a skin rash), and immediate vomiting and diarrhoea, occurred in a patient who had a history of allergic rhinitis.119 In addition, due to the traditional use of dill seed as an abortifacient and reports in the literature of its abortive and teratogenic (damage caused to the embryo or fetus) effects, some advise that it should not be taken/consumed during pregnancy118 although this advice is based on evidence from animal studies.120,121

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CHAPTER 14

Fennel (Foeniculum vulgare) 14.1 Names English: Fennel, common fennel, sweet fennel, Roman fennel Czech: Fenykl, fenýkl obecný, vlašský kopr, sladký kopr and řimský kopr Chinese: Xiao hui xiang Gujarati: Varyyali French: Fenouil Spanish: Hinojo Swahili: Shamari Xhosa: Imbambosi The original Greek genus name was Marathron, from maraino, which means to grow thin. The current genus name, Foeniculum, was given by the Romans. The name fennel comes from the old English finule, fenol, and from the Latin faeniculum, which is a diminutive of faenum which means hay.1

14.2 Taxonomy Order: Apiales Family: Apiaceae Genus: Foeniculum Species: Foeniculum vulgare

14.3 Origin, Description and Adulteration The genus Foeniculum belongs to the family Apiaceae, F. vulgare Mill. var. piperitum (Ucria) Cout. is called bitter fennel, and F. vulgare Mill. var. dulce Batt. et Trab. is called sweet fennel, a third variety F. vulgare Mill. var. azoricum Thell. is called Florence fennel and is less commonly used.2 Sweet fennel is used in foods, beverages and as a flavouring agent and bitter fennel is used in medicine. Fennel originates from the Mediterranean basin; it is a perennial (long-lived plant), covered in yellow flowers that bloom in early summer and then give fruit (which are the seeds).3 The whole plant has a characteristic, aniseed-like scent and taste, and is used for culinary purposes. The bulb can be eaten as a vegetable and seeds can be consumed fresh or dried. The flowers are attractive to a range of insect pollinators. Fennel likes a sunny spot in light, free-draining soil, and needs little maintenance. It can get infested by aphids (small sap-sucking insects), which encourage black mould. Fennel can often be eaten by slugs and snails. Diseases that

affect fennel include leaf blight (Cercosporidium punctum) which causes heavy leaf loss and damage to the developing flowers, and stem rot, (Sclerotinia minor). Fennel is grown in Bulgaria, Romania, Hungary, Greece, Turkey, Italy, France, Germany, Egypt, India and China, and most commerce comes from Bulgaria, Hungary, Romania, Egypt and China.4 It is also cultivated in North America, Asia and Egypt. Fennel essential oil is obtained from the dried, ripe fruits (the seed) via water steam distillation, and both bitter and sweet fennel oils are used as aromatic components in cosmetics and also in detergents. Fennel seeds were found to be adulterated with partially or fully exhausted fennel fruits (essential oils extracted), stem tissue, stalks of fennel and umbelliferous seeds, as well as Anethum graveolens (dill) and Cuminum cyminum (cumin) fruits.5 Fennel seeds covered with marble dust and dye are used as an adulterant of cumin seeds.6

14.4 Historical and Current Uses The ancient Egyptians, Greeks, and Romans ate the aromatic fruits as well as the tender shoots of fennel. It was among those seeds planted in the ritual of the midsummer festival Adonia for Adonis (Greek God of beauty and desire), intended to summon abundant rainfall to grow crops. Early Greek athletes ate fennel seeds during training to manage their weight. Dioscorides (a Greek physician 40–90 CE) distinguished fennel types narthex (Ferula communis – giant fennel) and marathon (Foeniculum vulgare). In 490 BCE the Ancient Greeks fought the Persians in a famous battle at the city of Marathon, the site of which, eastern Attica, was plentiful with fennel, and the word for fennel was then derived from the Greek word for “marathon”. Fennel stalk juice and leaves were drunk to improve eyesight. Pliny the Elder (a Roman author of the 1st century CE) commented that snakes rub against the fennel plant to sharpen their eyesight after they shed their skins. The Romans enjoyed the flavour of fennel; soldiers mixed fennel seed with their meals for strength and courage.7 Fennel was used to make olive relish, and its shoots were used and cooked as vegetables, in salads. The seeds were used in the baking of bread to add flavour. The Puritans (English Protestants in the late 16th and 17th centuries) brought fennel seeds to America, and called them “meeting seeds”; they chewed them to fend off hunger and tiredness. In the Apicius Roman cookbook fennel is mentioned in dozens of recipes including Julian pulses, peas, gruel, sauce for fowl, boiled chicken broth, roast loins, boar, venison, fricassee of veal, broiled mullet, tisane (herbal tea) and cold green sauce. Mortaria was a ready to use preparation made up of mint, rue (a herb commonly used then, Ruta graveolens), coriander and fennel seeds, crushed up in a mortar finely, to which lovage pepper, honey, broth and vinegar were added. It was used principally for cold green sauce to accompany dishes.8 Northcote mentioned fennel in the book of Herbs (1903): “…few realise from how high an estate fennel has fallen. In Shakespeare's time we have the plainest evidence that it was the recognised emblem of flattery. It is said that Ophelia's flowers were all chosen for their significance, so, perhaps, it was not by accident that she offered fennel to her brother, in whose ears the cry must have been still

ringing”. She quotes an Italian saying: “Dare Finocchio” (to give fennel), meaning “to flatter”. As for the reason why fennel was connected to sorrow, the clue is lost, but she quotes Miss Amherst: “to relieve the pangs of hunger on fasting days… eight and a half pounds of fennel seed was bought for the King's Household (Edward I., 1281) for one month's supply.” The author continues with examples of use of fennel for cooking fish, and added in pickled cucumbers, and other fruits. The roots were used with parsley roots in broths, and the seed added to pies, breads and baked fruits.9 Fennel seeds are normally retailed dried, alone or in blends. Fennel seeds are included in the five Chinese spice mix (with cassia, black pepper, ginger and clove) as well as in Cajun spice blend (fennel, paprika, basil, black pepper, garlic, onion, chilli, cumin and mustard). The unique fennel seed flavour and aroma is highly appreciated and used for drinks including liqueurs, digestives, fennel infused vodka and anisette. Fennel is also added to confectionery, biscuits, bread, cookies, cheeses, sauces, fish stocks, pickles and beverages. Fennel is popular in China, for example in sausages fried with fennel leaves, or shredded pork with fennel, and also in stews and casseroles, lentils and beans dishes.10 The United States Department of Agriculture (USDA)11 granted fennel seeds (spice) Generally Recognized as Safe (GRAS) certification, when used as food, and granted fennel essential oil GRAS certification when used as a food additive. Fennel was used in traditional Ayurvedic, Chinese, Japanese (Kampo) and Arabian medicine as a digestive support medicine. The modern therapeutic applications for fennel seed and oil are based on their history of use in wellestablished systems of traditional medicine. The therapeutic uses of fennel in Germany and the United States come directly from traditional Greek medicine. The Commission E monographs4 approve fennel seed (and fennel oil) preparations for dyspepsias (painful digestion) such as mild, spastic gastrointestinal afflictions, fullness and flatulence. Fennel syrup and honey are prescribed for catarrh in children. Fennel seed oil contains anethole and fenchone, and is prescribed as a carminative (relieving flatulence) in the German, French and British pharmacopoeias. The Commission E monographs do not recommend the use of fennel seed and fennel oil beyond two weeks without consulting a physician.4 Common doses include 5–7 g per day crushed or ground seeds for teas and tea-like products. Other preparations for internal use include fennel syrup or honey, 10–20 g, fennel tincture, 5–7.5 g, infusion, 1–3 g in 150 mL water, two to three times daily between meals. Fennel preparations are contraindicated in pregnancy. Cases of allergic reactions of the skin and the respiratory tract have been reported (see section on Safety and Adverse Effects). Ayurvedic Pharmacopoeia states that fennel can be used for gassy colic, in children, and indigestion. In traditional Chinese medicine, fennel is used to treat the liver, kidney, bladder and spleen meridians and is used to warm the inside, expel phlegm and alleviate pain by freeing the movement of liver energy. It is used to help with hernial disorders, abdominal pain, indigestion, reduced appetite and vomiting. It is also prescribed for headaches, malaise, urinary tract infection and urinary gout or kidney stone related symptoms. Fennel is also used to help relieve coughs with thin white phlegm, asthma, bruises, blemishes, rashes, loose spongy gums and as an antidote for parasites and poisoning from mushrooms and bites

(snakes).12

14.5 Chemistry, Nutrition and Food Science Fennel constituents include essential oil, fatty acid, phenylpropanoids, monoterpenoids, sesquiterpenes, coumarins. It also contains triterpenoids, tannins, flavonoids, glycosides and saponins.10 Phenol Explorer13 provides data on the polyphenolic composition of fennel. Dried fennel seeds contain the flavonol quercetin and also the phenolic acids gallic, caffeic and ferulic acids. Fresh fennel seed constituents include the flavonoids luteolin, isorhamnetin, kaempferol, myricetin and quercetin, the hydroxybenzoic acids 2-hydroxybenzoic acid and protocatechuic acid, and the hydroxycinnamic acids 5, caffeoylquinic acid, caffeic acid, ferulic acid and p-coumaric acid. The fruit of fennel (the seed) is made up of approximately 20% fatty acids, which includes petroselinic acid.10 Fennel seed also contains essential oils (46%), and its aniseed-like taste is mainly due to trans-anethole (50–70%). The oil also contains (+)-fenchone (9–22%), estragole (methyl chavicol) (25%), and a- and b-pinene, aphellandrene, limonene, camphene and traces of other constituents. The volatile oil of fennel seed showed strong antioxidant capacity comparable to the synthetic food antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).14 UK data on the nutritional composition of dried samples of fennel are similar to that of the US data (see Table 14.1).15,16 With regards to its nutritional quality, fennel is generally considered to be poor in energy yielding nutrients (carbohydrate, fat, protein), with good amounts of fibre and iron. Phytosterols are of interest in nutrition as evidence shows that 2 g per day is associated with a significant reduction in levels of low-density lipoprotein cholesterol (LDL-C) of 8–10%, suggesting it is linked to a reduction in cardiovascular disease risk.17 Plant foods, such as dried fennel seeds, contain phytosterols (0.66 mg g−1 of fennel seeds) (see Table 14.1) that could make some contribution to the 2 g per day of dietary phytosterol recommended to prevent cardiovascular disease if consumed regularly. Table 14.1 Nutrition composition of fennel seeds.15,16 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Fennel seeds (100 g)

UK data

US data

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg

Na Na Na 14.9 (0.50) 15.8 8.8 66 1200 1.07

345 52.29 39.8 14.87 (0.48) 15.8 8.81 66 1196 1.067

Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

Na 12.3 390 3.50 510 1660 Na 88 3.7 13 0.41 0.35 10.3 Na 0 0 Na —b Na

—b 18.54 385 6.533 487 1694 —b 88 3.7 7 0.408 0.353 6.05 0.47 21 —b —b —b —b

a N: Present in significant amounts but not determined. b—: Not assessed or not present.

Food preparation and cooking are known to modify the composition of foods and may affect their phytochemical constituents. A study compared the antioxidant capacity of fennel seed tea (1 g dried herbs in 100 mL boiled water) to that of fennel seeds stewed (1 g) in 100 mL boiled water for 10 minutes and simmered for 60 minutes (covered). It reported that stewing fennel increased the antioxidant capacity by 6.5-fold. In addition, its antioxidant capacity was significantly greater than that of the tea.18 The cooking water of the stew likely contained biologically active compounds that leached out of the spice which are then either ingested directly or through other foods that absorb the cooking water, or discarded. The increased liberation of biologically active compounds from the softening of the spice post exposure to heat, seemed a logical explanation for the effects observed. A study19 compared the impact of different cooking methods on the antioxidant capacity and total phenolic content of fennel leaves – 10 g per 100 mL. The antioxidant capacity and total phenolic content of the raw samples (80% methanolic) were compared to those of conventional cooked samples – cooked for 15 minutes, samples that underwent pressure cooking at 120 °C for 10–12 minutes, and samples that underwent microwave cooking for 5–8 minutes. Compared to raw samples, conventional cooking increased the antioxidant capacity by 108%, pressure cooking by 99% and microwave cooking by 136%. The total phenolic content, compared to raw samples, increased by 106% in conventional cooking, by 105% in pressure cooking and by 124% in microwave cooking.

14.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research

14.6.1

Antioxidant Properties

Fennel (seed extract, leaf and essential oils from its seed and aerial parts) possesses antioxidant capacity in vitro.20 A comparison of the antioxidant capacities of its seed extracts (aqueous, ethanol and hydroalcoholic) with those of other culinary herbs and spices indicates that its antioxidant capacity is comparable to those of paprika and turmeric, higher than those of ginger and coriander and lower than those of clove, rosemary, thyme, Mediterranean oregano and cinnamon. However, the antioxidant capacity varies based on the assays used as well the preparations and cultivars used.21,25 The antioxidant capacity of fennel (both the seed extract and seed essential oil) is reported to be comparable to those of BHT, alpha tocopherol (vitamin E) and ascorbic acid (vitamin C).14,22,26,28 For seed and leaf extracts of fennel, the constituents that contribute mainly to their antioxidant capacities are the polyphenols chlorogenic acid, quinic acid, pcoumaric acid, 4-O-caffeoylquinic acid, quercetin and caffeic acid.24,29,30 For seed essential oil, the main constituents reported to contribute to its antioxidant capacity are transanethole, estragole, limonene and fetchone. Both the seed extract and the seed essential oil inhibit lipid peroxidation (a marker of oxidative stress) in vitro, based on decreased malondialdehyde (MDA) levels.22,26,31,33 There is evidence that the essential oil's antioxidant properties may be of significance in the oil's ability to protect against genotoxicity (damaging to DNA).31 However, this effect has only been demonstrated using an in vitro cell based model. The seed extract's ability to facilitate recovery from peripheral nerve damage may be linked to its antioxidant properties. However, this ability has been demonstrated in an animal study only.34 The literature also associates fennel's antioxidant capacity with its ability to protect against and improve liver function (see section on Hepatoprotective Properties) and the management of gastrointestinal disorders (see section on Potential Use in the Treatment/Management of Gastrointestinal Disorders). It is also suggested in the literature that fennel's antioxidant properties may be of significance in the prevention/management of diabetes. However, there is currently little evidence to support this suggestion (see on G on glucose Lowering, Anti-diabetic and Lipid Lowering Properties).

14.6.2

Anti-inflammatory and Analgesic Properties

There is a small body of research concerning the anti-inflammatory properties of fennel. However, this work currently is limited to in vitro and animal studies. Fennel seed extract was reported, in animal studies, to inhibit inflammation, both acute and subacute, and also suppress allergic reactions in vivo.33 Fennel seed essential oil has been shown to possess anti-inflammatory activity in vitro via the inhibition of lipoxygenase35 – an enzyme involved in the regulation of the inflammatory response via the production of pro-inflammatory mediators. This activity may be of significance with regards to fennel seed essential oil's lipid lowering and hepatoprotective properties (see sections on Glucose Lowering, Antidiabetic and Lipid Lowering Properties and Hepatoprotective Properties) and also in the management of gastrointestinal disorders (see section on Potential Use in the Treatment/Management of Gastrointestinal Disorders).

With regards to its analgesic properties, Choi and Hwang33 demonstrated that the seed extract possessed significant pain relieving properties in vivo using animal models. The analgesic property of fennel has been investigated in humans, specifically in relation to irritable bowel syndrome (IBS) and dysmenorrhea (see sections on on Effect on Fertility and Lactation and Use in the Management of Polycystic Ovarian Syndrome and Menstrual Disorders and Menopause, and on Potential Use in the Treatment/Management of Gastrointestinal Disorders).

14.6.3

Glucose Lowering, Anti-diabetic and Lipid Lowering Properties

There is a very small amount of research in which the glucose lowering, antidiabetic and lipid lowering properties of fennel have been investigated. There is some evidence suggesting that fennel may confer protection against the development of, and/or may be used in the management of, diabetes and conditions associated with/caused by hyperlipidemia. Salami et al. 29 reported that both seed and leaf extracts displayed potent anti-glycation (protein glycation is a biomarker of diabetes and can lead to the vascular complications that result from this disease activity) in vitro suggesting that fennel may be of significance in the management of diabetes. The authors suggested that fennel's polyphenols may be responsible possibly via their antioxidant properties although they did not demonstrate an association in the study. Choi and Hwang33 reported that fennel seed extract significantly increased high density lipoprotein cholesterol (HDL-C), improved antioxidant status, via increases in antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and significantly decreased oxidative stress in non-hyperlipidemic/non-diabetic rats. Studies by Helal et al. 36 and Oulmouden et al. 37 reported that fennel, including a preparation of dried crushed bulbs, decreased total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C), increased HDL-C, improved liver function and hepatic tissue, and/or decreased the deposition of TG in fatty liver in animal models of hyperlipidemia. Although neither study elucidated the mechanism of action, both, based on findings in the literature, suggested that fennel's antioxidant properties, provided via its polyphenolic and non-polyphenolic constituents, contributed to the improvements reported. Helal et al. 36 suggested that fennel's polyunsaturated fatty acids may have contributed to the improvements in liver tissue reported. In another animal study, using a model of hyperlipidemia, fennel seed essential oil decreased levels of TC, LDL-C and TG. However, the decrease in the latter was not significant. In addition, HDL-C and fasting blood glucose were not affected.38 Although not all the improvements in lipid profile were significant, there was a significant improvement in the atherogenic indices (TC/HDL-C and TG/HDL-C), suggesting that fennel may decrease the risk of atherosclerosis and ultimately the development of cardiovascular disease (CVD) (atherogenic indices are used as markers of abnormal lipid levels and indicators of CVD risk). Furthermore, the essential oil decreased the levels of the proinflammatory cytokine tumour necrosis factor alpha, which bearing the role that inflammation plays in the development of CVD, could indicate a decreased risk of atherosclerosis and ultimately CVD. Fennel also decreased oxidative stress and

significantly improved hepatic function, with the authors of the study suggesting that the improvement in liver function could be due to fennel's antioxidant properties. Despite some positive findings, these studies are all in vitro or animal based. Furthermore, a lone human study does not support the findings above, specifically with regards to fennel's lipid lowering potential. Afiat et al.,39 in a double blind randomized controlled trial (RCT), reported slight decreases in LDL-C and TG, which were not significant, an increase in HDL-C, which was borderline significant, and a slight but not significant increase in TC compared to baseline in a group of women going through the menopause (a condition associated with changes in lipid profile and an increased risk of CVD40,41) given fennel (30% given in capsule form; one capsule was taken three times a day – morning, noon and night for three months). Compared to the placebo group, there were differences at baseline for LDL-C and HDL-C that, although not significant, were noticeably different. The authors noted the small sample size, no control of lifestyle factors – diet and physical activity – and the short duration of the study as limitations, and concluded that larger and longer studies using fennel at higher doses were needed to establish whether or not fennel has a significant effect on lipid levels in subjects going through the menopause.

