Ancient and Traditional Foods, Plants, Herbs and Spices used in the Middle East 1032152869, 9781032152868

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Ancient and Traditional Foods, Plants, Herbs and Spices used in the Middle East The use of different foods, herbs and spices to treat or prevent disease has been recorded for thousands of years. Egyptian papyrus, hieroglyphics and ancient texts from the Middle East have described the cultivation and preparation of herbs and botanicals to “cure the sick.” There are even older records from China and India. Some ancient scripts describe the use of medicinal plants that have never been seen within European cultures. Indeed, all ancient civilizations have pictorial records of different foods, herbs and spices being used for medical purposes. However, there are fundamental questions pertaining to the scientific evidence for the use of these agents or their extracts in modern medicine. There have been considerable advances in scientific techniques over the last few decades. These have been used to examine the composition and applications of traditional cures. Modern science has also seen the investigation of herbs, spices and botanicals beyond their traditional usage. For example, plants which have been used for “digestion” or “medical ills” since time immemorial are now being investigated for anti-cancer properties or their toxicity, using high throughput screening. Techniques also include molecular biology, cellular biochemistry, physiology, endocrinology, and even medical imaging. However, much of the material relating to the scientific basis or applications of traditional foods, herbs, spices and botanicals is scattered among various sources. The widespread applicability of foods or botanicals is rarely described, and cautionary notes on toxicity are often ignored. This is addressed in Ancient and Traditional Foods, Plants, Herbs and Spices used in the Middle East.

Ancient and Traditional Foods, Plants, Herbs and Spices in Human Health Series Editors Vinood B. Patel University of Westminster, London Victor R. Preedy King’s College, London Rajkumar Rajendram King Abdulaziz Medical City, Riyadh

Each volume in the series provides an evidence-based ethos describing the usage and applications of traditional foods and botanicals in human health. The content provides a platform upon which other scientific studies can be based. These may include the extraction or synthesis of active agents, in vitro studies, pre-clinical investigations in animals, and clinical trials. The key benefits of each volume are: • Chapters provide a historical background on the usage of food and plant-based therapies. • Chapters are based on the results of studies using scientific techniques and methods. • Presents wide references to other foods, herbs, and botanicals reported to have curative properties. • Chapters are self-contained, focused toward specific conditions. Ancient and Traditional Foods, Plants, Herbs and Spices used in Cardiovascular Health and Disease Edited by Rajkumar Rajendram, Victor R. Preedy, and Vinood B. Patel Ancient and Traditional Foods, Plants, Herbs and Spices used in Diabetes Edited by Rajkumar Rajendram, Victor R. Preedy, and Vinood B. Patel Ancient and Traditional Foods, Plants, Herbs and Spices used in the Middle East Edited by Rajkumar Rajendram, Victor R. Preedy, and Vinood B. Patel

For more information about this series, please visit: https://www.routledge.com/Ancient-andTraditional-Foods-Plants-Herbs-and-Spices-in-Human-Health/book-series/ATFHSH

Ancient and Traditional Foods, Plants, Herbs and Spices used in the Middle East

Edited by

Rajkumar Rajendram, Victor R. Preedy, and Vinood B. Patel

First edition published 2024 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487–2742 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2024 selection and editorial matter, Victor R. Preedy, Vinood B. Patel, and Rajkumar Rajendram; individual chapters, the contributors Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microflming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978–750–8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identifcation and explanation without intent to infringe. ISBN: 978-1-032-15286-8 (hbk) ISBN: 978-1-032-15289-9 (pbk) ISBN: 978-1-003-24347-2 (ebk) DOI: 10.1201/9781003243472 Typeset in Times by Apex CoVantage, LLC

Contents Editors ...............................................................................................................................................ix Contributors ......................................................................................................................................xi

SECTION I Overviews and Dietary Components Chapter 1

Grains and Pulses in Diets of the Middle East and a Focus on Buckwheat ................ 3 Hacı Ömer Yılmaz and Çağdaş Salih Meriç

Chapter 2

Dietary Patterns in the Middle East and Fatty Liver Disease .................................... 15 Makan Pourmasoumi, Farahnaz Joukar and Fariborz Mansour-Ghanaei

Chapter 3

Fatty Acids in Different Foods of Middle Eastern Diets: Implications for Health.................................................................................................................... 27 Ayoub Al-Jawaldeh and Lara Nasreddine

Chapter 4

The Link of Lifestyle Patterns and Nutrition in Iran with Health and Traditional Diets ......................................................................................................... 43 Mahdieh Abbasalizad Farhangi and Negin Nikrad

Chapter 5

Traditional Medicinal Foods in Persian Medicine: An Overview of Current Evidence ........................................................................................................ 55 Mahbubeh Bozorgi, Roodabeh Bahramsoltani and Roja Rahimi

Chapter 6

Traditional Dietary Patterns in the Elderly: Iranian Aspect ...................................... 71 Amin Mirrafiei and Sakineh Shab-Bidar

Chapter 7

Syrian Herbs in Health and Disease........................................................................... 83 Husam Abazid, Nour Alabbas and Manar Al Hamed

SECTION II Specific Agents, Items and Extracts Chapter 8

Aloe Vera (Aloe barbadensis) Usage in the Middle East: Applications for Gastroesophageal Reflux .......................................................................................... 105 Mohaddese Mahboubi

Chapter 9

Arta (Calligonum comosum) in the Middle East and Biomedical Applications ........... 117 Muna A. Ali, Naglaa S. Ashmawy, Kareem A. Mosa, Mohamed D. Al-Shamsi, Ali A. El-Keblawy and Sameh S.M. Soliman v

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Chapter 10 Conehead Thyme (Thymus capitatus) and Evidence-Based Usage in Eradicating Helicobacter pylori........................................................................... 135 Meryem Güvenir Chapter 11 Cumin (Cuminum cyminum) Usage in the Middle East and Biological Basis of Its Actions ................................................................................................... 143 Amir Hossein Faghfouri and Mahdiyeh Khabbaz Koche Ghazi Chapter 12 Frankincense (Boswellia sacra Flueck.) and Its Usage in the Middle East: Molecular, Cellular, and Biomedical Aspects .................................... 157 Ian Edwin Cock, Victor Akpe and Matthew James Cheesman Chapter 13 Khella (Ammi visnaga): Molecular and Cellular Aspects and Potential in Biomedicine .......................................................................................... 179 Samar Thiab, Rana Abutaima, Muna Barakat, Safa Daoud, May Abu-Taha, and Reem Abutayeh Chapter 14 French Marigold (Tagetes patula L.): Phytochemical and Bioactive Targets of Secondary Metabolites ............................................................................ 193 Ausama Abdulwahab Safar Chapter 15 Oak Gall (Quercus infectoria G. Olivier Gall): Pharmaceutical Usage and Cellular Targets ...................................................................................... 211 Parmis Badr and Fatemeh Etemadpour Chapter 16 Pelargonium Species and Their Usage in the Middle East as Medicinal Herbs ....................................................................................................... 227 Mohammad H. El-Dakdouki and Lina Fayoumi Chapter 17 Saffron (Crocus sativus) as a Middle East Herb: Traditional and Modern Medicinal Applications .............................................................................. 241 Mehrnaz Shojaei, Mohammad Bagherniya, Gholamreza Askari, Babak Alikiaii, Seyed Ahmad Emami, Eric Gumpricht and Amirhossein Sahebkar Chapter 18 Sage Plants (Salvia sp.; Lamiaceae) in the Middle East: Phytochemistry, Ethnopharmacology, and Traditional Use ................................................................ 263 Salar Hafez Ghoran, Fatemeh Taktaz, Ali Akbar Mozafari, Armin Saed-Moucheshi and Ali Hosseini Chapter 19 Paronychia argentea L. Usage in the Middle East (Jordan) and Its Biomedical Profles .................................................................................................. 279 Mohamad Shatnawi, Rida A. Shibli, Sobhia Saifan, Ashok K. Shakya, Tamara Al Qudah and Rajashri R. Naik