14.6.4

Cardioprotective Properties

In addition to its lipid lowering properties, fennel may also confer protection against the development of CVD, specifically coronary heart disease, via its reported hypotensive and anti-thrombotic activities and its ability to decrease body weight and body mass index (BMI). However, the evidence is currently limited to in vitro and animal studies. Fennel seed essential oil is reported to inhibit angiotensin converting enzyme in vitro. This enzyme plays a major role in the renin–angiotensin system, which regulates blood pressure. The inhibition of this enzyme has been used as a therapeutic target for treatment of hypertension.42 Trans-anethole may be the contributory constituent for this inhibitory activity. The essential oil has also been shown to inhibit platelet activity in vitro, based on decreased platelet aggregation and clot retraction (platelet aggregation – the clumping together of platelets – plays an important role in the development of arterial thrombosis). This anti-aggregation action is reported to be comparable to that of aspirin. In addition, the essential oil has been shown to inhibit thrombosis in vitro and in animal studies.43,44 Furthermore, the essential oil has also been shown to act as a vaso-relaxant in vitro, and thus may be of benefit in decreasing vascular pressure, which is due to a build up of tension of blood vessel walls.43,45 Evidence supports the constituents of the essential oil – estragole, and especially trans-anethole – as contributing to these activities.43,45 Extract of fennel has also been reported to inhibit platelet aggregation in vitro, but the level of inhibition was low (5%) compared to those of extracts of thyme (45%), basil (57%), tarragon (66%) and allspice (71%).46 Finally, with regards its effect on body composition, using an animal model of obesity, Nejatbakhsh et al. 47 reported that seed extract of fennel significantly decreased body weight, BMI and the hormone leptin, which is

produced by adipocytes (fat cells) and may play a role in the regulation of energy metabolism.48,49

14.6.5

Hepatoprotective Properties

There is some evidence of the hepatoprotective effect of fennel (seed and seed essential oil). However, this evidence is based solely on in vitro and animal studies.50,57 Fennel was reported to protect against chemically induced hepatotoxicity or limit/protect against liver tissue damage caused by hepatotoxicity and/or improve liver function affected by hepatotoxicity. In the majority of these studies, antioxidant status was improved and/or oxidative stress decreased, suggesting that fennel's hepatoprotective effect may involve its antioxidant properties. Furthermore, there is some evidence that the protective properties of fennel may involve its anti-inflammatory properties.56

14.6.6

Chemopreventive/Anti-cancer Properties

The chemopreventive/anti-cancer properties of fennel have been reported in the literature. However, this work is limited to in vitro studies, the findings of which are summarised below. The ability of fennel seed oil to protect against genotoxicity (damaging to DNA) is suggestive of the essential oil possessing chemopreventive properties.31 The essential oil has also been shown to inhibit the growth of human colon cancer cells (Caco-2 cells) via cell cycle arrest and apoptosis with trans-anethole and fenchone identified as the main constituents in the preparation.58 Ramadan et al. 59 reported that aqueous extracts of fennel seed decreased the viability of, and induce apoptosis in, human cervical cancer (HeLa) cells. In addition, a combination of this extract with cisplatin (a chemotherapeutic agent) increased the inhibitory effect. This demonstration of synergy appeared to be concentration dependent. In a study by Levorato et al.,60 the seed extract and seed essential oil of fennel were found not to be genotoxic to human liver cancer (HepG2) cells. However, unlike the seed extract, the essential oil was shown to induce apoptosis and cell cycle arrest in these cells in a dose-dependent manner. It is not clear why there was a differential effect between the extract and the essential oil, but the authors suggested that the complex makeup of the fennel matrices may be of significance. Based on an analysis of the chemical composition of the essential oil, anethole, estragole and fetchone appeared to be responsible, as they were the most abundant. These constituents were also present in the seed extract but their levels were not as high. The seed extract contained other constituents, namely polyphenols and fatty acids. Interestingly, methanol extracts of fennel seed were reported to stimulate the proliferation of the human breast cancer cells (MCF-7) in vitro along with a number of other culinary herbs, including dried parsley, rosemary leaf and dill seed. Extracts of the aerial parts of these herbs were shown to possess potent estrogenic activity, which may explain the proliferative effect on the MCF-7 cells.61

14.6.7

Effect on Fertility and Lactation and Use in the

Management of Polycystic Ovarian Syndrome and Menstrual Disorders and Menopause Fennel has a long history of use with regards to fertility, particularly in women, and for the management of menstrual disorders and menopause mainly in the Middle East. Below is a summary of studies, some in animals, but mainly RCTs, carried out to ascertain fennel's efficacy.

14.6.7.1 Fertility Some evidence from animal studies suggests that fennel, specifically its seed extract, enhances female fertility based on its ability to increase the weight of mammary glands and drive/increase the maturation of ovarian follicles.62,63 These effects may be due to the oestrogenic like properties of its constituents, namely trans-anethole.28 Other constituents, namely the flavonoids, of fennel are reported to exert anti-androgenic (male hormone-like) effects and thus block the action of testosterone, suggesting that fennel decreases male fertility; a suggestion supported by animal studies in which fennel seed extract decreased sperm cell maturation, sperm production and sperm count, and increased oestradiol and decreased testosterone.64,65 Furthermore, fennel essential oil caused damage to testicular tissue and decreased sperm count, sperm motility and sperm viability.66 However, there is also evidence to suggest that fennel enhances male fertility and decreases female fertility. In an animal model of obesity, fennel seed extract improved sperm count and sperm motility, and also decreased the number of abnormal sperm. However, none of these changes were significant.47 In another animal study, Minas et al. 66 reported that fennel essential oil suppressed pre-implantation embryo development. It is possible that these different outcomes could in part be due to the different models and fennel preparations used. In light of the latter, Mahboubi recommends the use of standardized preparations and doses in RCTs.67

14.6.7.2 Lactation Animal and human studies provide some support for fennel seed's ability to promote lactation.67,69 Focussing on the human studies, powdered fennel seed given to lactating women in the form of capsules (6 × 500 mg capsules three times a day for 15 days) stimulated the production prolactin, a hormone that increases the size of mammary glands during pregnancy, stimulates lactation following birth and increases the release of milk during breastfeeding.70 In other human studies in which fennel was given in combination with other culinary herbs and spices, including fenugreek, cumin, dill and parsley, or black tea, the findings were overall suggestive of increased lactation.68,71,74 However, there are safety concerns about the use of fennel during pregnancy and breastfeeding (see the section on Safety and Adverse Effects).67,70

14.6.7.3 Polycystic Ovarian Syndrome (PCOS)

In light of the oestrogenic properties of some of fennel's constituents, its efficacy in women with polycystic ovarian syndrome (PCOS) has been investigated. This condition results in high levels of luteinizing hormone (LH), which regulates the production of oestrogen and progesterone, and low levels of follicle stimulating hormone (FSH), which stimulates the growth of ovarian follicles. High levels of LH and low levels of FSH result in high levels of androgens, including testosterone, and poor ovulation, which results in low production of progesterone and ultimately the absence of menstrual periods, also referred to as amenorrhea. Ovarian cysts may also form. Although the animal studies indicated significant efficacy,75,76 via significant decreases in LH and testosterone and significant increases in FSH, efficacy was reported to be much weaker in RCTs, with a significant change in FSH compared to placebos but no changes in LH or androgen levels (in this RCT 92 mg (46 mg twice a day) of fennel was given to subjects with PCOS for 90 days) and no alleviation of symptoms caused by the presence of ovarian cysts (in this RCT, subjects with PCOS took essence of fennel seed in pill form; the essence was made by distilling fennel seeds with water vapour; subjects took one pill, which contained 46 mg of the essence, twice daily for 12 weeks). The low amounts of fennel used plus the small samples sizes (30 and 29 subjects) were given as possible reasons for the outcomes reported.77,78

14.6.7.4 Management of Menstrual Disorders 14.6.7.4.1 Premenstrual Tension A small number of RCTs have investigated the effect of fennel on symptoms of premenstrual tension (PMS), which include depression, anxiety, fatigue, headaches and tender breasts about a week to 10 days prior to menstrual periods. Overall, the studies reported that fennel oil (2%) on its own or in combination with exercise (aerobic exercise or Pilates, which is reported to improve symptoms of PMS79,80) decreased the severity of symptoms of PMS, specifically anxiety and depression, possibly via its oestrogenic, analgesic and anxiolytic effects compared to the placebos used.67 In studies in which the effects were compared to those of nonsteroidal anti-inflammatory drugs (NSAIDs) the effects of the fennel oil did not differ significantly. The dosages and durations of the fennel oil used in the RCTs are summarised below: Preparations, dosages and durations of fennel oil used in randomized control trials (RCTs) on the effect of fennel oil on subjects with premenstrual tension 20–30 drops of 2% fennel oil also referred to as Fennelin, given every 4–8 h from the beginning of pain during two menstrual cycles.81 20 drops of 2% fennel oil (Fennelin) used in three divided doses, three days before and after menstruation for two periodic cycles.82 Pilates exercises plus 30 drops of 2% fennel oil every 12 h for one month in combination within Pilates.83 Aerobic exercise, fennel, 20 drops of 2% fennel oil (Mahoubi67 describes

it as an oil but in the article the authors call it fennel extract) given in three divided doses, every 8 hours three days before and after menstruation for two periodic cycles.84 14.6.7.4.2 Primary Dysmenorrhea An animal study by Ostad et al.,85 based in part on fennel's use to promote menstruation, demonstrated the ability of fennel essential oil to decrease the intensity and frequency of uterine contractions induced by oxytocin and/or prostaglandin E2, both of which promote/stimulate/strengthen uterine contractions. This work, and/or possibly additional evidence of the spasmolytic and/or analgesic effects of fennel67, formed the basis for a small number of clinical trials – nonrandomized and randomized clinical trials and one cross over trial – in which the action of fennel in women with dysmenorrhea, specifically those with primary dysmenorrhea was compared to the effect of a placebo or no treatment or a NSAID – mefenamic acid or ibuprofen – (when compared to ibuprofen, fennel was given in combination with vitamin E) or vitamin E (vitamin E is reported to provide pain relief in women with this condition86). Overall, the studies reported that fennel provided pain relief that was comparable to or greater than that of the NSAID and/or fennel was more effective at providing pain relief vs. the placebo or no treatment. However, despite these positive outcomes, in their systematic review Pattanittum et al. 87 concluded, based on an analysis of studies that were RCTs and had appropriate inclusion criteria and baseline data, that there was no consistent evidence of the efficacy of fennel when compared to placebo, no treatment or NSAIDs. They highlighted issues concerning the quality of the studies, for example in relation to randomization and blinding – for some studies there was a lack of information as to how these were carried out, which suggested possible issues with selection bias. There were also issues raised regarding reporting bias due to the lack of statistical data and also concerns regarding the size of the studies. In contrast, in a much smaller systematic review, which included two of the trials analysed by Pattanittum et al.,87 Xu et al. 88 concluded that fennel's ability to decrease pain in primary dysmenorrhea was effective. However, in the latter systematic review, which included a meta-analysis, only studies in which fennel was compared to a placebo or mefenamic acid were included. These studies were classified as being of low to high quality based on randomization, blinding, allocation concealment and withdrawals (drop out rate). It is clear, based on work done to date, that multicentred (most of the studies were carried out in Iran), larger, RCTs are required to establish more fully the efficacy of fennel in the management of this condition. The RCTs summarised in the systematic reviews and meta-analyses summarised above, specifically the dosages and durations and the nature of the fennel preparation used plus whether fennel was compared to placebo, no treatment and/or a NSAID, are summarised below: Fennel vs. placebo or no treatment 25 drops of 2% essence of fennel seed every four hours given orally. The effect was compared to those of a control (no medication). The study was excluded by Pattanittum et al. 87 as it was not randomized.89

46 mg of fennel extract versus placebo every six hours for 3 days after their menstruation started for two consecutive menstrual cycles.90 30 mg of fennel in capsule form every four hours versus no treatment from about 3 days before menstruation until the end of the fifth day for 3 months.91 1% or 2% fennel oil (0.3 to 1 mL) versus placebo, fennel was taken as required (depended on pain severity) no more than four-hourly.92 20–30 drops of fennel oil (Fennelin) given every four to eight hours versus placebo for two successive menstrual cycles when pain began.81 30 mg of fennel extract in capsule form, four times a day for 3 days at the beginning of (from the first day) menstrual period.93 30 drops of Fennelin every 4 hours, 1 day before the start of the cycle until the third day. This study was a RCT but was excluded by Pattanittum et al. 87 as the pain severity of the subjects was low at baseline and included subjects with mild dysmenorrhea.94 Fennel vs. mefenamic acid: 25 drops of 2% essence of fennel seed every four hours given orally. The effect was compared to that of mefenamic acid. The study was excluded by Pattanittum et al. 87 as it was not randomized. 30 drops of fennel extract given at the onset of menstruation and then continuously every 6 hours for the first 3 days of menstruation. The effect was compared to that of mefenamic acid. The study was excluded by Pattanittum et al. as none of the inclusion criteria related to the severity of dysmenorrhea.95 20–30 drops of fennel oil (Fennelin) every four to eight hours versus mefenamic acid (250 mg every 6 hours) given for two successive menstrual cycles when pain began.81 2% fennel oil (Fennelin) versus mefenamic acid (250 mg) taken once pain commenced every 6 hours.96 Fennel plus vitamin E vs. Ibuprofen: Fennel extract (60 mg) in capsule form plus vitamin E (150 international units (IU)) versus ibuprofen 400 mg, four times a day.97 Fennel vs. vitamin E: 46 mg of fennel extract versus vitamin E (100 IU) every hours for 3 days after their menstruation for two consecutive menstrual cycles.90 Fennel extract (60 mg) versus vitamin E (150 IU), four times a day.97 14.6.7.4.3 Oligomenorrhea A recent RCT by Mokaberinejad et al. 98 reported that a fennel seed infusion

significantly decreased the severity of pain in women with PCOS who had oligomenorrhea (infrequent periods). The infusion was taken for 6 months in combination with dry cupping, which is a form of alternative therapy used in Asia, the Middle East, Eastern Europe and Latin America. It is also used by physical therapists, and involves applying suction, using a plastic cup, over a region of dry skin or skin to which lotion has been applied. It is used to give deep tissue massage to help with sore muscles, migraines and to improve immune function. However, it is unclear if it is effective. This combination of fennel and dry cupping is used in Persian medicine, and it was found to markedly decreased the mean number of days between periods compared to a group that received metformin, which is used to manage oligomenorrhea in those with PCOS as insulin levels are high in these subjects although it is reported to not be well tolerated and to have side effects.99,100 14.6.7.4.4 Effect on Menstrual Bleeding In light of the reported effects of fennel on dysmenorrhea and its use in some parts of the world to manage menstrual problems, clinical trials have been carried out to investigate the effect of fennel on menstrual bleeding, mainly in women with primary dysmenorrhea. However, the results are mixed, with some studies reporting that fennel significantly decreased menstrual bleeding or the menstrual period duration and others reporting no effect on bleeding severity and/or the duration of menstrual period (see the list below for a summary). Abdollahi et al.101 carried out a systematic review of six RCTs and a metaanalysis of four of the RCTs (those that recorded the mean plus the standard deviation of severity of bleeding (these are listed below with the other studies in bold)). They concluded that, based on their analysis, fennel significantly increases menstrual bleeding in the first cycle following treatment compared to controls but in the second cycle after treatment, fennel has no significant effect on menstrual bleeding compared to controls. Bearing in mind the heterogeneity of the study designs with different dosages, the starting points of the interventions and their durations and preparations, plus the low quality of the trials, the authors of this systematic review and meta-analysis highlighted the need for better quality trials in this area. Results of clinical trials in which the effect of fennel on menstrual bleeding was investigated Subjects with primary dysmenorrhea given 0.3–1 mL of 1% and 2% fennel essential oil. A significant decrease in menstrual bleeding compared with controls was reported.92 Subjects with primary dysmenorrhea given 20–30 drops of Fennelin every 4–8 h from commencement of pain. A decrease in menstrual bleeding with 3 days of treatment compared to control (placebo) was reported.81 Subjects given fennel seed ethanolic extract in capsule form (230 mg taken for the first 3 days of their menstrual period for 2 cycles). No effect on menstrual bleeding or duration of menstrual period was reported. Information about whether subjects had primary dysmenorrhea was not

available.102 Subjects with primary dysmenorrhea given 25 drops of Fennelin taken every 6 hours for 2 cycles. No effect on bleeding severity compared to controls was reported.96 Subjects with primary dysmenorrhea given 75 drops of Fennelin taken orally from the onset of pain. No effect on bleeding severity compared with control was reported.103 Subjects with primary dysmenorrhea given 120 mg fennel in soft capsule form for 2 and 3 months started 3 days before menstruation until the 5th day for 3 cycles. A significant decrease in the duration of menstrual period, but no effect on severity of bleeding, compared to baseline was reported.91 Subjects were given 30 drops of Fennelin every 4 hours. The effect was compared to that of 40 drops of vitagnus (a herbal remedy used for its phytoestrogenic properties104) and 250 mg of mefenamic acid. All interventions were given from the day before the onset of menstrual bleeding until the third day of menstruation and were all effective at reducing menstrual bleeding. Compared to vitagnus and mefenamic acid the effect of Fennelin was not significantly different.105 14.6.7.4.5 Menopause and its Associated Conditions Investigations, in the form of clinical trials, into the effects of fennel in women who were post-menopausal provide some evidence that it may be of benefit in the management of some of the conditions associated with the menopause. However, there are inconsistencies. A total of 15 RCTs, some using the same group of subjects, have investigated the effect of fennel, in the form of capsules, tablets, cream, and in combination with St John's wort or Mellissa officinalis (lemon balm) (see the list below for doses and durations). A systematic review and meta-analysis of 10 of these RCTs by Khadivzadeh et al. 106 concluded that fennel provided relief from/improvement in menopausal symptoms including hot flushes and night sweats, vaginal dryness and itching, and vaginal pain, sleeping problems, including sleep quality and sleep duration and distribution, and sexual function and satisfaction. Fennel did not have a significant effect on depression nor on bone mineral density and bone mineral content.39,107,113 In addition, it did not improve lipid profile, BMI, fat distribution and body weight. Other clinical trials (including an RCT in which 120 mg fennel was combined with 1000 mg chamomile and 60 mg saffron – see the list below for details) again provide some evidence of fennel's ability to improve menopausal symptoms as well as cardiac and urinary complaints.114,116 However, one RCT reported no improvement in menopausal symptoms,109 another reported no significant effect on sleep quality39 although an increase in sleep duration tended towards significance, and another reported no significant difference in the improvement of menopausal symptoms although in this study there was no placebo (the comparison was made with citalopram, which is an antidepressant) and the effects were for fennel in combination with Nigella sativa (black cumin) and Melissa officinalis.117 Short durations, small sample sizes and high placebo effects have been put forward as reasons for the inconsistent

outcomes, and/or the non-significant outcomes. In conjunction with the fact that all of these studies were carried out in Iran, and are thus considered to be single centred, the literature in this area highlights the need for caution in the interpretation of these findings and for larger, longer duration, multi centred studies.39,106,109,114,116 Details of randomized control trials (RCTs) reviewed by Khadivzadeh et al. 106

5% fennel vaginal cream vs. placebo for 12 weeks118 100 mg of fennel in capsule form given three times a day vs. placebo for 12 weeks108,109 300 mg of fennel and 300 mg of Melissa officinalis daily vs. placebo for 8 weeks119 5% fennel vaginal cream vs. placebo for 12 weeks110 100 mg of fennel in capsule form for 8 weeks111 100 mg of fennel in capsule form, three times a day vs. placebo for 12 week39,112 Fennel tablets (90 mg per day) plus St John's wort (total dose 160 mg of hypiran) vs. placebo for 8 weeks113 Details of other randomized control trials (RCTs) 100 mg of 30% fennel essential oil in capsule form; 2 capsules taken daily for 8 weeks116 5% fennel vaginal cream, 5 g per night for 8 weeks114 1000 mg per day combination of fennel, Melissa officinalis (lemon balm), Nigella sativa (black cumin) for 8 weeks117 100 mg of 30% fennel essential oil in capsule form; 3 capsules taken three times a day (morning, noon and night)109 Herbal extract of low dose fennel (250 mg chamomile, 30 mg fennel, 15 mg saffron) or medium dose fennel (500 mg chamomile, 60 mg fennel, 30 mg saffron) or high dose fennel (1000 mg chamomile, 120 mg fennel, 60 mg saffron) taken orally, 2 mL daily for 12 weeks.115

14.6.8

Potential Use in the Treatment/Management of Gastrointestinal Disorders

There is a small body of evidence obtained from animal and human studies which suggests that fennel on its own and in combination with other remedies may be of benefit in the treatment/management of gastrointestinal disorders via its antioxidant, anti-inflammatory, spasmolytic and also anti-apoptotic properties. A recent animal study provides some support for the use of fennel (powdered seed extract) in the treatment of the gastrointestinal disorder necrotizing enterocolitis, a condition which occurs primarily in newborns in which there is necrosis (death) of parts of the intestinal tissue. Based on a decrease in bowel damage, apoptosis, oxidative stress, DNA damage and inflammation of bowel

tissue, plus an increase in antioxidant status, it was suggested that fennel may be of benefit via its antioxidant, anti-inflammatory and anti-apoptotic properties.120 A small number of clinical trials indicate that fennel may be of benefit in improving intestinal function and/or recovery in: infants with colic; subjects who had undergone a laparotomy (surgery that involves an incision into the abdominal cavity); and in patients with irritable bowel syndrome (IBS). Alexandrovich et al. 121 reported in an RCT that a water emulsion of 0.1% fennel seed oil (at least 5 mL and no more than 20 mL) given four times a day orally before meals and at the onset of an episode of colic for 7 days improved colic symptoms, in infants with the condition, based on the decrease in cumulative crying to less than 9 hours a week compared to the placebo. In an RCT, Ma et al. 122 reported that fennel tea (5 g of dried seeds added to 130 mL of boiled water; only the filtrate (the liquid) was consumed) taken twice a day on the first day after surgery until the first bowel function (the first flatus) significantly decreased the mean times to the first flatus and defecation compared to the controls, who consumed water and suffered from more gastrointestinal symptoms that those who drank the fennel tea. In a small pilot study, fennel seeds, which were sugar coated, beginning with four seeds taken after meals for 1 week and gradually increasing to 8–12 seeds three times a day, were reported to improve the symptoms of IBS, specifically a decrease in abdominal cramps, and decreased dependence on laxatives and analgesics. In addition, patients reported they had more control of their social lives. The improvement, which was noted 2 weeks into the intervention, was suggested to be due to the spasmolytic (antispasmodic) effect (relieving spasm of smooth muscle) due to the constituents of the seed essential oil, namely trans-anethole and fechone.102 This finding formed, in part, the basis for a subsequent RCT in which the effect of fennel seed essential oil in combination with curcumin in patients with IBS was investigated.123 Curcumin is a major constituent of turmeric, which possesses potent anti-inflammatory properties and has been shown to be beneficial in patients with IBS and other gut disorders linked to inflammation. The bioavailability of curcumin is low so in this RCT, the fennel seed essential oil also acted as an emulsifier. A capsule of the combination (curcumin at 42 mg and fennel essential oil at 25 mg) was taken twice a day for 30 days under fasting conditions. The combination provided significant symptom relief, including a decrease in abdominal pain and abdominal distention, compared to the placebo. Those who received the combination also reported an improvement in quality of life. In addition, a larger percentage of those who received the combination were symptoms free. Although promising, the authors advised caution regarding the significance of these findings in relation to managing IBS due to the small sample size and the short duration of the intervention. The authors stressed the need for larger RCTs in which subjects with different types of IBS, and the investigation of repeated curcumin–fennel essential oil treatment with treatment free periods, were included. A subsequent RCT by the group investigated the same combination of turmeric with fennel essential oil, which the authors referred to as Enterofytol®. The study used subjects with different types of IBS – diarrhoea-predominant, constipation predominant and mixed – for 2 months irrespective of the types of IBS and the initial severity of symptoms. The combination resulted in a significant improvement in the severity of symptoms, abdominal pain and quality of life, further supporting

the potential beneficial role of both constituents in the management of IBS.124

14.6.9

Anti-microbial Properties

A number of in vitro studies highlight the antimicrobial potential of fennel as it acts against a number of bacteria and fungi which are pathogenic to humans.14,28 The constituents, trans-anethole, fenchone and its flavonoids are reported to be the main contributors to fennel's anti-microbial properties.125,127