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Chapter 20 Taily Weed (Ochradenus baccatus Delile) as a Middle Eastern Herb: Chemical Profile, Biological Activities, and Traditional Uses ................................. 293 Hamdoon A. Mohammed, Ehab A. Ragab and Riaz A. Khan Chapter 21 Tomato (Lycopersicon esculentum Miller) from Egypt and Phytochemical Usage: Phenolics and Flavonoids .............................................................................307 Manal M. Sabry, Fify I. Fathy and Sabah H. El Gayed Chapter 22 Turmeric (Curcuma longa L.) Usage in the Middle East: A Comprehensive Review ........................................................................................ 323 Sepide Amini, Zahra Kiani, Mohammad Bagherniya, Gholamreza Askari, Zahra Tayarani-Najaran and Amirhossein Sahebkar Chapter 23 Veined Dock (Rumex pictus Forssk.) Usage in the Middle East: Phytochemical Constituents and Biological Effects of the Extracts ........................ 343 Enaam AbouZeid, Lamiaa Abou El-Kassem and Nagwa Ammar

SECTION III

Resources

Chapter 24 Recommended Resources for the Scientific Study of Foods, Plants, Herbs, and Spices Used in the Middle East ............................................................. 355 Rajkumar Rajendram, Daniel Gyamfi, Vinood B. Patel and Victor R. Preedy Index.............................................................................................................................................. 367

Editors Rajkumar Rajendram, AKC, BSc (Hons), MBBS (Dist), MRCP (UK), FRCA, EDIC, FFICM, is a clinician scientist with a focus on internal medicine, anesthesia, intensive care and perioperative medicine. His interest in traditional medicines began at medical school when he attended the Society of Apothecaries’ history of medicine course. He subsequently graduated with distinctions from Guy’s, King’s and St. Thomas Medical School, King’s College London in 2001. As an undergraduate he was awarded several prizes, merits and distinctions in preclinical and clinical subjects. He completed his specialist training in acute and general medicine in Oxford in 2010 and then practiced as a consultant in acute general medicine at the John Radcliffe Hospital, Oxford. He also trained in anesthesia and intensive care in London and was awarded fellowships of the Royal College of Anaesthetists (FRCA) in 2009 and the Faculty of Intensive Care Medicine (FFICM) in 2013. He then moved to the Royal Free London Hospital as a consultant in intensive care, anesthesia and peri-operative medicine. He has been a fellow of the Royal College of Physicians of Edinburgh (FRCP Edin) since 2017 and the Royal College of Physicians of London (FRCP Lond) since 2019. He is currently a Consultant in Internal Medicine at King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia. He recognizes that integration of traditional medicines into modern paradigms for healthcare can significantly benefit patients. As a clinician scientist, he has therefore devoted significant time and effort to nutritional science research and education. He is an affiliated member of the Nutritional Sciences Research Division of King’s College London and has published over 300 textbook chapters, review articles, peer-reviewed papers and abstracts. Victor R. Preedy, BSc, PhD, DSc, FRSB, FRSPH, FRCPath, FRSC, is a staff member of the Faculty of Life Sciences and Medicine within King’s College London. He is also a member of the Department of Nutrition and Dietetics (teaching), Director of the Genomics Centre of King’s College London and Professor of Clinical Biochemistry (Hon) at Kings College Hospital. He graduated in 1974 with an honours degree in biology and physiology with pharmacology. He attained his University of London PhD in 1981. In 1992, he received his Membership of the Royal College of Pathologists and in 1993 he attained his second doctorate (DSc) for his outstanding contribution to protein metabolism in health and disease. He was elected as a Fellow to the Institute of Biology in 1995 and to the Royal College of Pathologists in 2000. Since then he has been elected as a Fellow to the Royal Society for the Promotion of Health (2004) and The Royal Institute of Public Health (2004). In 2009, he became a Fellow of the Royal Society for Public Health and in 2012 a Fellow of the Royal Society of Chemistry. He has carried out research when attached to Imperial College London, The School of Pharmacy (now part of University College London) and the MRC Centre at Northwick Park Hospital. He has collaborated with research groups in Finland, Japan, Australia, the United States and Germany. He is a leading expert on the science of health and has a long-standing interest in dietary and plant-based components. He has lectured nationally and internationally. He has published over 700 articles that include peer-reviewed manuscripts based on original research, abstracts and symposium presentations, reviews, and numerous books and volumes. Vinood B. Patel, BSc, PhD, FRSC, is currently Reader in Clinical Biochemistry at the University of Westminster and honorary fellow at King’s College London. He directs studies on metabolic pathways involved in liver disease, particularly related to mitochondrial energy regulation and cell death. Research is being undertaken to study the role of nutrients, antioxidants, phytochemicals, iron, alcohol and fatty acids in the pathophysiology of liver disease. Other areas of interest are identifying new biomarkers that can be used for the diagnosis and prognosis of liver disease and understanding mitochondrial oxidative stress in Alzheimer disease and gastrointestinal dysfunction in autism. He graduated from the University of Portsmouth with a degree in pharmacology and completed his ix

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PhD in protein metabolism from King’s College London in 1997. His postdoctoral work was carried out at Wake Forest University Baptist Medical School studying structural-functional alterations to mitochondrial ribosomes, where he developed novel techniques to characterize their biophysical properties. He is a nationally and internationally recognized researcher and has several edited biomedical books related to the use or investigation of active agents or components . . . These books include The Handbook of Nutrition, Diet, and Epigenetics; Branched Chain Amino Acids in Clinical Nutrition; Cancer: Oxidative Stress and Dietary Antioxidants; Diet Quality: An EvidenceBased Approach; Toxicology: Oxidative Stress; and Dietary Antioxidants; Molecular Nutrition: Vitamins. In 2014, he was elected as a Fellow to The Royal Society of Chemistry.

Contributors Husam Abazid Department of Clinical Pharmacy and Therapeutics Faculty of Pharmacy Applied Science Private University Amman, Jordan Enaam AbouZeid Department of Pharmacognosy National Research Centre Cairo, Egypt May Abu-Taha Department of Clinical Pharmacy and Therapeutics Faculty of Pharmacy Applied Science Private University Amman, Jordan Rana Abutaima Faculty of Pharmacy Zarqa Private University Zarqa, Jordan Reem Abutayeh Department of Pharmaceutical Chemistry and Pharmacognosy Faculty of Pharmacy Applied Science Private University Amman, Jordan Victor Akpe School of Environment and Science Griffith University Nathan, Australia Nour Alabbas Department of Clinical Pharmacy and Therapeutics Faculty of Pharmacy Applied Science Private University Amman, Jordan Manar Al Hamed Life Pharmacy Group Sharjah, United Arab Emirates

Muna A. Ali Department of Applied Biology College of Science University of Sharjah and Department of Clinical Sciences College of Medicine University of Sharjah Sharjah, United Arab Emirates Babak Alikiaii Anesthesia and Critical Care Research Center Isfahan University of Medical Sciences Isfahan, Iran Ayoub Al-Jawaldeh World Health Organization Regional Office for the Eastern Mediterranean Cairo, Egypt Tamara Al Qudah Hamdi Mango Center for Scientific Research University of Jordan Amman, Jordan Mohamed D. Al-Shamsi Abba Botanical Preparations Dubai, United Arab Emirates Nagwa Ammar Department of Pharmacognosy National Research Centre Cairo, Egypt Sepide Amini Department of Clinical Nutrition School of Nutrition and Food Science Food Security Research Center Isfahan University of Medical Sciences Isfahan, Iran Naglaa S. Ashmawy Department of Pharmacognosy Faculty of Pharmacy Ain Shams University Cairo, Egypt

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Gholamreza Askari Food Security Research Center and Department of Community Nutrition School of Nutrition & Food Sciences Isfahan University of Medical Sciences Isfahan, Iran

Safa Daoud Department of Pharmaceutical Chemistry and Pharmacognosy Faculty of Pharmacy Applied Science Private University Amman, Jordan

Parmis Badr Pharmaceutical Sciences Research Centre and Phytopharmaceutical Technology and Traditional Medicine Incubator Shiraz University of Medical Sciences Shiraz, Iran

Mohammad H. El-Dakdouki Department of Chemistry Beirut Arab University Beirut, Lebanon

Mohammad Bagherniya Food Security Research Center and Department of Community Nutrition School of Nutrition & Food Sciences Isfahan University of Medical Sciences Isfahan, Iran Roodabeh Bahramsoltani Department of Traditional Pharmacy School of Persian Medicine Tehran University of Medical Sciences Tehran, Iran Muna Barakat Department of Clinical Pharmacy and Therapeutics Faculty of Pharmacy Applied Science Private University Amman, Jordan Mahbubeh Bozorgi Department of Traditional Medicine Faculty of Medicine Shahed University Tehran, Iran Matthew James Cheesman School of Pharmacy and Medical Sciences Griffith University Gold Coast, Australia Ian Edwin Cock School of Environment and Science Griffith University Nathan, Australia