14.6.9.1 Anti-bacterial Activity Beginning with its anti-bacterial activity, fennel (mainly its essential oil from its seeds, and also seed extracts and extracts of aerial parts of fennel) has been shown to act against gram-negative bacteria pathogenic to humans including Helicobacter pylori, Klebsiella pneumonia, Campylobacter jejuni (C. jejuni), Salmonella typhimurium and Pseudomonas aeruginosa, and/or multi-drug resistant Acinetobacter baumannii. Seed extract of fennel is also reported to inhibit the production of cholera toxin from Vibrio cholera.128 Fennel (seed essential oil and extracts of seeds and aerial parts) also inhibits/acts against gram-positive bacteria pathogenic to humans including Staphylococcus epidermidis (S. epidermidis), S. aureus, Bacillus cereus, and Listeria innocua.22,28,29,127,129,132 However, fennel's anti-bacterial potency appears to vary based on the preparations of essential oil and seed extracts used.127,130,131,133

14.6.9.2 Anti-fungal Activity Fennel's seed essential oil, extract of seeds prepared following the extraction of the essential oil and extract of the bark of the plant, are reported to act against fungi that are pathogenic to humans, including Candida albicans and also those that are toxigenic (toxin producing), specifically Aspergillus niger (A. niger) and A. flavus.14,22,28,125,134,145 However, a study by Hitokoto et al. 136 reported that fennel seed extract had a minor effect on the growth of these species of Aspergillus, and also A. ochraceus, and the production of their mycotoxins. However, the level of inhibition was not specified.

14.6.10

Other Bioactive Properties

Fennel has been demonstrated to possess other bioactive properties, however the evidence is limited to a very small number of studies. Fennel essential oil from aerial parts has been shown to possess larvicidal activity, specifically against Aedes aegypti, which is the main vector (it carries or transmits) of Dengue fever and also yellow fever viruses. Fennel's anxiolytic (anti-anxiety) potential was demonstrated in animal studies using crude seed extract, fennel essential oil of its aerial parts, and also crushed fennel seeds added to their (the animals') diet.137,140 Furthermore, in another animal study, fennel plant extract and its major constituent trans-anethole, improved memory, learning, anxiety and depression.141 The enhancing of appetite

following the inhalation of fennel essential oil, again in an animal study, which may be due to its constituent trans-anethole, has also been reported.142

14.7 Safety and Adverse Effects Fennel when used for the purposes of food preparation is considered to be safe. Fennel oil is well tolerated and is also recognised as safe.143 However, there are concerns about the use of fennel due mainly to one of its main constituents, estragole, which has been shown to be carcinogenic based on its ability to be genotoxic; this activity has been demonstrated in vitro and in animal studies. In its public statement of the use of herbal products that contain estragole, the European Medicine Agency (EMA) provides an informative overview of dietary exposure to this compound.144 However, data in this area are limited. There are some data on the levels of estragole in fennel preparations with one study reporting that it is not a major component in fennel teas – tea bags, instant tea, freeze-dried tea and tea prepared by infusion or decoction of unbroken and crushed seeds.145 The amount of estragole appears to vary considerably based on the way in which fennel tea is prepared. For example, squeezing the tea bag at the end of infusion, and using broken seeds, are reported to increase the amount of estragole in tea preparations.145 Data concerning the daily exposure to estragole from fennel consumption are also limited; from the consumption of fennel teas it (exposure to estragole) also varies considerably based on data from Austria.146 Although the increased risk of exposure to estragole over a lifetime is unknown, the EMA states that the intake of this compound should be as low as possible in the general population. The EMA also recommends that daily intake of estragole should not exceed 0.05 mg per person per day, for women who are pregnant or breast feeding, and 1.0 µg kg−1 of body weight for children. Of the fennel RCTs summarised in the sections above which reported on/investigated adverse effects, most reported no or mild adverse effects. The following studies reported no adverse effect or that fennel was safe and well tolerated: Nazapour and Azimi.81 Nasehi et al.,97 Ghodsi and Asltoghiri,91 Mokaberinejad et al.,98 and Ghazanfarpour et al. 106,109 The following studies reported mild adverse effects: Bokaie et al. 96 reported no comparative data concerning adverse events, however they did note that many volunteers in the fennel group (Fennelin (2% fennel essential oil)) complained of nausea, due to the unpleasant smell and taste of the fennel drops. In addition, one subject had heavy menstrual bleeding after taking the fennel drops. Afiat et al. 39 reported mild adverse effects in a small number of subjects including allergic rash, weight gain, hypertension and vaginal bleeding with 3 capsules of 30% fennel a day for 30 days. Portincasa et al. 123 reported that just under 2% of subjects reported suffering from headaches when taking the combination of curcumin and fennel essential oil (one capsule of the combination (curcumin at 42 mg and fennel essential oil at 25 mg) was taken twice a day for 30 days under fasting conditions). However, the authors stated that this adverse effect was not related to the intervention. Rahimikian et al. 116 reported mild adverse effects in a small number of subjects including an allergic

reaction and a severe heat feeling; subjects took two 100 mg soft capsules (containing fennel essential oil (30%)) daily for 8 weeks. Exposure to fennel was reported to cause symptoms, including contact dermatitis, resulting from allergic reactions.147,150 A case of constipation was reported following regular consumption of a herbal tea containing fennel.151 Breast development in a prepubescent girl is believed to have resulted from regular consumption of fennel tea (2–3 teaspoon daily for 6 months).152 Regular consumption of fennel herb by women who were pregnant (consumption was throughout the pregnancy) also resulted in a significant decrease in gestational age,153 and newborns of women who regularly consumed fennel were small for their gestational age compared to newborns of non-consumers of fennel.

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CHAPTER 15

Fenugreek (Trigonella foenumgraecum) 15.1 Names English: Fenugreek, ox horn, goat horn Albanian: Kopër Greqie, trëndetina yzerlike, trëndetine, yzerlik Chinese: Hu lu ba Farsi: Shanbalile French: Fenugrec Spanish: Fenogreco Swahili: Uwatu The name fenugreek comes from the old English fenogrecum (old French fenugrec), from the Latin faenugraecum, from faenum graecum which means ‘Greek hay’.1 The generic name, Trigonella, means little triangle in Latin, and refers to the triangular shape of the flowers.2

15.2 Taxonomy Order: Fabales Family: Fabaceae Genus: Trigonella Species: Trigonella Foenum-groecum L.

15.3 Origin, Description and Adulteration Fenugreek (Trigonella Foenum-groecum L.) is thought to originate from India and Northern Africa, although this has been debated.3 The plant is an annual (so it germinates, flowers, sets seed and dies in one season) plant that belongs to the family Fabaceae; it is a legume and grows to 60 cm (2 feet high) on average. Two types of fenugreek flower (which is usually white) exist, the most common being the cleistogamous (closed) flower and the less common aneictgamous (open) flower.2 The leaves and seeds mature in long pods widely cultivated in Asia and Mediterranean countries, each pod contains about 10–20 yellow seeds. The brown– yellow coloured seeds have a strong, burnt sugar-like aroma and a farinaceous (starchy), slightly bitter taste.4 Fenugreek has been described as an “unpretentious crop” which rarely attracts diseases or pests.5

Reports of adulteration of fenugreek are rare, and this is presumably due to affordable pricing and/or abundance; a study suggested that triterpenoids were used to adulterate fenugreek (dried samples),6 and unsafe levels of salmonella were found in some samples.7

15.4 Historical and Current Uses The epithet foenum-graecum of the species was given by the Romans as it was a very common Greek plant, it was also called ‘ox horn’ or ‘goat horn’ because of the two seed pods projecting in opposite directions that look like ox or goat horns.2 Fenugreek usage was documented in ancient Egypt for embalming mummies. Roasted fenugreek seeds were consumed by harem women to increase buxomness, although this is likely to be an old wives tale as there is so far no scientific evidence to support it.8 Fenugreek was cultivated in ancient Assyria during the 7th century BCE.9 The Book of Herbs (1903) mentions fenugreek as a favourite of the ancients. The author explains that the herbs were never used for culinary purposes in England, only as a medicine: “Fenugreek was at one time prescribed by veterinary surgeons for horses…”. She says that the plant's tops were eaten like asparagus or in soups.10 The book of Ancient Herbs (1982) does not mention fenugreek, and it is sparsely mentioned in the Apicius Roman cookbook, again suggesting it was low in popularity in Europe at the time for the flavouring of food.11 Today, the herb fenugreek is a popular ingredient in curry powders and spice blends, as well as pickles, in India, Pakistan, Bangladesh and other Asian countries.12 Fenugreek is used in modern Egypt and Ethiopia as a nutritious supplement to wheat and maize flour for bread-making.8 A fenugreek paste called Cemen is used as an edible coating material in the production of the traditional meat product “pastirma”, which is a popular food in Turkey.8 In Switzerland fenugreek is used to flavour cheese. The United States Department of Agriculture (USDA) granted fenugreek (spice) Generally Recognized as Safe (GRAS) certification when used as food, and granted fenugreek essential oil GRAS certification when used as a food addidive.4 A maximum serving of 20 g per day is considered a reasonable portion of the seeds in food according to the European Food Safety Authority.13 The Commission E monographs approve fenugreek seed preparations for loss of appetite (for internal use at 6 g) and for inflammation when used externally as a poultice (50 g in water). Undesirable skin reactions have been reported (see section on Safety and Adverse Effects). The Commission E expanded monographs state that fenugreek seed is traditionally used to treat anorexia, indigestion and gastritis (inflammation of the stomach), and to support convalescence, whilst topically utilised for furunculosis (hair follicle infection with abscess), myalgia (muscle pain), lymphadenitis (enlargement in one or more lymph nodes), gout (severe inflammation of a joint), leg wounds, ulcers and eczema (dry and itchy skin inflammation condition).14 Fenugreek was mentioned in early medical records in ancient Egypt (Ebers

papyri – 1500 BCE) for its use in helping with childbirth and increasing breast milk production, and it is still used there today to relieve menstrual cramps. There are many folk uses of fenugreek, for the treatment of many ailments from indigestion to baldness, boils (painful infection of a hair follicle), and tuberculosis (bacterial infection affecting the lungs and other organs). In ancient Rome, it was used to aid labor and delivery. In India, fenugreek is still used as a lactation stimulant.8 Ayurvedic texts also mention its use as an aphrodisiac, but modern vaidyas (a doctor or traditional physician of Ayurvedic medicine) recommend it for digestive and respiratory conditions related to excess phlegm. Introduced in to traditional Chinese medicine (TCM) during the Sung Dynasty (11th century), fenugreek features in the online encyclopaedia of traditional Chinese medicine (TCM), where it is described as warm and bitter, and is used to treat the kidney meridian.15 In TCM the seeds are used as a tonic against feelings of cold in the lower abdomen, hernia, weakness and edema.8 In the United States, Lydia Pinkham (an inventor and developer of herbal remedies in the 19th century) used fenugreek as a key component of her remedy for dysmenorrhea (painful period) and postmenopausal vaginal dryness.

15.5 Chemistry, Nutrition and Food Science Phenol Explorer,16 provides data showing that fenugreek contains several phytochemicals, with some variations between fresh herbs and its seeds. The flavanol quercetin 3-O-rutinoside was detected in fresh leaves and the phenolic acids protocatechuic and gallic acids were detected in the seeds. Volatile oils are present in small amounts in fenugreek seeds and the aroma of fenugreek is due to a combination of the following constituents: diacetyl (buttery like), 1-octene-3-one (mushroom-like), sotolon (spicy), acetic acid (pungent); 3isobutyl-2-methoxypyrazine (roasty/earthy), butanoic acid (sweaty rancid), isovaleric acid (sweaty rancid), caproic acid (musty), eugenol (spicy), 3-amino-4,5dimethyl-3 (season-like), linalool (flowery), (Z)-1,5-octadiene-3-one (metallic), 4dihydro-2(5H)-furanone (sweaty/rancid).12, 17 Sotolon was reported to be predominantly responsible for the strong spicy aroma in fenugreek, which is linked to the maple-like odour generated with sweating after the consumption of fenugreek. The maple aromatic note of fenugreek is a useful imitation of maple syrup flavour in the food industry.17 Fenugreek is generally considered high in fibre, and nutrient levels vary significantly between the leaf and seed.18,19 These nutrient levels have to be considered in the context of the amount of herb used in the diet, which is small (see Table 15.1). Some studies have reported high levels of micronutrients, and, the chemical composition likely varies due to abiotic factors.20 Fenugreek seed has a central hard and yellow embryo, surrounded by a corneous large layer of white semi-transparent endosperm that is high in saponin (although this is poorly absorbed in human digestion) and high in protein; the husk is high in polyphenols.12 Fenugreek contains a balance of soluble and insoluble dietary fibre including the silicon-phosphoric ester galactomannan which affords emulsifying and stabilizing properties in baking. Fenugreek is therefore useful in flour blends

for bread, pizza, muffins and cakes, as it contributes to the organoleptic characteristics as well as to the lowering the glycemic index of the flour and appears to be appealing to the global functional food market.21 Table 15.1 Nutrition composition of fenugreek.18,19 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Fenugreek (100 g) – UK data

Leaf

Seeds

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

35 4.8 Na 0.2 (Na) 4.6 87.6 Na 140 0.26 Na 8.8 59 Na 45 31 Na 76 Na 893 0.12 0.28 1.4 Na 91 71 Na —b Na

Na Na Na 7.4 (1.10) 23.8 9.5 140 130 1.8 Na 23.3 170 1.1 340 650 Na 43 6.9 17 0.33 0.35 1.3 Na Trc Na Na —b Na

aN: Present in significant amounts but not determined. b—: Not assessed or not present. cTr: Trace.

Phytosterols are of interest in nutrition as evidence has shown that 2 g per day is associated with a significant reduction in levels of low-density lipoprotein cholesterol (LDL-C) of 8–10%, which is linked to a reduction in cardiovascular disease risk. Plant foods, such as fenugreek seeds (1.4 mg g−1 (see Table 15.1)), therefore may contribute to the 2 g per day of dietary phytosterol recommended to prevent cardiovascular disease if consumed regularly. Fenugreek is also a source of diosgenin which is a steroid precursor with potential pharmaceutical use.5 Food processing is known to impact the constituents in plant foods, and the

impact of processing techniques on constituents of fenugreek seeds was investigated. Roasting, germination, and germination then roasting, all led to increased amounts of crude protein, crude fibre and total ash contents, while fat and dietary fibre levels were decreased.22 A study26 compared the impact of different cooking methods on the antioxidant capacity and total phenolic content of fenugreek leaves – 10 g per 100 mL raw samples (80% methanolic) – with fenugreek leaves that underwent conventional cooking, cooked for 15 minutes; pressure cooking, at 120 °C for 10–12 minutes, and microwave cooking, for 5–8 minutes. Compared to raw samples, conventional cooking, pressure cooking and microwave cooking increased antioxdant capacity by 98%, 87% and 134%, respectively. The total phenolic content increased by 110% in conventional cooking, by 107% in pressure cooking and by 134% in microwave cooking, when compared to the content of raw samples. The use of herbs and spices as natural antioxidants in processed foods has become more widespread. These (natural antioxidants) work by reducing the oxidative degradation of constituents (normally lipids) and therefore preserve the nutritional composition of foods for longer. The use of fenugreek dried extracts and fenugreek gum in microencapsulated foodstuff shows promising results.23,24 A patent was filed for a fenugreek based substance suitable for the packaging and preservation of perishable foods, including fruits, vegetables, meat products and dairy products.

15.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 15.6.1

Antioxidant Properties

Fenugreek seed extract and seed oil have been shown to possess antioxidant capacity in vitro.25,28 A comparison of seed extracts (aqueous, ethanolic and methanolic) with other culinary herbs and spices indicates that fenugreek seed's antioxidant capacity is comparable to that of coriander leaves, higher than those of turmeric and cardamom and lower than those of clove, allspice and cinnamon.26,27 However, the antioxidant capacity varies based on the assays used, and also extraction and processing which affect its chemical composition. Its polyphenolic constituents are the main contributors to its antioxidant properties.25,32 Both the seed extract and fenugreek oil are reported to inhibit oxidative stress in vitro, and in vivo; the latter specifically in animal studies.33,35 Evidence suggests that fenugreek's antioxidant properties may be of significance with regards to its anti-inflammatory, anti-diabetic, hepato-, gastro-, renal, pancreatic and neuroprotective, and fertility-related and exercise performance-linked properties. However, the bulk of the evidence for many of these properties comes from animal studies (see sections on these properties below for more information).

15.6.2

Anti-inflammatory and Analgesic Properties

Fenugreek's anti-inflammatory properties, mainly of its seed extracts (mucilage (viscous/gelatinous substance of the seed), hexane, methanol, aqueous and ethyl acetate) but also its leaf extracts, have been demonstrated in a small number of in vitro and animal studies; the latter involving models of acute and chronic inflammation. These preparations of fenugreek decreased inflammatory cell infiltrations and inflammatory swelling, and/or inhibited pro-inflammatory mediators, including cyclo-oxygenase 2 – COX-2), lipoxygenase, myeloperoxidase and/or C-reactive protein (CRP). The pro-inflammatory cytokines interleukin 6 (IL6), interleukin 1 alpha and beta (IL-1α and IL-1β) and tumour necrosis factor-alpha (TNF-α) were also decreased by fenugreek in vivo. These decreases in vivo were associated with decreases in oxidative stress and improvements in antioxidant status.36,41 The constituents reported to be the major contributors to fenugreek's anti-inflammatory activities are hydroxyisoleucine (which is an amino acid), the apigenins, which are flavonoids, alkaloids and saponins all of which are reported to possess potent anti-inflammatory activities.38,42,46 The anti-inflammatory activity of fenugreek may contribute to its ability to protect against certain types of tissue damage (see section below on Hepato-/Renal/Gastro- and Pancreatic Protective Properties) and also its chemopreventive/anti-cancer properties in vivo (see section below on Chemopreventive/Anti-cancer Properties). A small number of animal studies have reported fenugreek's (seeds and leaves) analgesic effects, which are due mainly to its alkaloid constituents.44,47 The significance of this property for therapeutic purposes was investigated by Younesy et al. 48 who carried out a double blind randomized controlled trial (RCT) in which seed powder in capsule form (900 mg per capsule) was given to women with primary dysmenorrhea (subjects took 2–3 capsules a day for the first 3 days of menstruation for two consecutive menstrual cycles). The severity of pain was decreased in both groups but the decrease was significantly greater in the fenugreek group. In addition, the decrease in the duration of pain between the two menstrual cycles was also significant in the fenugreek group. Other symptoms of primary dysmenorrhea, including fatigue, headaches, nausea and vomiting, also decreased in both groups but the decrease was only significant in the fenugreek group. The authors recommended that the effects of fenugreek should be compared with that of non-steroidal anti-inflammatory drugs used to treat primary dysmenorrhea including, Ibuprofen and mefenamic acid.