Sabah H. El Gayed Department of Pharmacognosy Cairo University and 6 October University Cairo, Egypt Lamiaa Abou El-Kassem Department of Pharmacognosy National Research Centre Cairo, Egypt Ali A. El-Keblawy Department of Applied Biology College of Science University of Sharjah Sharjah, United Arab Emirates Seyed Ahmad Emami Department of Traditional Pharmacy School of Pharmacy Mashhad University of Medical Sciences Mashhad, Iran Fatemeh Etemadpour Department of Phytopharmaceuticals (Traditional Pharmacy) School of Pharmacy Shiraz University of Medical Sciences Shiraz, Iran Amir Hossein Faghfouri Maternal and Childhood Obesity Research Center Urmia University of Medical Sciences Urmia, Iran Mahdieh Abbasalizad Farhangi Department of Community Nutrition Tabriz University of Medical Sciences Tabriz, Iran

Contributors

Fify I. Fathy Department of Pharmacognosy Cairo University Cairo, Egypt Lina Fayoumi Department of Chemistry Beirut Arab University Beirut, Lebanon Mahdiyeh Khabbaz Koche Ghazi Nutrition Research Centre Faculty of Nutrition and Food Sciences Tabriz University of Medical Sciences Tabriz, Iran Salar Hafez Ghoran H.E.J. Research Institute of Chemistry International Center for Chemical and Biological Sciences University of Karachi Karachi, Pakistan Eric Gumpricht Isagenix International, LLC Gilbert, Arizona, USA Meryem Güvenir Department of Medical Microbiology Faculty of Medicine The Cyprus Health and Social Sciences University Omorphou, Cyprus Daniel Gyamf The Doctors Laboratory Ltd London, UK Ali Hosseini Department of Pharmacognosy School of Pharmacy Shiraz University of Medical Sciences Shiraz, Iran Farahnaz Joukar Gastrointestinal and Liver Diseases Research Center Guilan University of Medical Sciences Razi Hospital Rasht, Iran

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Riaz A. Khan Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy Qassim University Qassim, Saudi Arabia Zahra Kiani Department of Clinical Nutrition School of Nutrition and Food Science Food Security Research Center Isfahan University of Medical Sciences Isfahan, Iran Mohaddese Mahboubi Medicinal Plants Research Department Research and Development Tabib Daru Pharmaceutical Company Kashan, Iran Muhammed Majeed Sabinsa Corporation East Windsor, New Jersey, USA Fariborz Mansour-Ghanaei Gastrointestinal and Liver Diseases Research Center Guilan University of Medical Sciences Razi Hospital Rasht, Iran Çağdaş Salih Meriç Department of Nutrition and Dietetics Faculty of Health Sciences University of Gaziantep Gaziantep, Turkey Amin Mirrafei Department of Community Nutrition School of Nutritional Sciences and Dietetics Tehran University of Medical Sciences (TUMS) Tehran, Iran Hamdoon A. Mohammed Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy Qassim University Qassim, Saudi Arabia

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and Department of Pharmacognosy and Medicinal Plants Faculty of Pharmacy Al-Azhar University Cairo, Egypt

Makan Pourmasoumi Gastrointestinal and Liver Diseases Research Center Guilan University of Medical Sciences Razi Hospital Rasht, Iran

Kareem A. Mosa Department of Applied Biology College of Science University of Sharjah Sharjah, UAE

Ehab A. Ragab Department of Pharmacognosy and Medicinal Plants Faculty of Pharmacy Al-Azhar University Cairo, Egypt

Ali Akbar Mozafari Medicinal Plant Breeding & Development Research Institute and Department of Horticulture Faculty of Agriculture University of Kurdistan Sanandaj, Iran Rajashri R. Naik Faculty of Allied Medical Sciences Pharmacological and Diagnostic Research Center Al Ahliyya Amman University Amman, Jordan Lara Nasreddine Department of Nutrition and Food Sciences American University of Beirut Beirut, Lebanon Negin Nikrad Department of Community Nutrition Tabriz University of Medical Sciences Tabriz, Iran

Roja Rahimi Department of Traditional Pharmacy School of Persian Medicine Tehran University of Medical Sciences Tehran, Iran Rajkumar Rajendram College of Medicine King Saud bin Abdulaziz University for Health Sciences Riyadh, Saudi Arabia and Department of Medicine King Abdulaziz Medical City King Abdullah International Medical Research Center Ministry of National Guard Health Affairs Riyadh, Saudi Arabia Manal M. Sabry Department of Pharmacognosy Cairo University Cairo, Egypt

Vinood B. Patel School of Life Sciences University of Westminster London, UK

Armin Saed-Moucheshi Horticulture and Crop Research Department Kermanshah Agricultural and Natural Resources Research and Education Center (AREEO) Kermanshah, Iran

Victor R. Preedy School of Life Course and Population Sciences Faculty of Life Science and Medicine King’s College London London, UK

Ausama Abdulwahab Safar Department of Food Security and Public Health Khabat Technical Institute Erbil Polytechnic University Kurdistan Region, Iraq

Contributors

Amirhossein Sahebkar Applied Biomedical Research Center Biotechnology Research Center, Pharmaceutical Technology Institute Department of Biotechnology School of Pharmacy Mashhad University of Medical Sciences Mashhad, Iran Sobhia Saifan Faculty of Agricultural Technology Al Ahliyya Amman University Amman, Jordan Sakineh Shab-Bidar Department of Community Nutrition School of Nutritional Sciences and Dietetics Tehran University of Medical Sciences (TUMS) Tehran, Iran Ashok K. Shakya Faculty of Pharmacy Al Ahliyya Amman University Amman, Jordan Mohamad Shatnawi Faculty of Agricultural Technology Al Balqa Applied University Al-Salt, Jordan Rida A. Shibli Al Ahliyya Amman University and Faculty of Agricultural Technology The University of Jordan Amman, Jordan

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Mehrnaz Shojaei Food Security Research Center and Department of Community Nutrition School of Nutrition & Food Sciences Isfahan University of Medical Sciences Isfahan, Iran Sameh S.M. Soliman Department of Medicinal Chemistry College of Pharmacy University of Sharjah Sharjah, United Arab Emirates Fatemeh Taktaz Department of Biology Faculty of Sciences University of Hakim Sabzevari Sabzevar, Iran and Department of Advanced Medical and Surgical Sciences University of Campania “Luigi Vanvitelli” Naples, Italy Zahra Tayarani-Najaran Targeted Drug Delivery Research Center Pharmaceutical Technology Institute Mashhad University of Medical Sciences Mashhad, Iran Samar Thiab Department of Pharmaceutical Chemistry and Pharmacognosy Faculty of Pharmacy Applied Science Private University Amman, Jordan Hacı Ömer Yılmaz Department of Nutrition and Dietetics University of Gumushane Gumushane, Turkey

Section I Overviews and Dietary Components

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Grains and Pulses in Diets of the Middle East and a Focus on Buckwheat Hacı Ömer Yılmaz and Çağdaş Salih Meriç

CONTENTS 1.1 Introduction .............................................................................................................................3 1.2 A Pseudocereal: Buckwheat ....................................................................................................4 1.3 Characterization of Buckwheat ...............................................................................................5 1.4 Physicochemical and Functional Properties ...........................................................................5 1.5 Production of Buckwheat ........................................................................................................6 1.6 Usage Areas of Buckwheat .....................................................................................................6 1.7 As an Alternative Plant in Middle Eastern Agriculture..........................................................7 1.8 Nutritional Composition..........................................................................................................7 1.9 Bioactive Components and Effects on Health.........................................................................8 1.10 Antioxidant Effect ...................................................................................................................8 1.11 Hypocholesterolemic Effect ....................................................................................................9 1.12 Hypotensive Effect ..................................................................................................................9 1.13 Hypoglycemic Effect...............................................................................................................9 1.14 Neuroprotective Effect .......................................................................................................... 10 1.15 Antifungal Effect .................................................................................................................. 10 1.16 Toxicity and Cautionary Notes.............................................................................................. 10 1.17 Summary Points .................................................................................................................... 11 References........................................................................................................................................11

LIST OF ABBREVIATIONS CHD FAOSTAT HDL IgE LDL ROS TNF-α

coronary heart disease food and Agricultural Organization Corporate Statistical Database high-density lipoprotein immunoglobulin E low-density lipoprotein reactive oxygen species tumor necrosis factor-alpha

1.1 INTRODUCTION Middle Eastern countries’ health and nutritional status have altered throughout four decades as a result of changes in dietary practices, socioeconomic status, and lifestyle. In most of these countries, chronic non-communicable diseases such as diabetes, hypertension, and cancer have become health problems in society. The traditional diet, which was high in fiber and low in fat and cholesterol, gave way to a more westernized diet that was higher in fat, free sugars, sodium, and DOI: 10.1201/9781003243472-2

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Ancient and Traditional Foods Used in the Middle East

cholesterol (Aljefree and Ahmed 2015). Additionally, the consumption of fiber-rich foods such as whole grains, vegetables, and fruits is underappreciated in this dietary pattern (Micha et al. 2015). Pseudocereal grains, which are edible seeds from dicotyledonous plant species, are becoming a popular gluten-free grain in human diets because of properties such as high nutritional and nutraceutical value. Pseudocereals are high in carbohydrate, fiber, protein, minerals, vitamins, and phytochemicals such as saponins, polyphenols, phytosterols, phytosteroids, and betalains, all of which may be beneficial to health (Martínez et al. 2020). Furthermore, the use of whole grain products is commonly associated with better consumer health. Dietary fiber, which is abundant in whole grains, is considered to be (at least partially) responsible for a variety of health benefits (Martínez et al. 2020). The content of dietary fiber in whole grains varies greatly among grains. Whole grains of cereals and pseudocereals include a variety of soluble and insoluble functional dietary fiber such as cellulose, arabinoxylan, β-glucan, xyloglucan, and fructan (Prasadi and Joye 2020). Leguminous seeds that have been dried and consumed are known as pulses. Beans, peas, chickpeas, lentils, and lupines are among the many plant species in the genre of pulses. Pulses have been consumed for at least 10,000 years and are among the most popular foods in the world. Pulses may be cultivated in a wide range of climates across the world, making them both financially and nutritionally important. Pulses are high in protein, fiber, and vitamins and minerals including iron, zinc, folate, and magnesium (Singh et al. 2017). Moreover, phytochemicals, saponins, and tannins found in pulses have antioxidant and anti-carcinogenic characteristics, indicating that pulses could help fight cancer. Pulse consumption also improves serum lipid profiles and has a beneficial impact on blood pressure, platelet activity, and inflammation, all of which are risk factors for cardiovascular disease (Mudryj et al. 2014). In 2019 the global annual production of pulses was over 48 million metric tons, roughly half of which originated from Asia; India and Canada are the leading producers (FAOSTAT 2016). Pulses are commonly used in salads, soups, pilaf, köfte, and combined with meat throughout the Middle East, India, and the Mediterranean. Leblebi, or roasted chickpeas, are a Turkish food that has spread throughout North Africa, the Middle East, and Europe. Falafel is a typical Middle Eastern food prepared from deep-fried balls or patties of ground chickpeas and/or faba beans. Hummus is a popular chickpea- and tahini-based spread that originated in Middle Eastern cuisine (Sözer et al. 2017).

1.2 A PSEUDOCEREAL: BUCKWHEAT Buckwheat is one of the ancient domesticated crops of Asia, Central, and Eastern Europe and is among the various underutilized crops that has been mainly used as a staple food especially in arid regions of the world. The origin of buckwheat domestication dates back about 4000–5000 years in South China; it is believed to have originated in central Asia (Gondola and Papp 2010). China is considered as the original center of buckwheat and is extremely rich in buckwheat genetic resources. Although it can be grown in almost any region, including regions with harsh climate and soil conditions, buckwheat is mostly grown in the Northern Hemisphere. Buckwheat is chiefly cultivated in China, Russia, India, Nepal, Bhutan, Canada, Mongolia, North Korea, and Japan. However, buckwheat production declined during the first half of the 20th century, especially in Russia and France. The buckwheat plant will spread to the eastern, western, and colder climate regions in the future. Since the beginning of the 2000s, research, development, and production studies on buckwheat been carried out in the Middle East (Dizlek et al. 2009; Arslan 2014). Buckwheat is an annual dicotyledonous plant belonging to the Fagopyrum species of the Polygonaceae family. Known as a nutritious food with positive effects in the treatment of chronic diseases, buckwheat shows “pseudocereal” characteristics (as it shows both similarities and differences with cereals) and has great ecological adaptability. Buckwheat is not considered a true cereal, but the seeds contain a cereal-like, starchy endosperm. The genus Fagopyrum includes about 19 species besides four new species that have recently been included: namely Fagopyrum crispatifolium

Grains and Pulses and a Focus on Buckwheat

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(Liu et al. 2008); Fagopyrum pugense (Tang et al. 2010); Fagopyrum wenchuanense (Shao et al. 2011); and Fagopyrum qiangcai (Shao et al. 2011), and their taxonomic position and phylogenetic relationships have been clarified (Zhou et al. 2012; Shao et al. 2011).

1.3 CHARACTERIZATION OF BUCKWHEAT Buckwheat has been the subject of widespread academic research as a “rediscovered” pseudocereal in recent years, due to the important contributions of components such as antioxidative components, proteins, polysaccharides, resistant starch, and dietary fiber with high biological value and function to nutrition and its multifaceted benefits. The protein content of buckwheat is between 8.5% and 19% on average, depending on the type and variety. Buckwheat corresponds to 92.3% of the biological value of egg protein due to its balanced amino acid composition and high biological value. Buckwheat grain contains 64.5% globulin, 12.5% albumin, 8.0% glutelin, and 2.9% prolamine. Buckwheat is very rich in lysine amino acid, which is found in limited amounts in cereals, and is also richer in phenylalanine (862 mg/100 g) than quinoa, amaranth, and rice. The main difference between buckwheat flour and wheat flour is that buckwheat is rich in albumin and globulin compared to wheat, while the ratio of prolamin and glutelin is low (Cawoy et al. 2009). The total carbohydrate ratio of buckwheat grain was between 67.8% and 70.1%, of which 54.5% is starch. The average carbohydrate and starch concentrations in hulled buckwheat were 78.99 g/100 g and 49.35 g/100 g, respectively. The concentration of amylose in common buckwheat was between 22% and 26%, while the total concentration of amylose in starch was between 36% and 43%. Buckwheat has a low glycemic index because it contains a high percentage of resistant starch. The hull was removed and the resistant starch concentration in whole buckwheat was determined as 6.13–11.04 g/100g and 3.239–6.58 g/100 g, respectively. High levels of resistant starch are beneficial in preventing colon cancer, and it has a prebiotic effect by helping the development of lactic acid bacteria in the intestinal microflora (Krkoskova and Mrazova 2005). Enterobacteria and Bifidobacteria in the intestines of rats with buckwheat consumption were examined; it was determined that the ratio of aerobic mesophilic and lactic acid bacteria increased compared to the control sample, while pathogenic bacteria and bacteria belonging to the Enterobacteriaceae family decreased. The amount of starch and its digestibility may vary according to the applied heat treatment. For example, it was determined that the amount of resistant starch in buckwheat decreased from 33.5% to 7.5% in an autoclave drying process (Li and Zhang 2001).

1.4 PHYSICOCHEMICAL AND FUNCTIONAL PROPERTIES The effects of high hydrostatic pressure application on common buckwheat starch and Tartary buckwheat starch, and temperature-moisture treatment on in vitro digestibility, physicochemical and structural properties of Tartary buckwheat starch and common buckwheat starch were investigated. As a result of the studies, improvement in the physicochemical properties of modified starch, low in vitro hydrolysis, a small amount of fast digesting starch, and a high amount of slow digesting starch and non-digestible starch were determined. It has been stated that modified starch will provide higher benefits in the prevention of chronic diseases and in the production of food products that require thermal stability (Hore and Rathic 2002). In other studies investigating the effect of γ-irradiation on the physicochemical and functional properties of buckwheat starch, it was reported that amylose concentration decreased as the applied irradiation dose increased, while other decreases were observed in pH value and swelling (gelling) power, and syneresis (serum separation) was detected (Popovic et al. 2013a, 2013b; Ikanovic et al. 2013). It was determined that when buckwheat seeds were subjected to the wet milling process with and without hulls, the longer the soaking time, the lower the gelatinization temperature of the hulled buckwheat compared to the unhulled buckwheat, the increase in gelatinization enthalpy, the higher

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the protein ratio, and the greater the total amount of isolated starch. It was stated that the use of isolated starch in processed foods would not cause significant changes in the product, and it was stated that the usability of the shell part and the prolongation of the soaking period should be considered economically (Sobhani et al. 2014). Buckwheat groats are a rich source of total dietary fiber and soluble dietary fiber. Dietary fiber ratio in common buckwheat seed was reported as 27.38% and flour 6.77%, and Tartary buckwheat seed 25.98% and flour 6.29%. The average dietary fiber amount in the buckwheat husk was 79.11 g/100 g, and 4.43 g/100 g in the seed separated from the husk. In the bran fraction containing the bark, the total dietary fiber ratio was 40%, of which 25% was soluble dietary fiber (Björkman 2010; Hore and Rathic 2002). In buckwheat bran, which does not contain the hull parts, the total dietary fiber rate was 16%, and soluble dietary fiber constituted 75% of this rate. Crude fiber ratio in buckwheat grain was determined as 9.3%–10.9%, and the soluble dietary fiber ratio was determined as 20%–30%. The crude fiber ratio was determined as 10 g/100 g in buckwheat whole flour and 0.5 g/100 g in unshelled buckwheat flour (Ratan and Kothiyal 2011).