15.6.3

Glucose Lowering, Anti-diabetic, Lipid Lowering Properties

A number of animal and human studies have reported the glucose lowering, antidiabetic and/or lipid lowering properties of different preparations of fenugreek (seed extract, seed powder, leaf powder, germinated seed powder, and seeds in combination with other plant based foods including onion, garlic olive leaf and/or bergamot).12,31,49,51 Concerning its glucose lowering and anti-diabetic properties, animal studies have reported that fenugreek decreased fasting blood glucose (FBG), increased fasting

insulin levels, decreased glycated haemoglobin (HbA1c, a biomarker of diabetes and can lead to the vascular complications that result from this disease), protected against hepatic and renal damage, decreased total cholesterol (TC) and triglyceride (TG) levels, and increased high density lipoprotein cholesterol (HDL-C) levels in models of diabetes and/or hyperlipidemia. These effects were reported to be comparable to those of metformin and glibenclamide, drugs used to treat type 2 diabetes (T2D). In addition, animal studies provided some evidence that fenugreek's antioxidant properties may contribute to its glucose lowering and anti-diabetic effects by decreasing oxidative stress caused by hyperglycaemia.12,31,50,52,63 Studies in vitro and in vivo provide evidence suggesting that fenugreek's (seed extract) glucose lowering and anti-diabetic actions occur via increased glucose uptake, insulin secretion and glycogen synthesis.12,31,49,50,64 Evidence indicates that its bioactive constituents, including steroid saponins, galactomannan (a form of soluble fibre) and 4-hydroxyisoleucine (an amino acid), as well as a novel compound N5564 are the main contributors to some or all of these properties, via their ability to: increase insulin sensitivity; decrease insulin resistance; decrease the rate of postprandial glucose absorption; protect against pancreatic beta cell (insulin producing cells) damage; increase glucose uptake; promote the activity of glucose utilizing, gluconeogenic (glucose synthesizing) and glycogenic (glycogen synthesizing) enzymes; enhance the response of glucagon-like peptide 1, which plays a key role in regulating glucose homeostasis; and modulate gut microbiota.12,31,49,50,65,66 There is also evidence that these actions may be mediated via the suppression of pro-inflammatory mediators.67,68 Concerning the lipid lowering effects of fenugreek, in addition to this ability being reported in animal models of diabetes, animal models of hyperlipidemia have also been used to demonstrate these effects, mainly using diets supplemented with powdered seed. Changes in lipid profile typically included decreased TC, TG, low density lipoprotein cholesterol (LDL-C) and/or very low density lipoprotein cholesterol (VLDL-C) and/or increased HDL-C. There were also improvements in atherogenic indices TG/HDL-C, LDL-C/HDL-C and/or TC/HDL-C (these are used as markers of abnormal lipid levels and as indicators of risk of developing cardiovascular disease). Animal studies also reported decreases in blood platelet aggregation (the clumping together of platelets plays an important role in the development of arterial thrombosis), and improvements in glucose tolerance, and insulin resistance.69,71 Despite the reported effectiveness of fenugreek in improving the control of lipid and also glucose metabolism in such models, some authors have stated that lifestyle modifications, such as exercise, may be more effective.71 The possible constituents and mechanisms of action that may explain fenugreek's lipid lowering properties include some of those listed above. In addition, in vitro and animal studies provide evidence that the alkaloids and soluble fibre in fenugreek may inhibit a key regulatory enzyme in cholesterol synthesis, 3-hydroxy-

3-methylglutaryl coenzyme A (3-HMG-CoA) reductase, as well as increase faecal excretion of bile acids and cholesterol, upregulate fatty acid oxidation, increase the expression of the adipose tissue hormone adiponectin (which is involved in regulating the breakdown of fatty acids and glucose), and inhibit de novo lipogenesis (synthesis of TG) and inflammation in the liver. In addition, as with its glucose lowering effect, fenugreek's ability to modulate gut microbiota may be involved.49,69,71 Human studies, mainly involving subjects with T2D although there are a small number of studies in which type 1 diabetic, hypocholesterolemic, overweight and healthy subjects were used, provide some support for fenugreek's glucose lowering, anti-diabetic and lipid lowering properties although there are inconsistencies. Sharma72 reported that fenugreek seeds given to healthy subjects (as a single dose of 25 g) and subjects with diabetes (25 g per day for 21 days) prevented the rise in blood glucose after consumption of glucose or a meal, in the healthy subjects, and improved glucose and insulin responses in the subjects with T2D. The study also reported that fenugreek leaves had no effect on glycaemic control in the healthy subjects. Sharma et al. 73 reported that when given as part of a meal, fenugreek seed powder (given as two doses of 50 g with lunch and dinner) significantly decreased FBG, improved glucose tolerance, and significantly decreased TC, TG, LDL-C and VLDL-C in subjects with type 1 diabetes. However, HDL-C remained unchanged compared to levels in those who consumed the same diet minus fenugreek. In another study, this time focussed on subjects with T2D, Sharma et al. 74 reported that fenugreek powdered seed (25 g per day for 7 and 24 weeks) had a similar effect to that reported for those with type 1 diabetes, as the intervention decreased TC, LDL-C, VLDL-C and TG. In a clinical trial in which Sowmya and Rajyalakshmi75 investigated the effect of germinated fenugreek seed powder (12.5 or 18 g a day for 1 month) on the lipid profile of subjects who were hypocholesterolemic, TC and LDL-C significantly decreased but no effect was observed on TG, VLDL-C and HDL-C. The conclusions of systematic reviews and meta-analyses of a number of more recent clinical trials concerning fenugreek and its glucose lowering, anti-diabetic and/or lipid lowering effects are mixed. Suksomboon et al. 76 concluded from two RCTs,77,78 which suggested based on their findings that fenugreek may prove to be a useful adjunct therapy for the management of T2D, that based on the pooled analysis of data from these studies, fenugreek significantly decreases HbA1c but has no significant effect on FBG in subjects T2D. One of the studies also reported that fenugreek significantly decreased and increased TG and HDL-C, respectively, in these subjects.77 Neelakantan et al. 79 concluded, based on the pooled analysis of data from 10 clinical trials – it was not clear if they were all RCTs – that fenugreek may be of benefit in improving glycaemic control in subjects with T2D, although this review included studies in which overweight and healthy subjects were used. A more recent systematic review and meta-analysis by Gong et al. 80 in which clinical trials (again, it is not clear if all were RCTs), including some reviewed by Suksomboon et al. 76 and Neelakanthan et al.,79 concluded that fenugreek was effective in decreasing FBG, 2 h postprandial blood glucose, HbA1c and TC in prediabetic and T2D subjects. However, the effects on TG, LDL-C and HDL-C were not clear cut. For these systematic reviews and meta-analyses, the quality of the

studies, particularly with regards to bias as well as the heterogeneity of the studies concerning dosage, duration of intervention, the use of different combined interventions, the subjects used (not all had T2D, some were overweight, healthy or had type 1 diabetes), disease severity and the different preparations used, influenced the outcomes reported. The need for larger (multi-centered), longer and better designed clinical trials using a standard preparation of fenugreek were recommended.76,79,80 Some of the clinical trials analysed in these systematic reviews are summarised above but the details, specifically the preparations of fenugreek, plus the dosages and durations, used are listed below. Clinical trials which investigated the effect of fennel on subjects with and without diabetes: preparations, dosages, durations and used Debitterized fenugreek seed powder; 100 g in diet (unleavened bread) per day consumed by subjects with type 1 diabetes for 10 days.73 Debitterized fenugreek seed powder; 100 g in diet (unleavened bread) per day consumed by subjects with T2D for 10 or 20 days.81 Fenugreek powdered seed; 25 g in diet per day consumed by subjects with T2D for 15 days.82 Fenugreek powdered seed in capsules; 5 g per capsule per day taken for 30 days by subjects with mild and severe T2D (without coronary heart disease) and for 3 months by subjects with severe T2D (and coronary heart disease).83 Fenugreek capsules (equal to 1 g per day hydroalcoholic extract of fenugreek seed) taken by subjects with T2D for 56 days.77 Fenugreek powdered seed: 50 g per day taken by subjects with T2D for 3 to 6 weeks84 Fenugreek powdered seed or germinated fenugreek seeds (15 g per day and 100 g per day, respectively) in diet consumed by subjects with T2D for 1 week.85 Fenugreek pill (0.35 g of fenugreek powder per pill, each gram of powder was equal to 16 g of crude drug), six pills taken three times a day after meals for 84 days by subjects with T2D.78 Fenugreek hydroalcoholic extract in the form of coated tablets taken three times daily by healthy volunteers. Two daily doses taken, 588 mg and 1176 mg, for three 14 day treatment periods each separated by 14 days of washout.86 8 g per day of fenugreek, in 4 g doses, for 56 days taken by subjects with T2D.87 Fenugreek hydroalcoholic extract in capsule form; 1.176 g per capsule per day for 42 days taken by subjects who were overweight.88 Fenugreek seed: 10 g per day plus valsartan taken by subjects with T2D for 16 weeks.89 Fenugreek total saponins; 6.3 g per day taken by subjects with T2D for 12 weeks.90 Fenugreek powdered seed (10 g per day) plus glibenclamide or metformin taken by subjects with T2D for 8 weeks.91

Fenugreek seed plus exercise and diet; 10 g per day (5 g twice daily) taken by subjects with pre-diabetes for 3 years.92 Fenugreek seed; 30 g (10 g three times a day) taken by subjects with diabetes for 8 weeks.93 More recent RCTs have also reported mixed outcomes, which are likely due to the different subjects used. Rafraf et al. 91 reported that fenugreek (10 g of powdered seeds consumed a day for 8 weeks by subjects with T2D) resulted in a significant decrease in FBG, HbA1c, insulin resistance and TC, and a significant increase in adiponectin. However, this intervention had no effect on LDL-C and HDL-C. In healthy subjects, consumption of buns and flatbreads containing fenugreek (powdered seed at 10%) significantly decreased postprandial blood glucose.94 Verma et al. 95 reported that fenugreek seed extract in the form of a trade mark formulation Fenfuro™ (500 mg of fenugreek, taken twice a day for 90 days) significantly decreased FBG and post prandial blood glucose in subjects with T2D. Kiss et al. 96 reported that fenugreek, given in the form of capsules (500 mg per capsule; 2 capsules taken orally three times a day for 10 days; no additional information about the formulation was provided) improved glucose tolerance in subjects they termed as healthy, although they reported that this improvement was more marked in subjects who were insulin resistant. In this trial, fenugreek had no effect on lipid levels compared to the placebo. Florentin et al. 63 investigated the effect of fenugreek in combination with bergamot and olive leaf extract in subjects with pre-diabetes (200 mg of fenugreek seed extract, 200 mg of bergamot extract and 100 mg olive leaf extract) for 6 months and reported no effect on glycaemic control or lipid profile. Despite some inconsistencies, the glucose lowering, antidiabetic and lipid lowering potential of fenugreek seeds is apparent but clarity regarding these effects in different groups, that is subjects who are healthy, prediabetic, diabetic (T2D) and hyperlipidemic, is required so as to ascertain more fully its preventive and therapeutic potential.

15.6.4

Neuroprotective/Neurological Properties

A small number of animal studies provide some evidence of fenugreek's (seed extract or powdered seeds) ability to enhance memory and to act as an antidepressant. Evidence indicates that fenugreek's memory enhancing effects may be mediated by its antioxidant and anti-inflammatory properties, as well as its ability to inhibit the action of acetylcholinesterase, which plays a role in the pathogenesis of Alzheimer's disease.97,99 With regards to its antidepressant effect, this may be via its inhibition of the enzymes mono oxidase A and B, both of which contribute to the development of depression as they breakdown the neurotransmitters norepinephrine/noradrenaline, dopamine and serotonin; inhibitors of these enzymes are used to treat depression.100

15.6.5

Hepato-/Renal/Gastro- and Pancreatic Protective Properties

There is some evidence of the hepato-/renal/gastro- and pancreatic-protective

effects of fenugreek (seed extract). With some evidence that they (the effects) are comparable to those of standard treatments.101 However, this evidence is based solely on in vitro and animal studies.101,111 In the latter, fenugreek is reported to ameliorate tissue damage, associated with improved hepatic and/or renal function, based on the normalization/decrease of alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma glutamyl transferase, decreased oxidative stress and improved antioxidant status and/or decreased levels of inflammation in the affected tissue.101,103,104,106,109,112

15.6.6

Chemopreventive/Anti-cancer Properties

Although the majority of the evidence concerning the chemopreventive/anti-cancer properties of fenugreek (seed extract especially, but also whole plant extract, extracts of leaves and also seed oil) comes from in vitro and animal studies,12,31 the basis for some of this work comes from a case study reported by al-Ghamdi et al. 113 concerning a subject with primary T cell lymphoma of the central nervous system. The subject had been in remission but following recurrence of the lymphoma the subject was treated by family members using concentrated fenugreek boiled in water (the dosage was approximately 8 g per day of fenugreek seeds given over a 6 month period). Improvements were noted using magnetic resonance imaging at 3 months and complete resolution of the tumour was reported at 6 months. The subject was reported to be in remission for 11 years. However, the lymphoma did return. The cytotoxic action of fenugreek in vitro has been reported for a number of cancer cell lines including human colon cancer cells (HT29), human lung cancer cells (A-549), human liver cancer cells (Hep-G2), human neuroblastoma cells (IMR-32), human blood cancer cells (T and B cell lymphomas, HL60 leukaemic and K563 leukaemic cells), human breast cancer cells (MCF-7, MDA-MB-231, SKBR3 and T47D cells), human prostate cancer cells (LNCaP, DU-145 and PC-3) and human pancreatic cancer cells (MiaPaCa, HS766T, Panc1, L3.6PL and BXPC3).114,122 This cytotoxic action in vitro has been shown to be cancer cell specific and involves cell cycle arrest and apoptosis.115,123 In addition, the potency of this effect may be dependent on the cancer cell lines used.114,121 Animal studies have also demonstrated fenugreek's chemopreventive properties in models of breast cancer, colon cancer and skin cancer via the inhibition of tumorigenesis, which may be due to the induction of apoptosis, inhibition of the development of pre-cancerous lesions, and inhibition of the availability of free and active carcinogens, via the inhibition of carcinogen metabolizing enzymes.124,128 Some of these actions were associated with decreased oxidative stress and inflammation, and increased/improved/normalized antioxidant status, in vivo, suggesting that fenugreek's anti-cancer/chemopreventive actions may involve its antioxidant and anti-inflammatory properties.12,127,128 The constituents, diosgenin (a phytosteroid sapogenin – a breakdown product of a saponin), protodioscin (a steroidal saponin) and galactomannan (a form of soluble fibre) were reported to contribute to some of the cytotoxic and/or chemopreventive effects of fenugreek, via apoptosis, cell cycle arrest, and also inhibition of telomerase (this enzyme plays a key role in the survival of cancer cells) and cancer

metastasis.65,123,129,130

15.6.7

Effect on Fertility and Lactation, Weight Management and Use in the Management of Menopause

15.6.7.1 Male Fertility The effect of fenugreek on male fertility has been investigated in animal studies which have reported that the seed extract decreased/minimized chemically induced testicular toxicity, specifically degeneration/damage/necrosis of testicular tissue and inhibition of sperm production, which are associated with a decrease in oxidative stress.131,132 In addition, fenugreek's steroids were reported to increase testosterone levels, decrease sperm abnormalities and also improve sperm count.133 However, another animal study reported that a glycoside fraction of fenugreek had no effect on testosterone levels.134 An early human study by Steels et al. 135 reported that a standardized formulation of fenugreek extract (Testofen, which is in tablet form; 300 mg of fenugreek extract per tablet given twice a day so 600 mg a day for 6 weeks) significantly increased the libido of healthy male volunteers although there was no change in testosterone levels, which remained within the normal range. In a recent systematic review and meta-analysis of four RCTs (see list below for details) Mansoori et al. 136 concluded that fenugreek extract had a significant effect on testosterone levels in healthy men, including male athletes. In addition, in some of these RCTs decreased body fat and increased lean mass and fat free mass were reported.137,138 Another clinical trial (not an RCT) carried out by Maheshwari et al. 139 reported that protodioscin-enriched seed extract of fenugreek (Furosap™ at 500 mg per day for 12 weeks) increased testosterone levels and improved sperm morphology significantly in male volunteers. Although an analysis of the pooled data from the studies reviewed by Mansoori et al. 136 and the findings of Maheshwari et al. 139 provide consistency regarding the effect of fenugreek on testosterone levels, the small sample sizes, short durations and the variations concerning the dosages and preparations of fenugreek, highlight the need for larger studies of longer durations in which standardized preparations are used. The mechanism of action regarding the effect of fenugreek on testosterone levels, and sperm quality and motility is unclear currently. Animal and human studies suggest that fenugreek's antioxidant properties, and also the reported androgenic activity of its sapogenins glycosides,137 may contribute to the outcomes reported. In addition, its steroids may also have a role to play via the promotion of testosterone synthesis.139 Another possible mechanism of action may involve fenugreek's ability to inhibit the activities of aromatase, which is involved in the synthesis of oestrogens, and 5-α reductase inhibitor, which converts testosterone to dihydrotestosterone.140 Randomized control trials (RCTs) on the effect of fenugreek on testosterone: preparations, dosages and durations of fenugreek used

Fenugreek in capsule form (Furosap – a novel seed extract of fenugreek enriched with 205 protodioscin, a saponin): 250 mg per day taken by healthy male athletes for 12 weeks.138 Fenugreek seed extract; 600 mg per day taken by healthy males for 12 weeks.141 Glycoside fraction of fenugreek seeds; 300 mg twice a day taken by healthy males for 8 weeks.137 Fenugreek in capsule form; 500 mg per day taken for 8 weeks by resistance-trained men.140

15.6.7.2 Weight Management A small number of studies – both animal and human – have investigated fenugreek's weight management potential. Fenugreek has been shown to promote satiety in an animal model of obesity.142 In this study its constituent hydroxyisoleucine decreased TG levels. However, fenugreek was reported to have no effect on food intake and body weight in animals fed low and high fat diets.71 Human studies, specifically RCTs, reported that fenugreek, in the form of fibre powder (8 g were consumed with a breakfast meal consisting of a low fibre breakfast cereal, white toast, butter and jam/jelly) and also seed extract (1176 mg per day consumed for 14 days) significantly increased feelings of fullness, and decreased hunger, energy expenditure and/or fat consumption in obese and nonobese subjects.86,143 The link between fenugreek and weight management is linked to its fibre content, which may promote satiety.

15.6.7.3 Female Fertility and Sexual Function There is a limited amount of evidence concerning fenugreek and female fertility which is focused on its use in the treatment of polycystic ovarian syndrome (PCOS – an endocrine disorder that gives rise to a number of conditions in women of reproductive/child bearing age that can affect fertility). Evidence of fenugreek seed extract's, specifically a formulation called Fenfuro™, ability to improve glycaemic control in an animal model of diabetes led Swaroop et al. 144 to investigate the formulation's (in this study the formulation was called Furocyst™) effect on women with PCOS, as this condition is associated with insulin resistance. The outcome of the trial, which was non randomized and not controlled, was that 2 capsules (1 capsule equalled 500 mg of extract) of the formulation, which was enriched with saponins, taken daily for 90 days ameliorated the symptoms of PCOS. Cyst size decreased or cysts disappeared. Furthermore, for some women there was a return of a regular menstrual cycle, and others became pregnant. In addition, compared to baseline, the levels of luteinizing hormone, which triggers ovulation and the development of the corpus luteum – cells in the ovaries that produce progesterone during early pregnancy, and follicular stimulating hormone, which stimulates the production of ovarian follicles, increased significantly. Rao et al. 145 studied the impact of a standardized fenugreek seed (de-husked) extract (called Libifem) in their RCT, on sexual function in women who were menstruating, and reported that they had a low sex drive. Two capsules were given

daily (300 mg per capsule) over two menstrual cycles which resulted in significant increases in testosterone, oestradiol, sexual desire and arousal.