1.5 PRODUCTION OF BUCKWHEAT While buckwheat production in the world was approximately 1.4 million tons in 2010, it increased to 3.8 million tons in 2017, and the average yield per decare is approximately 100 kg. According to FAOSTAT data, buckwheat production in 2017 was 3,827,748 tons worldwide. Buckwheat production in 2017 was 1,619,429 tons in Asia, accounting for 40% of the world’s buckwheat production. The highest production in the world is Russia with 1,524,280 tons, followed by China (1,447,292 tons) and Ukraine (180,440 tons) (Food and Agriculture Organization 2019). Buckwheat is produced in many countries and has a high economic value; it is also one of the plants whose consumption is increasing day by day and has a versatile usage area. All buckwheat seeds or manufactured products that celiac patients must use as a food source are imported to our country (Türkiye), and this disease affects approximately 300,000 of our country’s population (Acar et al. 2011). Both the seeds and the herb of the buckwheat plant are used. The seeds of the buckwheat plant are distinguished from other grain-based food sources such as wheat, barley, oats, and rye as they contain essential amino acids and do not contain free gluten chemically. Food products such as gluten-free bread, pasta, and biscuits developed in recent years are produced from pseudocereals and are classified as grain-like. Amaranth, quinoa, and buckwheat are examples of pseudocereal foods (Yıldız and Yalçın 2013; Zhu 2016).

1.6

USAGE AREAS OF BUCKWHEAT

While buckwheat proteins are rich in albumin and globulin, they are poor in glutenin and prolamin content. For this reason, gluten does not occur in dough prepared with buckwheat flour or cracked wheat (Kan 2014). Buckwheat is a reliable food source for celiac patients. Buckwheat grains and products are recommended for gluten-intolerant individuals because they are gluten-free (Okudan and Kara 2015). Celiac disease is a small intestine disease that develops as a result of hypersensitivity to the subfraction of the gluten protein gliadin, which is found in cereals and cereal products, especially wheat and rye. Gluten-free foods are used because they make it difficult to absorb and digest nutrients from the small intestines. One of the agricultural products developed to prevent celiac disease is buckwheat. Due to the fact that buckwheat does not contain gluten, it has been increasingly consumed by people with celiac disease and gluten intolerance in recent years (Kılıç and Elmacı 2018). When the nutritional quality of gluten-free products is examined, it has been reported that they contain lower amounts of B1, B2, B3, folate, and iron compared to the wheatcontaining form, since most of these products are produced using refined flours and/or starches, and there is no nutritional fortification. Inadequate intake of fiber, iron, and calcium was reported in

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46%, 44%, and 31% of adult women with celiac disease who followed a gluten-free diet, respectively (Thompson et al. 2005). These and similar studies show that there is still a need for improvement in the nutritional quality of gluten-free products available on the market. Since epidemiological studies have shown that individuals who do not have to follow a gluten-free diet follow a healthy and balanced diet supplemented with nutritious ingredients play an important role in preventing many chronic diseases (De Caterina 2011), it is important to enrich food products with components such as buckwheat with high nutritional value.

1.7 AS AN ALTERNATIVE PLANT IN MIDDLE EASTERN AGRICULTURE In recent years, the demand for the use of alternative plants in agriculture has been increasing rapidly in the Middle East. In particular, the search for products with low water and nutrient consumption comes to the fore. With the decrease of water resources in the Central Anatolia Region and the barren lands, alternative plants such as buckwheat, which can alternate with the existing cereals, legumes, and other industrial plants, will make an important contribution to the agricultural development of the region. Due to the increase in demand for natural and herbal products in recent years, pharmaceuticals, food, and functional products whose raw materials are plants are increasing in Middle East and across the world (Kan 2011). Buckwheat is a food and pharmaceutical industry plant that will be used to meet the increasing demands in this context. Buckwheat is used as fodder in small and bovine breeding and egg-laying hens. In various studies, it has been stated that it can be added to the rations and one-third of the total mixture can be added (Yavuz 2014). Buckwheat is used in erosion control on sloping lands, in the cosmetic industry, green manure, the paint industry, and in the production of products such as vinegar, tea, and spirit (Dizlek et al. 2009). Buckwheat is used as a nectar source in honey production (Erekul et al. 2016). Buckwheat appears in different cultures for example, buckwheat noodles (soba-sobakiri, Japan); porridge (porridge, America); boiled, steamed, or oven-cooked grains (kasha-groat, Russia, Europe, America); a kind of dessert (crumpet, Netherlands); cold noodle soup (naengmyeon, Korea); and pasta (pizzoccheri, Italy). It is also used in different local products (Dizlek et al. 2009). It is thought that the flowers of the buckwheat plant are rich in nectar and have a long flowering period (40–50 days) during the vegetation period, so it will contribute to the development of beekeeping in highland conditions (Kan 2014). Because of the economic and nutritional physiology of the buckwheat plant, it is expected that the cultivation areas will increase in the future. As a result of efficient and high-quality production of buckwheat in the Middle East, it will bring along industrial investments based on buckwheat plants. The nutritional value of the buckwheat plant is extremely high. Buckwheat is an important food raw component of high quality, containing high levels of protein, dietary fiber, vitamins, mineral substances, basic polyunsaturated fatty acids, and antioxidants such as rutin and quercetin, and has a very important potential for the functional food industry (Acar et al. 2011).

1.8

NUTRITIONAL COMPOSITION

Buckwheat is regarded as a nutritionally beneficial food due to its high protein, fat, dietary fiber, and mineral content, as well as other health-promoting components. As a result, it is becoming increasingly popular as a potential functional food. Buckwheat has a higher amino acid composition and nutritional value than other grains, and it is also one of the protein sources with a high biological value (Zhang et al. 2012; Wronkowska et al. 2010). Buckwheat also includes minerals as zinc, copper, manganese, selenium, potassium, sodium, calcium, and magnesium, as well as vitamins B1, B2, B3, and B6, flavonoids, polyphenols, inositol, organic acid, and a high dietary fiber content (Wronkowska et al. 2010). The compound of buckwheat, which are common and Tartary, is shown in Table 1.1 (Wijngaard and Arendt 2006).

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TABLE 1.1 General Composition of Common and Tartary Buckwheat Groats and Sprouts   Compounds

Level (%) Common Buckwheat

Tartary Buckwheat

Groats (Dry Matter) Starch Soluble carbohydratesa Dietary fiber Protein Lipids Ash Other compoundsb

54.50 1.60 7.0 12.30 3.80 2.0 18.40

57.40 1.78 10.60 13.15 3.84 2.70 10.53

Sprouts (Fresh Weight) Water Dietary fiber Protein Lipids Ash

92.80 0.70 0.17 0.38 0.68

92.34 0.73 0.14 0.14 0.49

a

Including sucrose and fagopyritols. Organic acids, phenolic compounds, tannins, phosphorylated sugars, nucleotides and nucleic acids, and unknown compounds. b

1.9 BIOACTIVE COMPONENTS AND EFFECTS ON HEALTH Buckwheat has higher values in terms of phenolic component content and antioxidant activity compared to many cereals. It has been reported that antioxidant activity and total polyphenol and rutin concentrations increase with sprouting of common buckwheat seeds. Buckwheat has gained worldwide importance because of its important bioactive components, such as rutin, orientin, vitexin, quercetin, isovitexin, and isoorientin, besides other essential components like fagopyritols. These bioactive and phenolic components play important role for glycemic control in type 2 diabetics, positive cardiovascular effects, treatment of celiac disease, prevention of gallstones, and several hormone-dependent tumors (Verardo et al. 2018). Buckwheat is known as a major dietary source for rutin, which is missing from other grains and pseudocereals. Currently, various products of buckwheat like bread, biscuits, cookies, muffins, cakes, pasta, noodles, crackers, chips, and various fermented products and desserts are available in the market. Buckwheat has attracted worldwide attention, especially from food scientists, for its healing effects on chronic diseases (Kılıç and Elmacı 2018).

1.10

ANTIOXIDANT EFFECT

The scientific community’s acknowledgment of buckwheat’s nutritional and functional features has served as a direction for future investigations on its antioxidant effects. According to Zieliński and Kozłowska (2000), the antioxidant capacity of various cereals increases from rye, oats, and barley to buckwheat. The antioxidant capacity of blood plasma samples collected from healthy persons with intake of 1.5 g buckwheat per kilogram has been evaluated. Orientin, isoorientin, vitexin, isovitexin, rutin, and quercetrin are among the flavonoids found in buckwheat sprouts. Buckwheat’s antioxidant potential is enhanced by its high flavonoid concentration (Lee et al. 2016). Buckwheat performs key antioxidant functions such as reducing power, free radical scavenging, superoxide

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anion clearance, and iron ion binding. Flavonoids and large quantities of polyphenolic chemicals were also found in sprouted buckwheat. Buckwheat is believed to have favorable benefits on human health because of its high flavonoid and polyphenol content (Sytar 2015).

1.11

HYPOCHOLESTEROLEMIC EFFECT

Buckwheat is increasingly being used as a cholesterol-lowering functional food. Increased cholesterol consumption can lead to an increase in oxidative stress and plasma cholesterol levels. By increasing the regulation of LDL and oxide LDL, this potential rise may lead to the development of chronic disorders like atherosclerosis (Berger et al. 2015). The effects of buckwheat protein in mice with hypercholesterolemia were investigated in a research. Buckwheat reduced protein plasma cholesterol levels more than other grains, reduced sterols absorbed from the intestines, increased the amount of sterol removed from the body, and helped to regulate the activity of liver cells responsible for high cholesterol levels, according to the findings of the study (Zhang et al. 2017). A parallel research investigated the effect of buckwheat (Tartary) on sterol carriers in cholesterol absorption and protein genetic expression. The study’s findings revealed that buckwheat lowers plasma total cholesterol, non-HDL lipoproteins, and hepatic cholesterol concentrations. Buckwheat is regarded as a hypocholesterolemic food because to its ability to reduce cholesterol absorption in the gut (Yang et al. 2014).

1.12 HYPOTENSIVE EFFECT Buckwheat, which is a functional nutrient owing to its high rutin and quercetin concentration and is used to make some functional foods, is hypothesized to have an antihypertensive impact through modulating the renin-angiotensin system due to its high polyphenol content. Furthermore, buckwheat sprout contains more phenolics and has higher antioxidant activity than other grains (Merendino et al. 2014; Martín et al. 2017). A study was conducted to examine the immunoreactive effects of buckwheat on systolic blood pressure and aortic endothelial cells in rats after 5 weeks of intake. Buckwheat consumption reduced systolic blood pressure and oxidative stress by lowering immunoreactivity in aortic endothelial cells, according to the findings of the study (Kim et  al. 2009). In another research with hypertensive rats indicated that rats feeding buckwheat sprouts had higher amounts of endogenous vasodilators such bradykinin and nitric oxide, lower blood pressure, and a higher antioxidant capacity than rats consuming other cereals (Merendino et al. 2014).

1.13

HYPOGLYCEMIC EFFECT

The discovery of buckwheat’s therapeutic characteristics for decreasing hypertension and hypercholesterolemia has focused attention to the benefits of buckwheat on diabetes (Hosaka et al. 2011). Diabetes is a chronic condition characterized by insufficient insulin production or a rise in plasma glucose levels, resulting in inefficient insulin action. The consumption of carbohydrate-containing meals based on the glycemic index for diabetes control and therapy has a beneficial impact on the disease (Ortiz et al. 2014). Skrabanja et al. (2001) analyzed ten healthy persons who consumed boiled buckwheat groats, 50% buckwheat flour–enhanced bread, and white bread. As a consequence of the study, volunteers who consumed buckwheat products, particularly buckwheat groats, had lower postprandial plasma glucose and insulin production than those who received white wheat bread. Su-Que et  al. (2013) recruited ten diabetics at random and reported that those who consumed buckwheat bread had a 51% lower plasma glucose level 2 hours later than those who consumed white bread. Due to anti-nutritional components such as polyphenols and enzyme inhibitors, buckwheat digestion may be more difficult than wheat and legumes. The delay in digesting improves in blood glucose control.

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1.14 NEUROPROTECTIVE EFFECT Alzheimer’s disease is related to impairments in cognitive and mental abilities. The aggregation of amyloid beta peptides, the production of reactive oxygen species (ROS), and the activation of inflammatory mediators such as nitric oxide, prostaglandin E2, interleukins, and TNF-α are all major neuropathological signs of Alzheimer’s disease (Koppel and Greenwald 2014). In an in vitro study, it was shown that ethyl acetate and ethanol extracts of buckwheat root and seed had inhibitory effects on the development of neurological diseases by reacting as antioxidants and inhibiting acetylcholinesterase, butylcholinesterase, and tyrosinase enzymes (Gülpinar et  al. 2012). Buckwheat has been demonstrated to have inhibitory effects on neurological disorders in recent studies, however the relevant components for this effect have not been thoroughly explored (Choi et al. 2013). In this regard, more research is required.

1.15

ANTIFUNGAL EFFECT

Plant-derived phenolic and lipophilic substances, such as cereals and pseudocereals, have antifungal activity due to their antioxidant and hydrophobic qualities. Penicillium, Aspergillus, Fusarium, and Eurotium are the most prevalent fungi identified in cereal and pseudocereal commodities (Pleadin et al. 2019). Mycotoxin generation has been associated to oxidative stress and exposure to ROS, and buckwheat antioxidants are thought to be potential ROS scavengers (Masisi et al. 2016). Rutin, quercetin, and kaempferol, among flavonoids, have been shown to inhibit mycotoxin synthesis in Aspergillus and Penicillium species. Chitarrini et al. (2014), examined the anti-mycotoxin impact of rutin in vivo and proposed that a Tartary buckwheat rich in antioxidants was more resistant to Aspergillus flavus contamination. Furthermore, the metabolic conversion of rutin to quercetin was observed, as well as a higher antifungal efficiency of quercetin. Also, kaempferol was reported to be an effective inhibitor of A. flavus aflatoxin B1 production (Garcia et al. 2013). Furthermore, quercetin has been shown to inhibit patulin synthesis in Penicillium expansum and trichothecene biosynthesis in Fusarium culmorum (Schöneberg et al. 2018). Phenolics have been shown to interact with cell membranes. These interactions may result in ion leakage and the inhibition of fungal growth (Phan et al. 2014). As a result, buckwheat phytochemicals with antioxidant activity could be able to regulate and reduce mycotoxin synthesis. Mycotoxins are a type of harmful secondary metabolites that can have severe health consequences, and one of the most critical problems is eliminating mycotoxin contamination of cereal-based products.

1.16 TOXICITY AND CAUTIONARY NOTES Food allergies are a critical health problem, and their prevalence is rising across the world. Food allergy is defined as “an unfavorable reaction to food in which immunologic mechanisms have been demonstrated” (Renz et al. 2018). Allergic reactions to causative food components can be developed by ingestion, inhalation, or skin contact in individuals. Allergic symptoms are primarily caused by immunoglobulin E–binding proteins known as allergens or allergen components. Buckwheat allergy causes severe and life-threatening symptoms when even a small amount of common buckwheat flour or buckwheat-containing food products are consumed or inhaled (Satoh et al. 2020). The first case of severe allergy to ordinary buckwheat was documented in 1909 (Smith 1909). Buckwheat is also used in animal feed to provide nutrients, and its husk is used as bedding material to add comfort to the animal breeding places. However, buckwheat allergy in horses has recently been observed (Einhorn et al. 2018). Several buckwheat allergens, particularly seed storage proteins, have already been identified (Cho et al. 2015), and some of them have been reported in databases (Table 1.2). In Japan, Korea, and buckwheat-consuming parts of China, the prevalence of buckwheat allergy is estimated to be 0.1%–0.4% of the population. Buckwheat allergy has been verified in 2%–7% of individuals at allergy centers across the world. In Japan and Korea, school

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TABLE 1.2 Known Buckwheat Allergens Name

Protein Family/Characteristics

Fag e 1 Fag e 2 Fag e 3 Fag e 4 Fag e 5 Fag e 10 Fag e TI

13S globulin 2S albumin 7S globulin/vicilin Antimicrobial peptide Vicilin-like protein α-amylase inhibitor/trypsin inhibitor Trypsin inhibitor

MW (kDa) 22 17 19 4 55 16 9

studies showed 4 and 60 instances of buckwheat-related anaphylaxis per 100,000 students, respectively. According to Norbäck and Wieslander (2021), the incidence of severe allergic reactions to buckwheat, including anaphylaxis, is estimated to be 0.1–0.01 cases per 100,000 person-years.