15.6.7.4 Lactation Fenugreek is, based partly on anecdotal evidence, commonly recommended by healthcare workers and/or used by mothers to enhance the production of breast milk.146,148 A small number of human studies have shown that fenugreek promotes breast milk sufficiency in infants and lactation in women. An RCT by Ghasemi et al. 149 reported that a herbal tea containing 7.5 g of fenugreek seed powder and 3 g of black tea, given three times a day to infants who were exclusively breast fed for 4 weeks increased breast milk sufficiency based on a number of parameters, including increased body weight and the number of times the infants breast fed compared to the placebo (3 g of black tea). Bumrungpert et al. 150 in another RCT reported that fenugreek given in combination with ginger and turmeric (3 capsules a day for 4 weeks) significantly increased the volume of breast milk produced by lactating women compared to the placebo; there was no difference in the nutritional composition of breast milk between women given the herb formulation and women given the placebo. Animal studies indicate that fenugreek promotes lactation via an increase in the hormone prolactin, which is required for breast growth and development, and breast milk production.151,152

15.6.7.5 Management of Menopause Randomized controlled trials by Begum et al. 153 and Steels et al. 154 have investigated the effect of fenugreek seed extract on symptoms of menopause. Their work is based, in part, on the ability of fenugreek to increase oestrogen levels and to mediate its (oestrogen's) effects,135,145,155 and its reported effects on metabolic and pro-inflammatory changes in ovariectomized animals (an animal model of the menopause) – in this study fenugreek decreased the increase in blood glucose, and decreased body weight and the pro-inflammatory cytokines IL-1, IL-6 and TNF-α that resulted from the “ovariectomy”.156 The RCTs were also based on the findings of a clinical trial by Hakimi et al. 157 who reported that powdered fenugreek seed (6 g a day for 8 weeks) alleviated the symptoms of early menopause in perimenopausal women, although the effects were less than those of hormone replacement therapy. Begum et al. 153 reported that a standardized extract of fenugreek seed husk, rich in protodioscin, trigonellin and 4-hydroxyiosleucine, called FenuSMART™ (250 mg per capsule) taken by women in menopause (2 capsules twice a day so a total of 1000 mg a day for 12 weeks) decreased symptoms of menopause including hot flushes. This outcome was likely due to the significant increase in oestradiol levels, compared to baseline and the placebo group. In addition, the calcium and haemoglobin levels in the fenugreek group increased, and in contrast to the placebo group in which TC, TG and LDL-C were increased, the lipid profile of the fenugreek group was unchanged from baseline. This latter observation is in keeping with the findings of some of the lipid lowering studies summarised above. In the

RCT by Steels et al.,154 the standardized de-husked seed extract of fenugreek (Libifem) was used. Two capsules were given daily (300 mg per capsule; 600 mg a day) to women in menopause, and resulted in significant improvements in a number of symptoms including hot flushes, fatigue and emotional wellbeing. However, no increase in oestradiol was reported which may have been due to marked fluctuations in this hormone during the trial. There was no difference in lipid profile between the fenugreek group, baseline and the placebo group. Despite the promising outcomes, the authors of both RCTs highlighted the need for trials of a longer duration with larger sample sizes, the monitoring of other oestrogenic, and also androgenic, hormones and pro-inflammatory cytokines.

15.6.8

Impact on Exercise Performance

Due to the insulin-like action of hydroxyisoleucine, a constituent of fenugreek, including the promotion of glucose uptake and promotion of glycogen synthesis and storage, the effect of fenugreek on exercise performance has been investigated. A single animal study reported that fenugreek seed extract increased exercise endurance, with exercise increasing the levels of energy substrates (the fatty acids and glucose) with the consumption of fenugreek. The effects on fatty acid and glucose levels may explain the increased endurance. Fenugreek also decreased fat accumulation significantly.158 The positive effect on the availability of energy substrates was supported by a human study (a placebo controlled, double blind crossover trial) by Ruby et al. 159 who reported that in trained male cyclists who consumed a dextrose (glucose) beverage containing fenugreek seed extract (containing 2 mg kg−1 of body weight of hydroxyisoleucine), high intensity exercise significantly increased the rate of skeletal muscle resynthesis compared to those who consumed dextrose without fenugreek. However, in a later placebo controlled double blind crossover study, the same amount of fenugreek had no effect on trained male cyclists post low intensity exercise.160 The authors concluded that the type and duration of the exercises may explain the different outcomes. Some studies already summarised in the section above on male fertility have also reported improvements in exercise performance, which may in part be due to increased testosterone, although this was not always significant. Wilborn et al. 140 reported significant increases in testosterone levels with improvements in resistance exercise when 500 mg of a fenugreek preparation (in capsule form) was taken daily for 8 weeks in resistance-trained men. Interestingly, an earlier study by Poole et al., 161 using the same intervention, reported an increase in lower and upper body strength and a decrease in body fat. Improvements in testosterone and muscle endurance were reported but these were not significant. A more recent RCT by Wankhede et al. 137 reported that a fenugreek glycoside supplement (300 mg twice a day given for 8 weeks) provided some improvement to resistance exercise and also decreased body fat without a decrease in muscle strength; the increase in testosterone reported was not significant.

15.6.9

Anti-microbial Properties

Although not as numerous as for other spices, there are a number of in vitro studies which have highlighted the anti-microbial potential of fenugreek. The majority of the evidence concerning its action against microbes pathogenic to humans is focussed on its anti-bacterial action.

15.6.9.1 Anti-bacterial Activity Fenugreek, mainly its seed extracts but also extracts of aerial parts (leaves and shoot tips) has been shown to act against gram-negative bacteria pathogenic to humans including Helicobacter pylori (H. pylori) (although the potency of fenugreek's action against H. pylori appears to depend on the preparation,162,163 as fenugreek seed boiled in water is reported to have no inhibitory effect on it) Klebsiella pneumonia, Salmonella typhimurium and Pseudomonas aeruginosa, and gram-positive bacteria pathogenic to humans, specifically Staphylococcus aureus.121,164,165

15.6.9.2 Anti-fungal Activity Varadarajan et al. 166 reported that fenugreek seed extract inhibits the growth of fluconazole (an antifungal agent) resistant Candida albicans.

15.6.10

Larvicidal Properties

The literature provides a small amount of evidence concerning fenugreek's larvicidal properties. Leaf extracts of fenugreek were reported to possess larvicidal activity against Anopheles (the major vector (it carries or transmits) for malaria) and Aedes (the major vector for Dengue fever and yellow fever) mosquito larvae.167

15.7 Safety and Adverse Effects For the purposes of food preparation, fenugreek is considered to be safe, and is said to be well tolerated when used for medicinal purposes.31,168 However, gastrointestinal symptoms including vomiting, diarrhoea and flatulence have been reported, as well as liver toxicity, increased heart rate and allergic reactions (abdominal pain, asthma, rhinitis, urticaria and angioedema) when fenugreek was used on its own or as part of a herbal combination for medicinal use.168,176 Concerning allergic reactions, cross-reactivity with legumes including peanuts and chickpeas are possible.170 Fenugreek is also reported to cause a severe cutaneous adverse reaction called toxic epidermal necrolysis, which results in blisters, rash and skin erosions.177 In light of fenugreek's ability to lower blood glucose levels, and evidence that it could interact with warfarin,168,178 it is advised that those with diabetes and/or who take warfarin should avoid taking large amounts. Due to the sotolon in fenugreek, it may generate an odour of maple syrup in bodily excretions.148,168,179,180 The majority of clinical trials summarized above reported that the fenugreek

preparations used were either safe48,78,78,85,89,91,93,95,144,153,161 or caused mild symptoms, which were mainly gastrointestinal in nature in a small number of subjects.77,86,88,90,145

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153. S. S. Begum, H. K. Jayalakshmi, H. G. Vidyavathi, G. Gopakumar, I. Abin, M. Balu, K. Geetha, S. V. Suresha, M. Vasundhara and I. M. Krishnakumar, Phytother. Res., 2016, 30, 1775-1784. 154. E. Steels, M. L. Steele, M. Harold and S. Coulson, Phytother. Res., 2017, 31, 1316-1322. 155. S. Sreeja, V. S. Anju and S. Sreeja, Indian J. Med. Res., 2010, 131, 814-819. 156. M. Abedinzade, S. Nasri, M. Jamal Omodi, E. Ghasemi and A. Ghorbani, Iran. Red Crescent Med. J., 2015, 17, e26685. 157. S. Hakimi, S. Mohammad-Alizadeh Charandabi, M. R. Siahi Shadbad, R. Bamdad Moghadam, F. Abbasalizadeh, P. Mustafa Ghrebaghi, H. Babaei, S. Bamdad Moghadam and A. Delazar, Pharmaceutical Sciences, 2005, 10, 8390. 158. M. Ikeuchi, K. Yamaguchi, T. Koyama, Y. Sono and K. Yazawa, J. Nutr. Sci. Vitaminol., 2006, 52, 287-292. 159. B. C. Ruby, S. E. Gaskill, D. Slivka and S. G. Harger, Amino Acids, 2005, 28, 71-76. 160. D. Slivka, J. Cuddy, W. Hailes, S. Harger and B. Ruby, Amino Acids, 2008, 35, 439-444. 161. C. Poole, B. Bushey, C. Foster, B. Campbell, D. Willoughby, R. Kreider, L. Taylor and C. Wilborn, J. Int. Soc. Sports Nutr., 2010, 7, 34. 162. R. Randhir, Y.-T. Lin and K. Shetty, Asia Pac. J. Clin. Nutr., 2004, 13, 295307. 163. R. Randhir and K. Shetty, Asia Pac. J. Clin. Nutr., 2007, 16, 382-392. 164. R. O'Mahony, H. Al-Khtheeri, D. Weerasekera, N. Fernando, D. Vaira, J. Holton and C. Basset, World J. Gastroenterol., 2005, 11, 7499-7507. 165. N. Hani, A. Farhan, R. Bhat and M. Ahmad, Int. Food Res. J., 2015, 22, 12611271. 166. S. Varadarajan, M. Narasimhan, M. Malaisamy and C. Duraipandian, J. Clin. Diagn. Res., 2015, 9, ZC07-ZC10. 167. L. Ravi, L. B. Ebinezer, M. Pulijala, K. Saurav and K. Sundar, Curr. Res. J. Biol. Sci., 2010, 2, 154-160. 168. C. Ulbricht, E. Basch, D. Burke, L. Cheung, E. Ernst, N. Giese, I. Foppa, P. Hammerness, S. Hashmi, G. Kuo, M. Miranda, S. Mukherjee, M. Smith, D. Sollars, S. Tanguay-Colucci, N. Vijayan and W. Weissner, J. Herb. Pharmacother., 2007, 7, 143-177. 169. M. Ouzir, K. El Bairi and S. Amzazi, Food Chem. Toxicol., 2016, 96, 145-154. 170. N. I. Joseph, E. Slavin, B. P. Peppers and R. W. Hostoffer, Allergy Rhinol., 2018, 9, 2152656718764134. 171. B. Şahin, N. Kaymaz and Ş. Yıldırım, Women Birth, 2016, 29, e133. 172. L. Hillman, M. Gottfried, M. Whitsett, J. Rakela, M. Schilsky, W. M. Lee and D. Ganger, Am. J. Gastroenterol., 2016, 111, 958-965. 173. B.Partiula and R.Dougherty, presented in part at the Florida, World Congress of Gastroenterology, 2016, https://www.eventscribe.com/2017/wcogacg2017/ajaxcalls/PosterInfo.asp? efp=S1lVTUxLQVozODMy&PosterID=114879&rnd=0.6871091. 174. A. L. Silverman, A. Kumar and M. L. Borum, Breastfeed. Med., 2018, 13, 301. 175. R.Dougherty and R.Mazurkiewicz, presented in part at Hospital Medicine, 2018, Orlando, Florida, April, 2018, https://shmabstracts.org/abstract/thedangers-of-herbal-supplements-a-case-of-acute-liver-injury-from-fenugreek/. 176. N. Steyn, M. Zunza and E. H. Decloedt, S. Afr. J. Obstet. Gynaecol., 2017, 23,

20-23. 177. N. Bentele-Jaberg, E. Guenova, T. Mehra, M. Nägeli, Y.-T. Chang, A. Cozzio, L. E. French and W. Hoetzenecker, Dermatology, 2015, 231, 99-102. 178. A. M. Heck, B. A. DeWitt and A. L. Lukes, Am. J. Health-Syst. Pharm., 2000, 57, 1221-1227; quiz 1228–1230. 179. C. M. Betzold, J. Midwifery Women's Health, 2004, 49, 151-154. 180. D. Tiran, Complement. Ther. Nurs. Midwifery, 2003, 9, 155-156.

CHAPTER 16

Ginger (Zingiber officinale) 16.1 Names English: Ginger Chinese: Sheng jiang, gan-jiang Fante (spoken in Ghana): Akakdur, tsintsimir and tsintsimin Ga-Dangme (spoken in Ghana and Togo): Kakaotshofa, odzahui Hausa: Chittar and afu French: Gingembre Spanish: Jengibre Zingiber is derived from zingiberis (Greek), and Zingiber (Latin), and from singabera (Sanskrit), which means “shaped like a horn” and refers to the shape of its rhizome, singabera probably comes from siṅgivera, from an ancient Indian language called Pali.1,2

16.2 Taxonomy Order: Zingiberales Family: Zingiberaceae Genus: Zingiber Species: Zingiber officinale

16.3 Origin, Description and Adulteration Ginger is native to Southeast Asia, probably India. The ginger family (Zingiberaceae) with 49 genera and 1300 species, also include cardamom (Elettaria cardamomum) and turmeric (Curcuma longa). Zingiber officinale Roscoe is also called garden ginger, and red ginger (Z. officinale var. Rubra) is a variety of the Z. Officinale species cultivated in Indonesia and Malaysia.1 Ginger is a warm season crop that requires hot (25–28 °C), humid, partly shaded or full sun conditions, and grows best in rich loam as it is nutrient hungry.1 Shoots rise up to 1.2 m tall, and buds form on the rhizome, annually, from a series of leaf bases (sheaths) wrapped tightly around one another with long (up to 7 cm), narrow (up to 1.9 cm wide), and alternate, mid-green leaf blades. The flowers are rare in cultivated plants; they are pale yellow with a purple lip and yellow dots with striations, and emerge from flowering heads, which are cone-shaped spikes and made up of a series of greenish to yellowish leaves (bracts). The thickened, branched rhizome (underground stem) which has been described as a “swollen

hand”, has a brown cork-like skin and a pale yellow centre with a spicy lemon-like aroma. The fresh or dried rhizomes are used as the spice (cut, chopped, grated, squeezed) and for medicinal purposes. For the latter it is used internally and externally for a variety of ailments (see section Historical and Current Uses below). Ginger is available in different forms. Fresh (root) ginger is usually consumed in the area where it is produced, with mature and immature rhizomes eaten as a fresh vegetable. Fresh root ginger, specifically the immature rhizome, is preserved in brine or syrup to make preserved ginger, which is produced in China and Australia. Most preserved ginger is exported to Hong Kong. Dried ginger spice is produced from the mature rhizome. It is usually exported in large pieces and ground in the country of destination. Ginger oil and ginger oleoresin can be extracted from dried ginger. Both the oil and the oleoresin are rich in flavour and are used in foods and medicines.1 Ginger, as it is a tropical and subtropical plant, is widely grown in South and Southeast Asia, tropical Africa (especially Sierra Leone and Nigeria), Latin America, the Caribbean, mainly Jamaica, and Australia for export. According to the Food and Agriculture Organization (FAO), 3 038 120 tonnes of ginger were produced in 2017, 83.7% from Asia (Mainly India and China) and 15.3% Africa (mainly Nigeria).3,4 Ginger was reported to be adulterated with lime, capsaicin and exhausted ginger (ginger extracted of volatile oil), and adulteration of ginger powder with lime, capsicum, grains of paradise, turmeric, exhausted ginger with added synthetic flavours, or Japanese ginger (Zingiber mioga) has also been reported.5

16.4 Historical and Current Uses In China, dried ginger is mentioned in the earliest Chinese herbal record, which is attributed to Emperor Shen Nung (around 2000 BCE). The Greeks wrapped ginger in bread which they ate as a digestive aid after a meal. Ginger was later incorporated into bread, now known as gingerbread.6 The 13th century Venetian merchant Marco Polo brought ginger back to Europe from China and Sumatra.1,7 During the same century, ginger was introduced to East Africa by the Arabs and it reached West Africa by way of the Portuguese in the 16th century.8 Ginger was one of the earliest oriental species introduced to Europe; it was used in Germany and France in the 9th century and in England in the 10th century for its medicinal properties.6,9 The Spanish were so fond of ginger that Francesco de Mendoza (a nobleman) had the plant cultivated in Jamaica and Mexico in the 1600's. Some eclectic 19th century physicians used ginger to induce sweating, help with nausea and improve appetite. Ginger preserve (syrup) was prepared by boiling the rhizome in sugar, and used in cooking and medicine. Crystallised ginger, which was eaten at Christmas in Anglo-Saxon times, was prepared by coating dried ginger preserve with sugar to form a “meaty” consistency; it is still used in many recipes for mince pies today. Ginger oil was (and still is) used to flavour ginger beer and ale, and is commonly used as an ingredient in cosmetics and medicines.6 Ginger is mentioned in the

Apicius Roman cookbook10 in recipes for sauces, jelly and appetisers, and with other expensive spices – saffron and black pepper – it is referred to as one of the “spices that should be in the house on hand so that there may be nothing wanting”. In the Book of Herbs (1903), Northcote writes: “With the juice of licorice, ginger and other spices there is made a certain bread or cakes, which is very good against the cough.”9 Today, ginger's versatile flavour means that it continues to be used in a variety of sweet and savoury recipes, as well as drinks for which recipes are available in cookbooks and all over the internet. These include alcoholic drinks Moscow mule (vodka, ginger beer and lime juice) and a cranberry ginger mimosa cocktail. Ginger is an ingredient in soft drinks that contain ginger including, ginger lemonade, ginger latte, countless ginger tea blends with other herbs and spices and chopped fresh ginger tea infusions. Ginger is part of the popular five Chinese mixed spice blend with fennel, cassia, black pepper and clove. Savoury dishes with ginger include Japanese ginger pork (shogayaki), which contains cabbage, ginger, beef, and also ginger flavoured sausages or meatballs, ginger soups and sauces, and dishes to which a sprinkle of dried ground ginger is added. Sweet foods include gingerbread (gingerbread men/women/gender neutral),11 biscuits, pastries, chocolates and sweets. Sliced crystallised ginger (candied ginger) was used to make tea; pickled ginger slices (Gari) was (and still is) used as a condiment in Japan. Ginger mincemeat is still a favourite for festive mince pies, so is ginger caramel. Ginger is also used to flavour ice creams, puddings, syrups, preserves, jams, porridge and many more foods. The United States Department of Agriculture (USDA) granted ginger (spice) Generally Recognized as Safe (GRAS) certification when used as food, and ginger essential oil was granted GRAS certification when used as a food additive. A maximum serving of 20 g per day is considered a reasonable portion in food according to the European Food Safety Authority.12,13 Traditional uses of ginger in medicine include morning and motion sickness, nausea, vomiting and vertigo. The German Commission E monographs and the British Herbal Compendium approve the use of ginger root for the stimulation of the secretion of saliva and gastric juice, for dyspepsia (indigestion) and the prevention of motion sickness (2–4 g per day).14 The expanded monographs state that modern therapeutic applications of ginger are supportable based on traditional use; ginger is contraindicated for those with gallstones.14 The Commission E contraindicates ginger as a remedy for morning sickness during pregnancy, whilst the British Herbal Compendium does approve this use (see section on Safety and Adverse Effects). The British Herbal Compendium also approves ginger for use in anorexia, bronchitis, and rheumatic complaints.15 The Chinese have used ginger for 2500 years or more as a digestive aid and nausea remedy. It is also used for bleeding disorders and rheumatism.6 It is also prescribed to treat stomach ache, diarrhoea, cholera and toothaches; ginger is still used in about half of all traditional Chinese medicine herbal prescriptions today. Ginger features in the online encyclopaedia of traditional Chinese medicine,16 in which it is described as hot and pungent and used to treat the meridians of lung, spleen, stomach and heart. An online source described ginger as dry and warming, and used for ailments triggered by cold, damp weather. It is used when inducing

sweating does not improve symptoms. The skin of ginger is also used as a diuretic.17 Ginger is used extensively in Ayurveda to stop excessive clotting, reduce cholesterol and help with symptoms of arthritis (painful inflamed joints). In Malaysia and Indonesia, ginger soup is consumed by new mothers for a month postdelivery to help “sweat out impurities”. In Arabic medicine, ginger is used as an aphrodisiac. Some African countries consume ginger regularly to help repel mosquitos.6

16.5 Chemistry, Nutrition and Food Science Phenol Explorer,18 provides data on the polyphenol composition of fresh ginger, which contains the lignan secoisolariciresinol; dried samples contain caffeic acid and 6-gingerol. The most biologically active compounds are thought to be the nonvolatile phenolic compounds gingerol, gingeridione and shogaol.19 The characteristic ginger flavour is thought to be due to a combination of volatile and non-volatile phenolic compounds (gingerol, gingeridione and shogaol). More than 94% of the components of ginger essential oil (which are volatile compounds) have been identified,20 and the most abundant compounds were α-zingiberene (15.20%), β-phellandrene (13.51%), camphene (7.69%), (E,E)-α-farnesen (7.04%), β-sesquiphellandrene (6.96%) and ar-curcumene (5.60%). With regards to nutritional quality, ginger is generally considered to be poor in energy yielding nutrients (carbohydrate, fat, protein). Most nutrient levels vary significantly between fresh and dried samples, and these values have to be considered in relation to the proportions of the spice used in the diet, which are small. However, the main nutritional interest of ginger lies in its volatile and nonvolatile phytochemical composition, which confers a fragrant lemon and spicy flavour. Phytosterols, presented here with the main nutrients in Table 16.1,21 are of interest in nutrition as evidence has shown that 2 g per day is associated with a significant reduction in the levels of low-density lipoprotein cholesterol (LDL-C) of 8–10%, which is linked to a reduction in cardiovascular disease risk.22 Ginger, which contains 0.35 mg g−1, therefore may contribute to the 2 g per day of dietary phytosterol if consumed regularly. Table 16.1 Nutrition composition of ginger.21 Adapted from https://www.gov.uk/government/publications/composition-of-foodsintegrated-dataset-cofid, under the terms of the Open Government license 3.0 Ginger (100 g)

Fresh

Dried

Energy/kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg

44 60 14.1 0.8 (0.2) 7.4 78.9 —a

284 8.1 2 3.3 (1.7) 1.8 9.4 35.6

Calcium/mg Iron/mg Copper/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

16 0.6 23 43 0.23 34 415 13 0.3 0 0.02 0.03 0.8 0.16 5 11 0.26 0.1 0.2

97 46.8 0.45 130 28 140 910 34 4.7 37 0.05 0.19 5.1 0.01 0 0 0 0 1.27

a—: Not assessed or not present.

Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. A study compared the antioxidant capacity of fresh ginger tea (1% v/w; 1 g fresh ginger in 100 mL boiled water) with that of stewed fresh ginger (1 g in 100 mL of water boiled for 10 minutes and simmered for 60 minutes (covered)). Antioxidant capacity was measured via the trolox equivalent antioxidant capacity assay (TEAC). The stewed fresh ginger had an antioxidant capacity four times higher than that of the fresh ginger tea.23 The same study found that the antioxidant capacity of ginger was the lowest compared to those of other herbs studied (cinnamon, cloves, fennel, ginger, lavender, parsley, rose, rosemary, sage and thyme). This result is thought to reflect ginger's low polyphenol content, however it does possess gingerol and zingerone. Interestingly, in another study on ground ginger,24 it was shown to have the highest antioxidant capacity, which was, assessed using ferric reducing/antioxidant power (FRAP). The difference between the studies may be partially explained by the different assays used and also the form of ginger used (fresh ginger root versus ground ginger).24 Cooking ginger correlated with an increase in antioxidant capacity in agreement with previous literature on other plant foods and herbs.23,25 A study26 tested ginger's antioxidant scavenging ability against a panel of reactive oxygen species (ROS) (hydroxyl radical, superoxide, alkoxyl radical, peroxyl radical and singlet oxygen). The impact of heat treatment on ginger (grated fresh root juice was squeezed in a cloth to obtain the control, and for heated samples the juice was kept at 80 °C in a water bath for 120 min) was also investigated. The authors concluded that ginger's constituents (6-gingerol, 6shogaol, and zingerone) were responsible for the antioxidant scavenging ability observed, with 6-gingerol playing a major role in ginger's overall scavenging ability. For example, 6-gingerol showed a high scavenging ability against the hydroxyl radical and singlet oxygen (mainly via a charge transfer mechanism). Finally, the authors showed that heat transformed the parent compound 6-gingerol into 6-shogaol. This change did not necessarily decrease the scavenging ability, but its ability to scavenge antioxidants was dependent on the ROS used.

Ginger is traditionally used in the food industry to add flavour,27 and research has focussed on optimisation of delivery (and sensory attributes) of ginger flavour rather than its potential usefulness as a natural preservative (via its antioxidant and antimicrobial actions). A Nigerian study28 showed that the incorporation of ginger extracts (5%) into ogi (a fermented cereal porridge made from maize, guinea corn and millet) modestly reduced the oxidative rancidity of cooked ogi during storage for 8 days. Ginger may have potential uses in food preservation that have not previously been fully explored.27

16.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 16.6.1

Antioxidant and Anti-inflammatory Properties

Ginger (root, powder and essential oil) possesses both antioxidant and antiinflammatory properties in vitro. Its antioxidant capacity is reported to be much lower than those of other culinary herbs and spices, including clove, coriander and turmeric.24,29,33 However, ginger's antioxidant capacity varies based on the nature of the preparation and the assay used. Although there are a considerable number of studies concerning the antioxidant and anti-inflammatory properties in vitro and in animal models which indicate that ginger may confer some benefit via them,29,34 there are relatively few human studies (detailed in this section and summarised in Table 16.2). Furthermore, concerning its antioxidant properties, the studies do not focus on ginger alone and are mixed in terms of outcome. Li et al.,35 using hamburger meat seasoned with an antioxidant rich herb and spice blend, which included ground ginger (1.2 g), black pepper (0.7 g), clove (0.5 g), cinnamon (0.5 g), powdered garlic (1.5 g), Mediterranean oregano (3.0 g), paprika (3.4 g) and rosemary (0.5 g), reported a reduction in malondialdehyde in the hamburger meat as well as in the plasma and urine of healthy subjects following their consumption of the herb and spice blend seasoned hamburger meat. Malondialdehyde (MDA), which is a product of lipid peroxidation, reacts with DNA to form DNA adducts that can give rise to mutations and ultimately cancer. This compound also reacts with protein or amino acids to form MDA adducts, which can promote atherosclerosis.36 The effect on urinary MDA was repeated using the same herb and spice blend seasoned hamburger in men with type 2 diabetes (T2D).37 Thus, the findings of these studies suggest that ground ginger, in combination with other culinary herbs and spices, may confer protection against the development of atherosclerosis and cancer. In contrast, a similar culinary herb and spice blend but with turmeric included (the blend contained ginger - see below for details of the amount used, black pepper 0.91 g, cloves 0.61 g, cinnamon 0.61 g, powdered garlic 1.81 g, Mediterranean oregano 2.26 g, paprika 2.85 g, rosemary 0.61 g and turmeric 2.79 g) used to season different foods, namely dessert biscuit, coconut chicken and cheese bread, did not increase all the markers of antioxidant status measured in

healthy men who were overweight.38 (The amounts of the herbs and spices used varied with the non-herb foods; for ginger the stated total used was 1.51 g although the amounts added to the individual non-herb foods were stated as being 0.38 g in the dessert biscuit and 0.75 g added to the coconut chicken, which totals 1.13 g). Table 16.2 Dosages/amounts of ginger with potential health/therapeutic benefits Dosages/amounts and Frequency and form of ginger duration of daily intake

Outcome

Referenceb

1.2 g ginger, part of a herb and spice blend

Reduction in plasma and urine malondialdehyde compared to control

Li et al. (2010)35

Decrease in postprandial insulin and triglyceride levels in healthy, overweight subjects

Skulas-Ray et al. (2011)38

Protection against DNA damage and expression of proinflammatory markers – TNF-α, IL-1α and IL-6

Percival et al. (2012)39

Markers of chronic inflammation decreased in healthy subjects of normal or increased risk of developing colorectal cancer. Decreased proliferation of colonic epithelial cells, increased apoptosis and differentiation of these cells Increased cellular immunity, significantly lowered scores for fatigue, pain, anxiety in colorectal cancer patients receiving chemotherapy

Zick et al. (2011)64 and (2015)65 Jiang et al. (2013)66 Citronberg et al. (2013)68

Effective in preventing and/or treating nausea and vomiting during pregnancy, chemotherapy and postoperatively and seasickness when compared to placebo or vitamin B6. Similar efficacy or not as effective as medication used to treat nausea and vomiting

**Ernst and Pittler (2000)71 **Chaiyakunapruk et al. (2006)72 **Thomson et al. (2014)73 **Ding et al. (2013)74

Herb and spice blend consumed once with cooked hamburger meat 1.51 g (1.13 g)a Herb and spice blend ginger, part of a consumed herb and spice once in the blend form of a meal 2.8 g ginger in One capsule capsule form containing 1.4 g of ginger taken twice daily 7 times a day 2 g ginger, capsule of Eight capsules extract of each powdered ginger containing root standardized 250 mg of to contain 15 mg of ginger taken total gingerols a day for 28 days 0.05 mL ginger, Massaged for coconut oil 45 minutes at containing ginger a time three oil times over a week using light Thai massage of the head, neck, face, back, shoulders, arms, hands, lower legs and feet 600 mg–2500 mg 600 mg–2.5 g ginger, ginger given/taken biscuits, ginger daily for powder or root between once extracts in to 14 days capsules, essence of capsules or ginger syrup

Khiewkhern et al. (2013)69

100 mg–1 g ginger, ginger powder or ginger root/rhizome powder, ginger powder with cinnamon powder, ginger with exercise, heat treated ground ginger, ginger root, ginger extract, extract of dried ginger rhizomes and dried galangal rhizomes

100–2 g per day for 2 days to 12 weeks

Provided better pain relief when compared to placebo but effect comparable to or less than that of non-steroidal anti-inflammatory drugs in subjects with dysmenorrhea, osteoarthritis and/or muscle pain following exercise

2 g ginger, ginger powder

2 g per day for 12 weeks

2 g ginger, drink which contained ginger powder 2 g ginger, ginger powder

Single dose

Small but significant changes in body weight, BMI, waist and hip circumferences and a significant decrease in appetite when compared to placebo in women who were obese Decrease in appetite with an increase in satiety in men who were overweight Significantly reduced hip circumference compared to the placebo in patients with nonalcoholic fatty liver disease

500 mg–3 g, ginger powder, capsules or tablets

500–3 g per day for 30 days to 3 months

2 g per day for 12 weeks

Decreased fasting blood glucose, insulin resistance, insulin, and/or glycated haemoglobin in subjects with type 2 diabetes, hyperlipidemia, who were obese or were hyperglycaemic or dyslipidemic and receiving peritoneal dialysis. Significantly decreased TC, TG and/or LDL-C, and significantly increased HDL-C in subjects with type 2 diabetes, hyperlipidemia, who were obese (for women only), or were

**Borelli et al. (2005)75 **Marx et al. (2013)76 **Lee and Oh (2013)77 **Chang (2019)78 Viljoen et al. (2014)79 **Pongrojpaw et al. (2007)80 **Mohammadbeigi et al.(2011)81 **Chen et al. (2016)83 **Lakhan et al. (2015)84 **Terry et al. (2011)85 **Bartels et al. (2015)86 **Daily et al. (2015)87 **Wilson (2015)88 **Leach and Kumar (2008)89 **Chen et al. (2016)83 **Daily et al. (2015)87 **Terry et al. (2011)85 Attari et al. (2016)51

Mansour et al. (2012)52 Rahimlou et al. (2016)45

**Zhu et al. (2018)57 **Mazidi et al. (2016)40 **Pourmasoumi et al. 56

10 g and 20 g ginger, part of a spice blend used to season a vegetable curry 1.5 g ginger, part of a herb and spice blend

Spice blend consumed once in the form of a meal Capsule containing herb and spice combination, which totalled 5 g, taken daily for 2 weeks

hyperglycaemic or dyslipidemic and receiving peritoneal dialysis Significant dose-dependent decrease in postprandial glucose in healthy subjects with BMIs in the normal and overweight ranges Beneficially modified gut microbiota of healthy humans

Haldar et al. (2019)59

Li et al. (2019)50

aTotal amount of ginger used is stated as being 1.51 g but the amount of ginger added to the

individual non herb/spice foods are 0.38 g and 0.75 g which totals 1.13 g. b** Indicates systematic reviews.

Abbreviations: TNFα – tumour necrosis alpha; IL-1α – interleukin-1 alpha; IL-6 – interleukin-6; BMI – body mass index; TC – total cholesterol; TG – triglyceride; LDL-C – low density lipoprotein cholesterol; HDL-C – high density lipoprotein cholesterol.

Percival et al.39 investigated the impact of this spice on inflammatory and oxidative markers using healthy human subjects. Ginger was consumed in capsule form (1.4 g per capsule – a capsule was taken twice a day for 7 days, so 2.8 g per day for seven days). Despite having the lowest antioxidant capacity of the herbs and spices that were investigated (paprika, cayenne pepper, cinnamon (Cinnamomum loureiroi), cumin, turmeric, Mediterranean oregano, black pepper, rosemary, sage and clove) and having no impact on the antioxidant capacity of serum taken from subjects who consumed ginger at the amounts stated above, ginger protected against DNA damage, induced by the oxidant/reactive oxygen species hydrogen peroxide in vitro, and significantly decreased oxidation of low density lipoprotein (a marker for atherosclerosis) induced by tumour necrosis factor alpha (TNF-α). In addition, serum from subjects who consumed ginger reduced the pro-inflammatory cytokines TNF-α, interleukin-1 alpha (IL-1α) and interleukin-6 (IL-6). This study demonstrated that ginger's protective capacity against oxidative damage and inflammation, appeared not to be associated with its antioxidant capacity. Ginger is also reported to affect other markers of inflammation. A small number of clinical trials plus a meta-analysis reported that ginger can lower C-reactive protein at dosages of 1600 mg per day for 12 weeks in subjects with T2D, 1 g per day for 10 weeks in subjects who were obese, 1 g per day for 10 weeks in subjects who received peritoneal dialysis (removal of waste via the peritoneum), 1 g per day for 12 weeks in subjects with osteoarthritis (nitric oxide and other markers of inflammation, were also decreased in these subjects) and 2 g per day for 12 weeks in subjects with non-alcoholic fatty liver disease (NAFLD), in this study TNF-α was also decreased).40,45 A recent systematic review and meta-analysis concluded that ginger supplementation had a significant effect on serum markers of oxidative stress and inflammation.46 The antioxidant and anti-inflammatory properties of ginger, as well as many of

the other bioactive properties reviewed below, are ascribed primarily to a group of volatile phenolic compounds known collectively as the gingerols, which at high temperatures are converted to the shogaols, which are also bioactive. Other bioactive compounds in ginger include zingerone, gingerenone-A and 6hydrogingerdione, which are also phenolic, and terpenes, which are the major constituents of ginger's essential oils, including zingiberene.30,47,48

16.6.2

Glucose Lowering, Anti-diabetic, Lipid Lowering and Weight Management Properties

The ability of ginger to lower weight in animal models of obesity, possibly via a number of mechanisms, which include increasing energy expenditure and lipolysis, and the inhibition of lipogenesis, fat storage, adipogenesis, intestinal storage of fat and appetite regulation,49 has led to research on its weight management efficacy in humans who are overweight, obese, and have T2D, markers of metabolic syndrome (MetS), chronic kidney disease or NAFLD. In one systematic review, no significant changes in body composition were reported in the randomized clinical trials (RCTs) reviewed.49,50 However, these trials did report the following: small but significant changes in body weight, body mass index (BMI), waist and hip circumference, and a significant decrease in appetite, when compared to placebo following a 12 week supplementation with ginger powder at 2 g per day in women who were obese;51 a decrease in appetite with an increase in satiety, in men who were overweight, from a single dose of a ginger drink, which contained 2 g of ginger powder.52 Ginger powder at 3 g per day for 8 weeks and 1 g per day for 10 weeks for subjects with T2D and patients with peritoneal dialysis, respectively, had no significant effect on body weight compared to the placebos.53,54 At 2 g per day for 12 weeks, ginger powder in patients with NAFLD significantly reduced hip circumference compared to placebo, but other anthropometric markers were reported not to be significantly different between the ginger and placebo groups.45 Another systematic review by Maharlouei et al.55 indicates that ginger can lower low density lipoprotein cholesterol (LDL-C), fasting glucose and also insulin resistance, but not insulin, as well as body weight and waist-hip ratio. In their systematic review and meta-analysis of clinical trials on the effect of ginger supplementation on lipid levels in subjects with T2D or hyperlipidemia, or in subjects (women) who were obese, or in patients receiving peritoneal dialysis (who were either hyperglycemic or dyslipidemic – abnormal, normally high lipid levels), Pourmasoumi et al. 56 suggest that ginger might have a beneficial effect on triglyceride (TG) and LDL-C. They go on to suggest that dosages equal to or lower than 2 g per day had a greater lipid lowering effect, specifically on TG and total cholesterol (TC) than dosages higher than 2 g per day. Other systematic reviews on ginger have reported that it improves glycaemic indices in subjects with T2D or in subjects (women) who were obese or in subjects who were hyperglycaemic or

dyslipidemic and receiving peritoneal dialysis. In the studies reviewed, ginger at dosages ranging from 500 mg–3 g per day were reported to decrease fasting blood glucose (FBG), insulin resistance, insulin and/or glycated haemoglobin (HbA1C); the duration of the studies ranged from 30 days–3 months.40,57 However, a study by Zanzer et al.,58 which was not included in the reviews discussed above, reported that ginger consumed in the form of a beverage (137 mL extract) was reported to have no effect on lowering early increases in blood glucose, following consumption of white wheat bread containing 50 g of carbohydrate in healthy subjects with BMIs in the healthy and overweight ranges. Although the overall trend from the analyses carried out in some of these systematic reviews suggests that ginger is able to lower lipid and glucose levels, concerns about the quality of some of the trials, and also their heterogeneity with regards to their design, were highlighted as limitations and raised the importance of larger and more uniform clinical trials. A study in which ginger was combined with other spices and consumed as part of a meal has generated results that suggest that in a ‘real-world’ context, a spice blend containing ginger has the potential to confer protection against the development of chronic non-communicable diseases. Haldar et al. 59 have reported that fresh ginger (10 g and 20 g) in combination with a number of other spices (namely cayenne pepper (0.5 g and 1 g), cinnamon powder (0.25 g and 0.5 g), clove powder (0.25 g and 0.5 g), cumin seed powder (1 g and 2 g), fresh garlic (10 g and 20 g), Indian gooseberry ‘amla’ powder (1 g and 2 g) and turmeric (2 g and 4 g)) and consumed as part of a vegetable curry, improved postprandial glucose homeostasis in a dosedependent manner in men with BMIs in the healthy and overweight ranges. This effect was possibly via a dose-dependent increase in the levels of the hormone glucagon-like peptide-1 (GLP-1) which plays a key role in improving glucose homeostasis.60,61 Interestingly, this spice blend increased postprandial TG levels, which contrasts with the findings of Skulas et al. 38 (see above for details) in which a herb and spice blend was used. However, Haldar et al. 59 suggest that the decrease in eggplant with the increase in the amounts of the spices added to the curry might explain the increase reported, as eggplant is reported to possess lipid lowering effects (albeit in rats). See Table 16.2 for a summary of the systematic reviews, RCTs and other human studies.

16.6.3

Chemopreventive/Anti-cancer Properties

Clinical trials on the chemopreventive/anti-cancer properties of ginger are limited, and those that have been reported have to date been focussed on the action of this spice against gastrointestinal cancers, specifically colorectal cancer (CRC) (because of ginger's anti-inflammatory activity and the fact that chronic inflammation can be precursor for CRC).62,63 One set of clinical studies stems from work done by the same research group using healthy subjects at normal or increased risk of developing CRC. In these studies ginger, specifically powdered extracted (in ethanol) root, was given in capsule form, with each capsule containing 250 mg of extract of powdered ginger root standardized to contain 15 mg of total gingerols – the gingerols were 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol. A dosage of 2 g per day (8 × 250 mg capsule per day) for 28 days was used, and in all the studies ginger was reported to lower markers of chronic inflammation.64,66 Ginger, at the

same dosage, was also reported to decrease the proliferation of epithelial cells of the colon (in CRC, the epithelial cells of the colon transform into cancerous cells,67 and their sustained proliferation is a major feature of the cancer) and increase apoptosis and differentiation.68 The process of differentiation plays a key part in cell development as it allows cells to become specialized so that they can carry out specific functions. A main feature of cancer is the ability of cancer cells to evade apoptosis and not to differentiate. The efficacy of ginger has also been investigated on CRC patients receiving chemotherapy. In a study by Khiewkhern et al.,69 CRC patients received aromatherapy treatment using a light Thai massage in which the head, neck, face, back, shoulders, arms, hands, lower legs and feet were massaged with coconut oil that contained 0.05 mL of ginger oil. The patients were massaged 45 minutes at a time, three times over a week. This treatment regime resulted in an increase in cellular immunity, specifically there was a significant increase in lymphocyte count after the treatment. In addition, the severity scores for fatigue, pain, stress, or anxiety, were significantly lower in those that received the treatment. Despite the small number of studies and limitations in relation to sample size and duration of treatment, the studies do indicate that ginger, via its action on inflammation, proliferation, apoptosis and differentiation, which are all key anticancer targets, may possess significant chemopreventive potential.70 For a summary of these human studies see Table 16.2.