1.17

SUMMARY POINTS

• This chapter focuses on buckwheat in diets of the Middle East and its important effects on health. • Buckwheat (Fagopyrum esculentum Moench and Fagopyrum tataricum (L.) Gaertn.) is believed to have originated in central Asia. • Buckwheat is a pseudocereal containing high protein, important antioxidants, and phenolic compounds. • Buckwheat is an important alternative food with high nutritional value suitable for the diet of celiac patients because it does not contain gluten. • Buckwheat has gained worldwide importance because of the presence of some important bioactive constituents such as rutin, orientin, vitexin, quercetin, isovitexin, and isoorientin. • Various products of buckwheat like flour, bread, biscuits, cookies, muffins, cakes, pasta, noodles, crackers, chips, and various fermented products and desserts are available in the market. • Buckwheat has attracted worldwide attention, especially from food scientists, for its healing effects on chronic diseases.

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Dietary Patterns in the Middle East and Fatty Liver Disease Makan Pourmasoumi, Farahnaz Joukar and Fariborz Mansour-Ghanaei

CONTENTS 2.1 Background ............................................................................................................................. 15 2.2 Different Dietary Patterns in the Middle East ........................................................................ 17 2.3 Role of Unhealthy Dietary Patterns in NAFLD ..................................................................... 17 2.4 Role of Healthy Dietary Patterns in NAFLD ......................................................................... 19 2.5 Role of Traditional Dietary Patterns in NAFLD .................................................................... 19 2.6 Role of Mediterranean Dietary Pattern in NAFLD ................................................................ 21 2.7 Other Diets in the Middle East ............................................................................................... 22 2.8 Conclusion ............................................................................................................................... 22 2.9 Summary Points ...................................................................................................................... 23 References ........................................................................................................................................23

LIST OF ABBREVIATIONS NAFLD NASH PUFA SSB

2.1

non-alcoholic fatty liver non-alcoholic steatohepatitis polyunsaturated fatty acid sugar-sweetened beverage

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic hepatic disorders worldwide and is the second cause of liver transplantation (Sanai et al. 2020). It is defined by excessive fat accumulation in hepatocytes, with a broad manifestation spectrum ranging from asymptomatic steatosis to hepatic cirrhosis and hepatocarcinoma (Bellentani et al. 2010). If NAFLD is not early diagnosed and treated, it will progress to a severe condition called nonalcoholic steatohepatitis (NASH), resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma (Lupsor-Platon et al. 2021). The global prevalence of NAFLD ranges from 6% to 35% (Sayiner et al. 2016; Bellentani 2017), which is predicted to increase in the following years (Estes et al. 2018). The prevalence is also substantial in Middle Eastern countries (Hashem et al. 2021), with Oman experiencing the most marked increase in the rate of NAFLD patients (Ge et al. 2020). It also imposes a drastic economic burden on both patients and healthcare systems (Golabi et al. 2021). This indicates that NAFLD is becoming an alarming public health concern that needs to be urgently addressed. Non-alcoholic fatty liver disease is diagnosed by the presence of hepatic steatosis, which can be recognized by either histology or imaging, in the absence of secondary causes such as hepatitis, autoimmune liver diseases, hereditary disorders, hepatotoxic medications, and excessive alcohol consumption more than 30 g/day in men and 20 g/day in women (Chalasani et al. 2018). Several risk factors are suggested for NAFLD, such as age, gender, genetics, ethnicity, and lifestyle. In addition, DOI: 10.1201/9781003243472-3

15

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FIGURE 2.1

Ancient and Traditional Foods Used in the Middle East

An overview of the definition, prevalence, and risk factors of non-alcoholic fatty liver disease.

obesity, type 2 diabetes, and metabolic syndrome are strongly correlated with NAFLD risk (Huang et al. 2021). Some researchers consider NAFLD the hepatic manifestation of metabolic syndrome since insulin resistance is the primary pathologic mechanism proposed for NAFLD (Vanni et al. 2010). Diet can be a cause of the disease pathogenesis among all risk factors contributing to a fatty liver. On the other hand, a common agreement is that dietary modification and enhancing physical activity can be the first steps toward and the cornerstone of NAFLD treatment (Anania et al.

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2018). While high-fat meals, fast food, sweet drinks, and refined grains are claimed to be strongly associated with NAFLD risk, a low-carbohydrate diet, whole grains, vegetables, and fruits are suggested to be inversely related to the odds of the disease (Asrih and Jornayvaz 2014). Nutritionists and healthcare practitioners frequently advise weight-loss diets, energy intake decrease, and healthy food consumption to alleviate liver dysfunction. However, exploring whether different dietary patterns are associated with NAFLD risk is still an exciting area of study. Enhancing the knowledge of dietary patterns that can address all human nutritional requirements is a priority to establish nutritional guidelines for treating diseases. However, peoples’ usual diets can vary across countries based on their culture, religion, and accessibility of foods, which necessitates dietary assessment in all regions. Accumulating data have been reported on nutrition and its effect on NAFLD (Zhao et al. 2021). Given that foods are consumed together as a meal and they interact (i.e., have synergic or antagonistic effects on each other), diets as a whole can give us a better insight into nutritional approaches to the prevention and treatment of NAFLD (Calle and Andersen 2019). This chapter reviews the available evidence on major dietary patterns and typical diets among people in Middle Eastern countries and their association with the risk of NAFLD. Since most people living in the Middle East are Muslim and alcoholic drinks are banned in this religion, alcoholic fatty liver disease is not prevalent; therefore, we only focused on NAFLD in this chapter.

2.2

DIFFERENT DIETARY PATTERNS IN THE MIDDLE EAST

Dietary choices and habits have changed over time, and Middle Eastern countries are no exception (Ronto et al. 2018). Urbanization, a sedentary lifestyle, and an increased desire to consume processed food products can be the main reasons for nutritional transitions, leading to health consequences. The greater adherence to an unhealthy diet, the greater the rate of chronic diseases such as obesity and NAFLD. To address this issue, assessing the dietary pattern followed by people is the primary strategy. Researchers and scientists estimate the diets via posterior and priory methodology approaches (Kastorini et al. 2013) to explore the possible correlation between the diet and NAFLD risk. According to what has been reported, the primary dietary patterns people follow in the Middle East can be categorized as unhealthy, healthy, and traditional diets, as well as the Mediterranean diet, which is popular in some parts of this area. The information about these diets relating to NAFLD In Middle Eastern communities is detailed below.

2.3

ROLE OF UNHEALTHY DIETARY PATTERNS IN NAFLD

A prevalent dietary pattern in Middle Eastern countries is an unhealthy diet, the so-called Western diet consisting of fast food, high-fat dairy, and red and processed meats (Carrera-Bastos et al. 2011; Cordain et al. 2005). Although the Western diet could be considered an emerging diet in this area, its adverse effects on health are undeniable (Azzam 2021). It is not surprising that many studies have indicated the direct correlations of this diet with type 2 diabetes, obesity, and metabolic syndrome as the main risk factors of NAFLD (Takemoto et al. 2010). It was also true for the studies that directly assessed the relationship between the diet and NAFLD. Accumulating documents indicate that there is a direct association between Western dietary patterns and the risk of NAFLD (Ghaemi et al. 2018; Salehi-Sahlabadi et al. 2021), such that following the Western diet is positively correlated with greater levels of alanine aminotransferase, triglyceride, fasting blood sugar, and malondialdehyde (Moradi et al. 2022). In addition, patients with NAFLD with higher adherence to a Western diet are four times more likely to be affected by liver fibrosis (Soleimani et al. 2019). Therefore, nearly all evidence consistently indicates that Western dietary patterns, directly or indirectly, could increase the risk of NAFLD in the Middle Eastern population.