16.6.4

Anti-nausea/Antiemetic Properties

A not inconsiderable number of clinical trials have been carried out to investigate the effect of ginger on nausea and vomiting. In a recent overview of eleven systematic reviews of RCTs (it must be noted that some of the RCTs included in most, if not all, of these systematic reviews are the same), Li et al.50 reported that ginger, in the form of biscuits, powder or root extract in capsules, essence capsules or syrup, was significantly efficacious in the prevention and/or treatment of nausea and vomiting during pregnancy, chemotherapy and post operatively at dosages that ranged from 600 mg per day to 2500 mg per day for durations of between 4 and 14 days, for the pregnancy and chemotherapy studies. For the postoperative studies ginger was given just before anaesthesia was given, and in one of the postoperative studies ginger was also given before discharge. In all the studies, the effect of ginger was compared to that of placebos or vitamin B6 (studies suggest that this vitamin may be effective in improving symptoms of morning sickness during pregnancy).71,79 Some of the studies included in these systematic reviews investigated ginger in the form of ginger essence capsules (600 mg per day for 5 days) and found it to be similar in efficacy, or not as effective, as medication used to treat nausea and vomiting, namely dimenhydrinate and metoclopramide respectively.80,81 A systematic review by Ernst and Pittler71 included a study by Grøntved et al. 82 on the effect of ginger powder (1 g; one dose only) on seasickness, and reported that the spice was more effective than the placebo after 4 hours. Despite limitations highlighted by these systematic reviews which included variation in form, dosage and duration, and the small sample sizes, all of which highlighted the need for larger more rigorously designed clinical trials, it is clear

that ginger is an effective alternative treatment for nausea and vomiting, particularly during pregnancy, chemotherapy and post-surgery. A summary of these systematic reviews is provided in Table 16.2.

16.6.5

Nociceptive/Analgesic Properties

The efficacy of ginger in providing pain relief, particularly in primary dysmenorrhea, osteoarthritis and muscle pain following exercise, has been investigated in a number of clinical trials, the quality of which has been commented on in a number of systematic reviews (some including the same studies)83,89 and an overview of these by Li et al. 50 The limitations were focussed on the heterogeneity of the trials reviewed, which differed in dosage and formulation – the latter included ginger powder or ginger root/rhizome powder, ginger powder with cinnamon powder, ginger with exercise, heat treated ground ginger, ginger root, ginger extract, extract of dried ginger rhizomes and dried galangal rhizomes (galangal rhizomes originate from Indonesia; they are related to ginger but have a taste which is described as bitter and aromatic90). Duration also varied, and for some trials there was a lack of clarity over the blinding of the studies, which is important as ginger has a strong and distinctive aroma, and the randomization process. In addition, no information about the constituents or sources of the ginger used was provided in some of the trials. Furthermore, studies not published in English were not included as only English databases were used. As a result of these limitations, interpretation of the evidence in some of the systematic reviews was done with caution, in fact in some systematic reviews the use of ginger was not recommended for treating pain due to the lack of well designed and well conducted trials, and some systematic reviews were unable to draw any definitive conclusions.83,85,87,89 Other systematic reviews highlighted the consistency regarding the effect of ginger on pain relief caused by the conditions listed above, specifically when compared to placebos, and of these (systematic reviews) one noted a dose–response relationship.84,86,88 When compared to non-steroidal antiinflammatory drugs, such as ibuprofen and mefenamic acid, some systematic reviews noted that the effect of ginger was either less or comparable.87,89 The dosages of ginger reported to be effective, for pain caused by primary dysmenorrhea, were 100 mg per day to 1000 mg per day (given for the first 3 days of a period, 2 days prior and to 3 days of having a period, for 2 menstrual cycles, or until pain relief was achieved).83,88 For osteoarthritis of the hip or knee, the effective dosages reported were 500 mg per day to 1000 mg per day given for 3 weeks, 4 weeks, 6 weeks and/or 12 weeks.84,86,89 The relief from pain in osteoarthritis was also accompanied in some studies by a reduction in disability which was significant when compared to a placebo but not when compared to ibuprofen.86,89 For the relief of muscle pain following exercise, the systematic review by Wilson88 concluded that based on the evidence 2 g per day of ginger may decrease, modestly, muscle pain due to eccentric resistance exercise (for example lowering the body during a push up or crunch or the downward motion of a push up or squat) and 2 g per day for 5 days may reduce muscle soreness as a result of long distance running. A summary of these systematic reviews is in Table 16.2.

16.6.6

Anti-microbial Activity

Studies in vitro have demonstrated the action of ginger, including ethanolic extract, soybean oil extract of dried ginger powder and ginger essential oil, against bacteria and fungi pathogenic to humans. Its gingerol constituents, 6-gingerol, 10-gingerol and 12-gingerol, are reported to be the main contributors to its anti-bacterial and anti-fungal activity; zingiberene and endoborneol in its essential oil have also been identified as being possible contributors to ginger's anti-fungal activity.30,47,48,70,91,95

16.6.6.1 Anti-bacterial Activity Concerning its anti-bacterial activity, the forms of ginger listed above inhibit gramnegative pathogenic bacteria, including Klebsiella spp., Pseudomonas aeruginosa, Salmonella enterica (S. enterica) and S. typhi and/or Vibrio cholerae, and grampositive pathogenic bacteria, including Listeria monocytogenes and Staphylococcus aureus.96,98 Extracts of ginger (ethanol and hexane) have also been shown to have bactericidal activity against gram-negative oral pathogens, which cause periodontitis (gum disease). These include Porphyromonas gingivalis, Porphyromonas endodontalis, and Prevotella intermedia.99 Evidence indicates that gram-negative bacteria are more resistant to ginger (its essential oil) than grampositive bacteria.91,100

16.6.6.2 Anti-fungal Activity Ginger extract (ethanol) and its essential oil also act against pathogenic and toxigenic (toxin producing) fungi including Candida albicans, Microsporum gypseum, Pseudallescheria boydii, Rhizopus spp., Trichophyton mentagrophytes, Aspergillus flavus (A. flavus) and A. niger.101,104

16.6.7

Prebiotic Potential

Evidence is now emerging that culinary herbs and spices may work to maintain digestive health via their prebiotic potential. A prebiotic is a dietary constituent that is defined as “a selectively fermented ingredient that results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health.”105 There is a growing body of evidence that suggests that these benefits include protecting against the development of chronic noncommunicable diseases.106 Although herbs and spices are not fermented and are thus not prebiotics based on the definition above, their prebiotic potential, that is their ability to beneficially modify human gut microbiota, has been demonstrated in recent studies by Lu et al. 107 in vitro and, very importantly, in humans by Peterson et al. 108 (the amounts used were not specified in this study) and Lu et al., 109 who used ginger (1.5 g) in combination with cinnamon (1 g), Mediterranean oregano (1.5 g), black pepper (0.85 g) and cayenne pepper (0.15 g) (see Table 16.2 for a summary of the study by Lu et al. 109). Although larger, longer term and diet

controlled (as diet influences the profile of gut microbiota) studies are required to better establish the prebiotic potential of ginger, with the role of a diverse gut microbiota being linked to protection against the development of chronic non communicable diseases,110 this is an exciting area of research.

16.7 Safety and Adverse Effects Generally ginger is considered to be safe, with a number of the clinical trials discussed above reporting no or mild to moderate adverse effects. The mild to moderate side effects included gastrointestinal complaints such as flatulence, burping, nausea, vomiting, diarrhoea, constipation and general abdominal discomfort. Heartburn, drowsiness, palpitations, bad taste, reflux, conjunctivitis and skin allergy were also reported. The European Medicines Agency's assessment on ginger includes a breakdown of adverse events reported by subjects involved in clinical trials published up to 2009.111 In addition, reports of adverse events are summarised in systematic reviews of recent clinical trials.56,57,73,74,76,77,79,83,86,88,112 Ginger at doses higher than 6 g has been reported to cause gastric irritation and heartburn.113 Ginger at such doses is also linked to depression, and cardiac arrhythmia, and may worsen cholelithiasis, which is gallstone formation.74,114 In addition, it is reported that ginger decreases gastric bleeding time and so it is recommended by some that it not be taken with anticoagulant (anti-clotting) medication,88,115,116 although this recommendation is said to be based mainly on in vitro work in which ginger inhibited the synthesis of thromboxane and platelet aggregation (thromboxane stimulates platelet aggregation and thus promotes clotting).117,118 However, findings from human studies have been mixed, with some reporting no significant effect on bleeding time and thromboxane synthesis, and others reporting significant decreases in both platelet aggregation and the production of thromboxane.66,118,122 Two case reports suggest that in patients being treated with anticoagulants orally, over anticoagulation may be an issue if ginger is consumed during treatment.111,123,124 Concerning other interactions, an in vitro investigation reported inhibition of substrates for isoforms of the drug metabolising enzyme cytochrome P450 by aqueous extracts of ginger. Furthermore, gingerol has been reported to inhibit P-glycoprotein (a protein that transports drugs into cells) in multidrug resistant human epidermal carcinoma (skin cancer) cells that over express this protein. Both studies suggested that ginger and its constituents may influence drug efficacy, and although the clinical significance of these effects is yet to be established fully, it is clear that a more detailed assessment of the implications of these interactions is needed.125,128 Concerning pregnancy, generally, clinical trials investigating the use of ginger to treat nausea and vomiting during pregnancy have not reported severe side effects or any significant differences in adverse pregnancy outcomes compared to a placebo or vitamin B6.73,75,77,79,111

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CHAPTER 17

Lemon Grass (Cymbopogon citratus/Cymbopogon flexuosus) 17.1 Names English: Lemon grass, West Indian lemon grass or American lemon grass, Thai lemon grass Chinese: Xiang mao Danish: Citrengras, sereh and kamelhewe Ga-Dangme: Ti-ba Icelandic: Sitrónugras French: Verveine des Indes Thai: Takrai, Krai, serai Citratus derives from ancient Latin, meaning lemon-scented leaf, and the name Cymbopogon is derived from the Greek words kymbe meaning boat and pogon meaning beard, given due to the spike configuration of the flower.1

17.2 Taxonomy Order: Poales Family: Poaceae2 Genus: Cymbopogon Species: Cymbopogon citratus3

17.3 Origin, Description and Adulteration Cymbopogon is a genus of the Poaceae family of about 55 species, native to tropical and semi-tropical areas of Asia. Lemon grasses (Cymbopogon citratus)3 are edible bright blue-ish green perennial (lasting over 2 years) tufted grasses with many stems with short rhizome bases, also known as West Indian or American lemon grass, with a strong lemon-like aroma. The essential oil of lemon grass contains 74– 76% citral (the constituent of main interest in lemon grass; citral is measured to determine quality). 2 The lemon grass plant makes a fountain arching foliage reaching up to 1.5 m, it grows in sunny positions and cannot traditionally stand frost, although exceptions have been shown with some species (see below).4 The plant thrives under warm, sunny yet humid conditions and favours well-drained soils, although it can adapt to different soils, including saline soils.5 Other grass

species have been identified:6 Cymbopogon flexuosus (Nees ex Steud) Wats, known as East Indian, Cochin or Malabar grass can reach 2 m high, is a tufted stringy perennial, with linear and lanceolate (shaped like a lance) leaves. C. flexuosus var. flexuosus has a reddish-purple stem and leaf sometimes called “the true lemon grass” and contains 75–80% citral in its essential oil. C. flexuosus var. albescens grows in the wild and possesses white colour stems with 65–70% citral in its essential oil, and is often considered to be of inferior quality. C. pendulus (Nees ex Steud) Wats is also white but short and frost resistant with 75–80% citral in its essential oil.6 Lemon grasses are cultivated in tropical areas such as South and Central America, and Africa.2 Centre for Agriculture and Bioscience International (CABI) who produce the Invasive Species Compendium (ISC), states that once established it can spread fast and become invasive, and lemon grass is currently listed as a weed in Mexico and is considered invasive in St. Lucia. The high oil content in the plant, leads to an increase in fire risk in areas such as Pigeon Island and Dennery quarry.5 Lemon grass is not expensive and is therefore unlikely to be adulterated, however citral extracted from lemon grass can be used to adulterate other essential oils such as melissa oil.7

17.4 Historical and Current Uses Lemon grass (C. citratus) was intentionally introduced in tropical and subtropical regions for commercial reasons (to produce leaves and leaves oil extract, and as an ornamental plant).5 After the First World War, large-scale plantations were established in South and Central America, then in Africa, Madagascar and neighbouring islands.5 Lemon grass arrived in Puerto Rico and the Virgin Islands in 1876 and 1860, respectively. Lemon grass has and is used to flavour foods been used to flavour foods, and its essential oil (mostly composed of citral) is used in aromatherapy, in candle making, in perfumery and cosmetics, and is well known to be a natural insect repellent.8 Lemon grass is not mentioned in the Apicius Roman cookbook suggesting it was either low in popularity or availability in Europe.9 The Book of Herbs (1903) does not mention lemon grass,10 and it does not feature in The Book of Ancient Herbs (1982) either,11 suggesting its use in Europe is recent. Lemon grass is an essential ingredient in Thai cuisine. It is one of the most common home garden plants and available culinary herbs in Thai domestic kitchens.12 A syrup can be obtained by steeping lemon grass in a mix of equal parts of hot water and sugar to enhance fruit desserts or mixed with seltzer (carbonated water). A blend of lemon grass, garlic, ginger and oil will keep well in the freezer during winter months, and can be added to sauces for noodles and other dishes. Lemon grass oil is used in both non-alcoholic and alcoholic beverages, such as tea and flavoured wine, and it is added to sauces. Lemon grass is used to flavour frozen dairy desserts, sweet baked foods, gelatins, meat and fish products, fat and oils.6 The United States Department of Agriculture (USDA)13 designated lemon grass essential oil as Generally Recognized as Safe (GRAS) when used as a food

additive. In Suriname (in South America) traditional medicine, uses of lemon grass include helping with coughs, asthma, as well as bladder disorders, and also to treat cuts. In Suriname, Indian and Chinese medicine, it is used for headaches. In Mexican folk medicine, the tea of lemon grass (infusions or decoctions of either dry or fresh leaves), is used to treat nervous gastric disturbances and it is used the same way in Thailand and China. Lemon grass is used as an antispasmodic (muscle relaxant) in Brazil, Cuba, Egypt and Nigeria. It is used as a diuretic (to promote urination) in Brazil and Egypt. In Argentina, a leaves decoction (matte) is used for sore throats. In Brazil, lemon grass is used as an anti-inflammatory, and sedative (to induce sleep). In Cuba, the hot tea from dried leaves is prescribed to help reduce blood pressure, and reduce catarrh production.8 Lemon grass tea is also used in Indonesia and Malaysia as an emmenagogue (to stimulate menstrual flow). In the United States of America, hot water extracts are used for healing wounds and bone fractures.8 In India and Brazil, there has been reported usage of lemon grass as a sedative. In Suriname medicine, Nigeria, India and China lemon grass tea is used to reduce fevers.1,14 In Trinidad and Tobago it is prescribed to help with diabetes.15 In traditional Chinese medicine, lemon grass is used to treat the stomach, lung and heart meridians. It is used to help treat respiratory disorders, colds, and rheumatic pain, as well as insomnia, anxiety, stress.16 Research has been carried out to investigate lemon grass' natural mosquito repellent abilities, and found that combinations of essential oils from cinnamon bark, lemon grass and rosemary can enhance the insect repellent effect of one single plant, via synergistic interactions.17 A blend of lemon grass and cinnamon bark essential oils was studied for its spatial repellent action against a cool weather mosquito; the authors reported that this combination could help protect humans interacting in small outdoor gatherings from mosquito-borne diseases.

17.5 Chemistry, Nutrition and Food Science Phenol Explorer does not contain information on lemon grass.18 Lemon grass has been reported to contain high levels of phenolic acids;19 elemicin, catechol, chlorogenic acid, caffeic acid and hydroquinone, and flavonoids;19,20 luteolin, isoorientin 2′-O-rhamnoside, quercetin, kaempferol and apigenin, as well as tannins. Lemon grass' aroma is due to the presence of 75–85% citral in its essential oil, which is obtained from steam distillation or hydrodistillation, although other methods have been investigated to improve the quality of yield, including microwave-assisted hydrodistillation.21 Citral is in fact a blend of two acyclic monoterpene aldehydes: geranial (transcitral) and neral (cis-citral). Lemon grass' essential oils also contain various levels of geraniol, geranyl acetate, limonene (in C. flexuosus) and myrcene (in C. citratus).2 The nutritional quality of lemon grass is generally considered to be poor based on the energy yielding nutrients (carbohydrate, fat, protein). The nutritional values also have to be considered with the proportion of herbs used in the diet, which is small, nevertheless, lemon grass can be considered high in folate (3.07 µg g−1 dried herbs)

(see Table 17.1).22 Table 17.1 Nutrition composition of fresh lemon grass22 Lemon grass fresh (100 g)

US data

Energy/Kcal Carbohydrates/g Dietary fibre/g Fat/g (Saturated/g) Protein/g Water/g Phytosterols/mg Calcium/mg Copper/mg Iodine/µg Iron/mg Magnesium/mg Manganese/mg Phosphorus/mg Potassium/mg Selenium/µg Sodium/mg Zinc/mg Provitamin A/µg (retinol equivalent) Thiamin/mg Riboflavin/mg Niacin/mg Vitamin B6/mg Vitamin C/mg Folate/µg Vitamin E/mg Vitamin K1/µg Pantothenate/mg

99 25.31 —a 0.49 (0.11) 1.82 70.58 —a 65 0.266 —a 8.17 60 5.224 101 723 0.7 6 2.23 0 0.065 0.135 1.101 0.08 2.6 75 —a —a 0.05

a—: Not assessed or not present.

Food preparation and cooking are known to impact the composition of foods, and may affect the phytochemical constituents in aromatic plants. However, there is a paucity of data concerning the impact of food processing on lemon grass. One study did not find significant differences in antioxidant capacity between tea made with fresh or dried leaves of lemon grass.23 The use of herbs and spices as natural antioxidants in processed foods has become more widespread. These work by reducing the oxidative degradation of constituents (lipids) and therefore preserve the nutritional quality of foods for longer. Lemon grass (extract) was shown to possess antioxidant capacity and antimicrobial capacity, and a concentration of 1% of the extract protected fresh chicken sausages against growth of mesophilic aerobes and psychrotrophic bacteria.24 The treatment of cooked and shredded chicken breasts with 1% lemon grass extract lead to reduced lipid oxidation, and the formation of free fatty acids, peroxides, and thiobarbituric acid reactive substances after 60 days of storage, compared to the untreated control.25 Camel burgers formulated with 1% lemon grass oil had lower bacterial count compared to control and lower oil concentrations, with a good sensory score for aroma, taste, colour, texture and

overall acceptability (the control burger had the lowest score).26 Lemon grass is a useful ingredient of functional foods27 and its potential as a food preservative is good.28 Lemon grass oil also offers potential as a food preservative, however its intense aroma limits its uses as a food additive. Microencapsulation with gum arabic has been investigated as a process to overcome the oil's aroma intensity, and the authors concluded that lemon grass may be a viable alternative (as a food preservative) because of its low cost. Carnauba wax– lemon grass oil nanoemulsions were used for coating grape berries and were successful in inhibiting food pathogens and extending the shelf life of grapes.24,29 Nanoemulsions of lemon grass and rosemary essential oils were incorporated in starch based edible film on bananas and were successful at inhibiting food pathogens and extending shelf life.30

17.6 Bioactive Properties, Purported Health Benefits and Therapeutic Potential: Current and Emerging Research 17.6.1

Antioxidant Properties

Lemon grass, its stem and leaves, possesses antioxidant capacity in vitro.31,32 A comparison of the antioxidant capacity of the herb with that of other culinary herbs and spices indicates that its antioxidant capacity is comparable to those of black pepper, dill, caraway, coriander, cumin, parsley, ginger and cardamom (green), and is lower than those of clove, cinnamon (Cinnamomum zeylanicum), sage (Salvia officinalis), Mediterranean oregano, thyme, rosemary, bay leaf and mint (mentha Canadensis). However, values and thus comparisons with other culinary herbs and spices vary due to variations in constituents, see below, based on the nature of the preparation. Variations also occur due to the assay used.1,31,33 The constituents of lemon grass that are believed to be the contributors to its antioxidant capacity are the polyphenols, specifically the phenolic acids, including caffeic acid, chlorogenic acid and p-coumaric acid, and flavonoids including luteolin-7-o-glycoside, and also polyphenols in its essential oils. However, constituent content and contribution also vary due to the factors stated above.32,34,35 There is little in the current literature concerning the possible health beneficial/therapeutic potential of lemon grass' antioxidant properties. Cheel et al. 35 reported that lemon grass inhibits lipid peroxidation in red blood cells in vitro. In addition, Campos et al. 34 reported that a polyphenol rich fraction of the aerial parts of lemon grass was able to decrease levels of reactive oxygen species using a human endothelial cell based model of oxidative stress. Furthermore, the preparation of lemon grass inhibited vasoconstriction, suggesting that it could prevent endothelial, and thus vascular, dysfunction via its ability to inhibit oxidative stress. Li et al. 36 recently reported that lemon grass' essential oil decreases hepatic oxidative stress in vivo (in an animal study) although it had no protective effect

against chemically induced hepatotoxicity. There is also a small amount of evidence suggesting that lemon grass' antioxidant properties may be of significance in the prevention/inhibition of cancer development (see section below on Chemopreventive/Anti-cancer Properties).

17.6.2

Anti-inflammatory Properties

Lemon grass has been shown to possess anti-inflammatory activity, although this work is limited to in vitro and animal studies. Studies in vitro using human dendritic cells and also murine immune cells report that an infusion of dried leaves, polyphenolic rich extracts, extracts of aerial parts and essential oil of lemon grass inhibit the production or expression of pro-inflammatory markers, including nitric oxide, inducible nitric oxide synthase,37 interleukin 6 (IL-6) production,38,39 although the production of this cytokine has also been reported to be induced by lemon grass extract,39 and interleukin 1 beta (IL-1β). Lemon grass' antiinflammatory activity has been reported in animal studies but the potency of this activity appears to depend on the preparation used. In fact, early studies in which leaf extracts were used reported weak or no anti-inflammatory activity.40,41 In an animal study, lemon grass essential oil was reported to inhibit acute inflammation.28 The compounds that are believed to contribute to lemon grass' antiinflammatory activity are the flavonoids, including the luteolin glycosides, and also linalool oxide and epoxy-linalool – all from extracts of the herb – and from the essential oil the citrals, neral and geranial.37,39

17.6.3

Chemopreventive/Anti-cancer Properties

Lemon grass (extracts) has been shown to possess anti-mutagenic activity, although this activity appears to be dependent on the mutagen. Cytotoxic activity against cancer cells in vitro has also been reported.1,33,42,43 This activity has been reported against human cancer cells, including colorectal cancer cells (HCT116), breast cancer cells (MCF-7 and MDA-MB231), and ovarian cancer cells (SKOV-3 and COAV), and is dependent on the solvent used to prepare the extract. There is also evidence that lemon grass' cytotoxic activity is cancer cell specific.33 Lemon grass essential oil is reported to sensitize doxorubicin resistant human ovarian cancer cells to the drug in vitro (doxorubicin is a chemotherapeutic drug).43 Lemon grass extract has also been shown to inhibit and/or prevent the development of colorectal cancer (CRC) and liver cancer in vivo (using animal models). Concerning the action on CRC, the study reported that lemon grass acted to prevent its development via inhibition of the formation of DNA adducts and aberrant crypt foci (ACF) – precancerous lesions in the colon that are indicative of initiation of colorectal carcinogenesis – and also inhibition of the enzyme glucuronidase, which is involved in the conversion of pro-carcinogens to carcinogens.44 For the model for liver cancer, there was evidence that lemon grass' antioxidant properties may be of significance, as it inhibited oxidative damage to DNA.45 The compounds in lemon grass that evidence suggests contribute to these activities are beta-myrcene, which possesses anti-mutagenic activity,46 d-limonene and geranial, which are reported to

increase the activity of glutathione S-transferase, a phase II enzyme involved in the detoxification of carcinogens,47 neral and citral,48,49 which are reported to increase the cytotoxic and apoptotic effect of doxorubicin on human lymphoma cells in vitro.50 (Citral is a mixture of geranial and neral). In addition, citral is reported to inhibit the development of breast cancer cells, in animals, via the induction of apoptosis and the down regulation of aldehyde dehydrogenase in breast cancer cells (aldehyde dehydrogenase activity is a marker of breast cancer stem cells).51 The anti-cancer action of geranial may also involve down regulation of the activation of key regulator and initiator of inflammation – nuclear factor-κB (NF-κB).52 In addition to the chemopreventive/anti-cancer properties summarised above, recent studies have reported on the inhibition of the formation of carcinogens, known as heterocyclic amines, in grilled and/or fried red meat (beef and lamb) that is marinated with lemon grass (10 g per 100 g of meat) prior to cooking.53,55 Heterocyclic amines are formed when meat is cooked at high temperatures.56

17.6.4

Anxiolytic (Calming), Antinociceptive/Analgesic and Sedative Properties and Effect on Cognitive Function and Mood

A small amount of research has been done on the central nervous system (CNS) mediated properties of lemon grass with evidence suggesting that the nature of the preparation influences/impact on such effects. Animal studies report that lemon grass essential oil exhibits analgesic properties centrally as well as peripherally, which may be due to its constituent myrcene.1,57,58 However, in contrast, the leaf extract was reported to possess no analgesic effect in vivo.41 The essential oil has also been shown to possess anxiolytic (calming/antianxiety), sedative and also anti-convulsant activities in an animal study by Blanco et al.;59 this effect appears to be mediated by the gamma-aminobutyric acid (GABA) mediated system60 (GABA is an inhibitory neurotransmitter which decreases central nervous system activity). However, a study carried out using human volunteers reported that lemon grass tea made from powdered dried leaves (4 g) added to boiling water (150 mL) and filtered before consumption, taken either as a single dose or daily for 2 weeks, had no anxiolytic or sedative effect.61 A recent randomized controlled trial (RCT) reported that inhalation for 5 minutes of lemon grass essential oil enhanced cognitive function and mood.62

17.6.5

Hypotensive Effect

Animal studies have reported the hypotensive effect of lemon grass extract and essential oil, and the decrease in bradycardia (a slow heart rate) by the essential oil.40,63,64 However, in an RCT by Sriraksa et al.,62 inhalation of lemon grass essential oil had no effect on blood pressure or heart rate.

17.6.6

Neuroprotective Effect

There is evidence from an animal study by Tayeboon et al., of lemon grass essential oil's ability to protect against chemically induced neurotoxicity.65

17.6.7

Anti-microbial Activity

Lemon grass' anti-microbial action, both antibacterial and anti-fungal, is well established using in vitro studies. This activity includes action against a number of bacteria and fungi, which are pathogenic to humans.1

17.6.7.1 Anti-bacterial Activity Lemon grass, mainly its essential oil but also its plant oil and extract, has been shown to act against gram-negative bacteria pathogenic to humans, including Escherichia coli O157:H7, Neisseria gonorrhoeae, Salmonella typhimurium, Shigella flexneri, Proteus mirabilis, Pseudomonas aeruginosa and Acinetobacter baumannii (including a multi-drug resistant strain). Lemon grass also acts against gram-positive bacteria pathogenic to humans, including Enterobacter faecalis, Listeria monocytogenes, Staphylococcus aureus, Streptococcus gordonii, and Streptococcus pneumonia. However, the level of potency appears to vary based on the source and nature of the lemon grass preparation.1,43,66,71 There is evidence that lemon grass essential oil increases the anti-bacterial activity of the cosmetic preservative phenoxyethanol. However, this effect appears to be dependent on the pathogen.72,73 Lemon grass essential oil is also reported to be more potent than some oral antiseptics against oral bacterial pathogens.69 More recent evidence indicates that the essential oil and also its main constituent, citral, act against bacteria pathogenic to humans via inhibition of bacterial communication and adhesion.43 The individual citrals – geranial and neral -- also possess anti-bacterial activity, and myrcene has been shown to enhance this activity when mixed with either citrals.73

17.6.7.2 Anti-fungal Activity Lemon grass, again mainly its essential oil but also its plant oil and plant extract, is reported to act against fungi that are pathogenic to humans, including those that are toxigenic (toxin producing). These include Candida spp. including Candida albicans (C.albicans), C. tropicalis and Aspergillus niger (A. niger) and A. flavus.1,28,66,67,69 Furthermore, lemon grass has been shown to be of greater potency against oral fungal pathogens compared to oral antiseptics. This finding, in part, formed the basis for an RCT in which the effect of lemon grass on HIV patients with oral thrush was investigated. Patients were instructed to consume initially 125 mL of a lemon grass infusion made using dried lemon grass (12.5 mL) and boiling water (500 mL) – infused for 10 minutes and then cooled. After the initial treatment, the patients were instructed to consume the infusion (at least 250 mL twice a day for 10 days) which was made fresh every 24 h. The effect of lemon grass was compared to that of lemon juice and an aqueous solution of gentian violet, which is used to treat oral thrush in HIV/AIDS patients.74,76 The findings of

the study indicated that lemon grass was much more effective at treating oral thrush in these patients than gentian violet. However, the authors acknowledged the small scale of the study and the need for larger RCTs.

17.6.8

Anti-malarial Activity

Based on its traditional use in the treatment of malaria, lemon grass' anti-malarial activity has been investigated, albeit in animal studies only. This work suggests that the essential oil and also the infusion and whole plant possess significant antimalarial potential. Ntonga et al.77 reported that lemon grass essential oil had a potent activity against the malaria vector (transmitter) Plasmodium falciparum and larvae of another vector Anopheles funestus in vitro. Anti-malarial activity of lemon grass has also been reported in animal studies by Tchoumbougnang et al. 78 and Chukwoocha et al. 79 who reported that lemon grass essential oil, dried powdered lemon grass and lemon grass infusion acted against Plasmodium chabaudi AS and/or Plasmodium berghei ANKA infection, with the dried powdered preparation proving to be more potent than the herbal infusion and also the anti-malaria drug chloroquine.

17.7 Safety and Adverse Effects Lemon grass when used for the purpose of preparing food is safe. However, there is limited information concerning the safety of lemon grass in peer reviewed literature. General websites (non-peer reviewed sources) state that when used for medicinal purposes it is safe. Such sites also state that the use of lemon grass oil (it is not clear if they are referring to the essential oil) can cause irritation or a rash, and inhalation may cause respiratory problems. These sites also caution against the use of lemon grass for medicinal purposes by women who are pregnant or lactating, and that medicinal use may cause miscarriages.80 It is likely that some of these concerns are due to citral.81 Of the few human studies involving lemon grass that have been carried out, not all have reported on adverse effects. Sriraksa et al. 62 reported that inhalation of lemon grass essential oil had no effect on blood pressure or heart rate. Leite et al. 61 in their study of the anxiolytic and sedative effects of lemon grass reported that a tea made from 4 g of powdered dried leaves in 150 mL of boiling water, had no effect on renal function and on most markers of hepatic function when consumed daily for 2 weeks. However, they did note that post the intervention there was an increase in the levels of direct bilirubin, which could be an indication of problems with bile flow due to blocked bile ducts or liver cell damage. Other side effects reported were somnolence – sleepiness/drowsiness, polyuria – frequent urination, and dry mouth plus diarrhoea and dizziness. They also noted that a small number of volunteers reported a bitter taste and slight gastric discomfort following consumption of tea made using 10 g of powdered dried leaves. The essential oil of lemon grass contains the compound methyl eugenol, which in vitro and in animal studies has been shown to be genotoxic (damaging to DNA) and carcinogenic. Although it is yet to be established if this constituent is carcinogenic

in humans, caution concerning the level of use of herbal products that contain this compound is advised.82

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CHAPTER 18

Mint – Mentha piperita (Peppermint), Mentha spicata (Spearmint), Mentha aquatica (Water Mint), Mentha arvensis (Corn, Field, Wild Mint, Japanese Mint, Marsh Mint) 18.1 Names English: Mint, peppermint, spearmint. Arabic: Eqama, nana, nana al-fulfuli Chinese: Bo he French: Menthe anglaise, menthe poivrée, sentebon Lao: Bai hom lap, Bai kankam, Phak hom lap, Phak kan kam and saranae Snanish: Menta The word mint is from the old English minte, which is related to the German Minze, which is from the Latin via the Greek minthē. 1 The genus name Mentha comes from the Greek Mintha, which is the name of a mythical nymph who morphed into the plant. The species name piperita is from the Latin piper, meaning pepper, referring to the pungent taste of mint (peppermint).2,3

18.2 Taxonomy Order: Lamiales Family: Lamiaceae Genus: Mentha Species: numerous natural hybrids and intermediate forms exist; Peppermint (Mentha piperita) is a natural hybrid of Mentha aquatica L. (water mint) with M. spicata L. (spearmint).

18.3 Origin, Description and Adulteration The mint plant is described as a perennial (lasting more than 2 years) strongly aromatic herb, it grows 0.5–1 m high with 1–1.5 m spread,4 with stems and leaves that have flushes of purple and rhizomatous roots (resembling rhizomes). The stems have opposite, toothed leaves and tiny, pale tubular purple flowers that bloom in

late summer, in spikes. It is an important garden bee-attracting plant. Mint grows in any moist soil; chalk, clay, sand and loam, in any situation and therefore can be easily invasive. Mint is prone to get leafhoppers (minute insects), caterpillars and shiny green beetles (round black larvae which feed on the foliage of mint plants in summer that can cause severe damage). Mint can be affected by powdery mildew (fungi) and mint rust (orange, yellow or black spots or blisters that form on leaves, which in severe cases causes the plant to die). According to the Food and Agriculture Organization (FAO), there were 99 768  000 tonnes of peppermint produced in 2017, 69.5% from Africa (mainly Morocco) and 7.2% from Argentina.5 Adulteration of peppermint mint oil with dementholised Japanese oil (menthene) which is cheaper is common. Camphor oil, cedarwood oil and oil of African Copaiba, rosemary, and turpentine are occasionally used as adulterants as well.6

18.4 Historical and Current Uses Archaeologists Nadel et al. produced evidence from ancient burial sites of Natufian people in Israel dating back nearly 14 000 years ago that contained impressions of sage and mint flowers; these are thought to be the most ancient example of humans adding flowers to graves. The authors explain that the Natufian people were the first to transition from a nomadic, hunter-gathering lifestyle to sedentary fixed settlements, built furniture, domesticated the wolf, and experimented with domesticating wheat and barley.7 Pottery jars from ancient Egyptian culture, dating back to 3150 BCE were recently re-analysed and revealed that a selection of herbs and tree resins were added to grape wine, suggesting ancient Egyptians used organic medicinal remedies; previous evidence was based only on notes in medical papyri dating back to 1850 BCE. These remedies included Abydos wine, which contained rosemary, mint (M. spp. species was not specified) and thyme, added to a fermented Emmer wheat and barley.8 Records of mint leaves used as a medicine date back to the ancient Greeks and Romans (probably M. pulegium and M. aquatica) and ancient Egyptians, although the origin of peppermint cultivation remains uncertain.2 The Roman physician Pliny the Elder (23–79 CE) recorded uses of mint by the Greeks and Romans to scent tables, to add to sauces used in food preparation and to flavour wines (probably spearmint). Along with myrtle and rosemary, mint was used in funerals in ancient Greece and Rome.9 Most of the Greek physician Hippocrates' (460–375 BCE) materia medica came from the plant world, with a list of several hundred, from which fifteen are still in general use today, including sage, coriander, rosemary, and mint, although he claimed too much mint may cause impotence.9 Mint was added to milk for drinking as it prevents curdling. Aristotle (Greek philosopher and scientist 384–322 BCE) prohibited the consumption of mint by soldiers because it was believed it would lessen or destroy their aggression. Dioscorides' (Greek physician 50–70 CE) records included the use of six varieties of mint plus peppermint (it was thought that peppermint was not used as a medicine at this time). The Apicius Roman cookbook shows records of recipes with mint, for example

chicken in its own broth, with thyme, fennel seeds, mint, rue (Ruta graveolens, a herb commonly used at that time) laser root (Silphium was a plant, now extinct, which had a powerful sulfurous smell), cumin and pepper. Perhaps one of the most notable of recipes is this one entitled: ‘treatment of strong smelling birds of every description with a goatish smell’, with pepper, lovage, thyme, mint (dried), sage, dates, honey, vinegar, wine, broth, oil, and mustard. Mortaria was a ready to use preparation made up of mint, rue, coriander and fennel seeds, crushed up in a mortar finely to which lovage pepper, honey and broth plus vinegar were added. It was principally used for ‘cold green sauce’ to accompany dishes.10 In The Book of Herbs (1903) mint is cited as quoted: “The healthful balm and mint… that Cheeses will not corrupt, if they be either rubbed over with the juice or a decoction of Mints, or they laid among them… Peppermint is still retained, as is Spearmint, in the British Pharmacopoeia and… the leaves have an intensely pungent aromatic taste similar to pepper, and accompanied with a peculiar sensation of coldness”.11 Today, mint is a popular flavour across the globe. It is one of the rare cooling flavours available to our culinary panel, in contrast to pungent flavours offered by many spices, such as black pepper, ginger or nutmeg. Mint leaves have a cooling effect largely due to menthol and menthone, which are both found in mint's essential oils. Mint leaves are infused in hot water to make tea. Peppermint is different to spearmint which is a milder flavoured mint. Mint leaves are added fresh or dried to sweet or savoury dishes. In the UK, recipes include apple and mint jelly, mint sauce for roast lamb, pea and mint fritters, mint chocolates and mint chocolate cookies. In Asia, meat dishes marry well with mint, for example pork and mint stir fry, Burmese chicken with mint, Thai chicken stir fried with basil and mint, or Vietnamese chicken and mint. In Indian cuisine, mint is used to flavour rice dishes such as Pudina Pulao or to make mint chutney. There are also recipes of African mint chutney. North Africans are fond of mint tea, which is the national beverage in Morocco, and an essential part of hospitality customs (blended green tea with spearmint and sometimes some peppermint may also be added to the tea blend (for a more pungent flavour)), recipes for beef carrot stew with mint are also available there. South African mint crisp or mint crisp fridge tart are popular treats. Mint syrups and liqueurs are used in cocktails like crème de menthe in the Grasshopper. The cucumber mint cooler and the mojito cocktails would not be the same without fresh mint garnish. The United States Department of Agriculture (USDA) granted peppermint and spearmint Generally Recognized as Safe (GRAS) certifications when used as food, and their essential oils GRAS certification when used as food additives.12,13 Peppermint first officially became part of the London Pharmacopoeia in 1721. Today, peppermint leaf and/or its oil feature in many European (Austria, UK, Hungary, Switzerland, France), and also the Russian, pharmacopoeias.2, 14 In Germany, peppermint leaf is one of the most economically and medicinally important plant crops. The British Herbal Compendium indicates peppermint leaf for dyspepsia (indigestion), flatulence, intestinal colic and biliary disorders, and the European Scientific Cooperative on Phytotherapy (ECOP) adds gastritis (inflammation of the stomach) and enteritis (inflammation of the small intestine) to this list of indications. The German Commission E monographs approve dosages of peppermint leaf and oil for spastic (muscle spasm) complaints of the gastrointestinal tract, gall bladder and bile ducts. It is contraindicated for gallstones, and has no side

effects or interactions with other drugs2, 15 (see section on Safety and Adverse Effects). Peppermint oil is used for irritable bowel, respiratory catarrh and oral mucosa inflammation; as well as myalgia (muscular pain) and neuralgia (nerve pain) in external use only for the latter conditions.14 In the United States of America peppermint oil is used as an antacid, and is included in topical analgesic preparations in sunburn creams, decongestant inhalants and throat lozenges. Corn/field mint oil is used to produce menthol, obtained by steam distillation of the fresh, flowering herb; isolated and purified from the essential oil it is used in the French, Chinese and Indian pharmacopeias, and approved in the Commission E monographs in a similar way to peppermint oil. It is contraindicated in bile duct obstruction, inflammation of the gallbladder and severe liver damage. It should be avoided on the face and the nose of infants and young children, and people who are sensitive to mint may experience stomach upset.14 In traditional Chinese medicine, peppermint is not traditionally used, but Bo He (M. haplocalyx, and M. arvenis) are used instead. Corn/field mint, described as a cool acrid herb that promotes sweating, is used specifically to treat the lung and liver meridians used for colds with fever, headache, cough, sore throat and red itchy eyes. It is used in the early stages of measles to bring the rash to the surface and speed up recovery. It can also help with anxiety and asthma.16

18.5 Chemistry, Nutrition and Food Science Phenol Explorer17 shows that dried peppermint contains the flavonoids, flavanones; heriocytrin, hesperidin, narirutin and flavonones; diosmin, gadenin B, isorhoifolin, luteolin-7-o-glucoside luteolin-7-o-rutinoside and pebreellin, and the phenolic acids; rosmarinic acid. Spearmint (dried) contains the phenolic acids; 5caffeoylquinic, caffeic and rosmarinic acids as the major constituent. Mint oils are obtained by steam distillation of fresh flowering sprigs. Peppermint leaf oil (volatile oil; 1.2–3%) is made up of 29–55% menthol, 10–40% menthone, 2–13% cineole, 1–11% pulegone, 1–10% menthyl acetate, 0–10% menthofuran, and 0.2–6% limonene.14 Corn/field mint contains 30–45% menthol; 17–35% menthone; 5–13% isomenthone; 2–7% menthyl acetate; 1.57% limonene;