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The possible mechanism for this association might be explained by the high amount of saturated fats and refined carbohydrates in the absence of sufficient vegetable and fruit consumption. Foods with high glycemic index and glycemic loads, such as soft drinks and refined grains, can contribute to insulin resistance, abdominal obesity, and increased hepatic de novo lipogenesis, which may consequently increase the risk of hepatic steatosis (Abid et al. 2009). What is more, meals and foods containing high saturated fat can also stimulate lipid-induced apoptosis, upregulate the pro-inflammatory cytokine expression, reduce insulin responses, and accelerate the progression of NAFLD to NASH (Leamy et al. 2013). Ultra-processed foods are also a component of the Western dietary pattern that is blamed for a negative impact on NAFLD as well (Zhang et al. 2022).

FIGURE 2.2 An unhealthy dietary pattern, its food components, and the mechanism by which it increases the risk of non-alcoholic fatty liver disease.

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2.4 ROLE OF HEALTHY DIETARY PATTERNS IN NAFLD A healthy diet with high consumption of vegetables, fruits, nuts, fish, low-fat dairy products, and poultry is considered a preventive approach to chronic conditions. Besides, a higher adherence to a healthy dietary pattern is related to lower odds of NAFLD (Moradi et al. 2022; Salehi-Sahlabadi et al. 2021), which might be mediated by waist circumference (Ghaemi et al. 2018). It is also correlated with a decreased level of glycemic markers, lipid profile, and total antioxidant capacity (Moradi et al. 2022). Moreover, not only does evidence imply the protective effect of a healthy diet on the odds of NAFLD, but also it shows a positive relationship between this diet and the diseases known as the NAFLD risk factors (Esmaillzadeh and Azadbakht 2008; Aljefree and Ahmed 2015). In addition, a healthy diet is inversely correlated with the risk of fibrosis among NAFLD patients (Soleimani et al. 2019), which indicates the importance of healthy adherence among both patients and at-risk individuals. General belief on the beneficial effect of a healthy diet is about its low energy density, which is true to some extent. However, a healthy diet can have preventive effects on NAFLD through high antioxidant and anti-inflammatory capacity as well. The high polyphenol content of vegetables and fruits can improve insulin resistance by increasing β cell functions, improving insulin signaling and secretion, preventing hepatic gluconeogenesis, and delaying carbohydrate digestion and intestinal glucose absorption (Salomone et al. 2020). Functional oligosaccharides, known as prebiotics, improve gut flora composition by facilitating the proliferation of probiotic bacteria and inhibiting pathogenic bacteria growth. Probiotic bacteria, then, enhance intestinal barrier function and the immune system and manage glucolipid metabolism (Bai et al. 2018). The indigestible fiber is also fermented by gut microbiota, and short-chain fatty acids are produced by the bacteria activity in the lower gastrointestinal tract, which can positively impact controlling metabolism (Ji et al. 2020). Moreover, the omega-3 polyunsaturated fatty acid (PUFA), which is plentiful in fish and nuts, can mitigate hepatic inflammation, decrease endotoxin content, and modulate fatty acid metabolism by suppressing de novo fatty acid synthesis and upregulating the hepatic fatty acid β-oxidation (Ji et al. 2020). These represent the main potential preventive effect of a healthy dietary approach toward preventing or treating NAFLD.

2.5

ROLE OF TRADITIONAL DIETARY PATTERNS IN NAFLD

A traditional dietary pattern may vary based on the region/country or the common foods consumed in that country. For example, the traditional Iranian dietary pattern includes a high intake of refined grains, potatoes, whole grains, tea, hydrogenated fats, legumes, and broth (Esmaillzadeh et al. 2007), whereas the traditional diets in the countries near the Mediterranean basin would be similar to the Mediterranean diet. The traditional diet of Jordan is the same as a healthy dietary pattern, with a high to moderate intake of vegetables and fruits (Ismail et al. 2013); however, due to industrialization, the common Jordanian diet has changed to be similar to a Western diet (Musaiger 2002). In general, traditional dietary patterns have a complex nature in some Middle Eastern countries, including both healthy and unhealthy foods. That might be the reason for the insignificant association between Iranian and Iraqi dietary patterns and NAFLD risk (Al Khalidi et al. 2021; Salehi-Sahlabadi et al. 2021). The essential characteristic of traditional Iranian dietary patterns is the consumption of grains, particularly refined grains. Indeed, white rice and bread are the main staple foods of the Iranians (Bahreynian and Esmaillzadeh 2012). It was reported that total carbohydrate intake is positively related to NAFLD prevalence in the Iranian population (Mosallaei et al. 2015). While a high-carbohydrate diet is considered the leading cause of NAFLD (Thuy et al. 2008), the evidence favors the low-carbohydrate diet since it significantly reduces hepatic lipid content in NAFLD patients (Haghighatdoost et al. 2016). In fact, refined carbohydrates via postprandial hyperglycemia could worsen impaired glucose tolerance and insulin response (Agius 2013). Another source of carbohydrates with an approved impact on NAFLD is sugar-sweetened beverages (SSBs),

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FIGURE 2.3 A healthy dietary pattern, its ingredients, and protective mechanism against non-alcoholic fatty liver disease.

the consumption of which has increased significantly in recent years worldwide. The intake of SSBs with high fructose content is proven to be correlated with hepatic disorders (Maersk et al. 2012). Excessive fructose consumption could stimulate lipogenesis, oxidative stress, and hepatic inflammation (Basaranoglu et al. 2015). It is also linked with a higher risk of metabolic syndrome features, insulin resistance, and hyperlipidemia, which may in turn trigger NAFLD (Basaranoglu et al. 2015). In contrast to refined grains, whole grains contain higher fiber, antioxidants, and phytoestrogens than refined carbohydrates. As a source of vitamins, minerals, phytochemicals, and soluble fibers, whole grains can improve glucose and insulin homeostasis, lipid profile, and weight status, followed by decreased risk of hepatic disorders (Esmaillzadeh and Azadbakht 2012).

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Another traditional dietary pattern in the Middle East is the traditional Lebanese dietary pattern containing vegetables, legumes, seeds, and olive oil. The traditional Lebanese pattern exerts protective effects on NAFLD, which may be due to the high content of antioxidants in this pattern (Fakhoury-Sayegh et al. 2017). Tea is the most popular beverage in most Middle Eastern countries. Due to the high source of catechin and polyphenol ingredients, tea is a food item that can prevent NAFLD (Masterjohn and Bruno 2012). Condiments, such as curcumin, cinnamon, ginger, cardamom, and black pepper, are the other food components widely used in Middle Eastern countries, with protective effects on the liver via antioxidant and anti-inflammatory function (Al Khalidi et al. 2021). Given the complex nature of traditional diets, including healthy and unhealthy foods, and the different effects of traditional patterns on NAFLD, it is paramount to choose healthier foods to improve health outcomes.

2.6

ROLE OF MEDITERRANEAN DIETARY PATTERN IN NAFLD

The Mediterranean diet is one of the healthiest eating patterns people traditionally followed in the countries located in the Mediterranean basin during the 1950s and 1960s (Rishor-Olney and Hinson 2021). This diet is defined as a high amount of olive and olive oil, red wine, fruits, vegetables, nuts, legumes, fish, and seafood. It is also limited in red meat, mainly processed meat, and moderate in dairy products (De Pergola and D’Alessandro 2018). Being enriched in nutrients and sufficient in calories and consisting of various functional foods makes it one of the healthiest diets with a wide range of health benefits. That is why the Mediterranean diet is recommended as a practical approach to NAFLD treatment (Aller et al. 2018). Generally, the Mediterranean diet is relatively similar to the content of the healthy dietary pattern described earlier. However, there are some differences in food components and their consumption. For example, olive oil consumption as the primary source of dietary lipids and the moderate intake of red wine and dairy products is an inevitable part of the Mediterranean diet but is not exactly true for the healthy dietary pattern (García-Fernández et al. 2014).

FIGURE 2.4 Mediterranean food pyramid.

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The beneficial association between adherence to the Mediterranean diet and NAFLD risk has been documented in Middle Eastern countries. A large cross-sectional study conducted on 3220 adults in the north of Iran showed that greater adherence to the Mediterranean diet was indirectly correlated to the disease, which was true for patients with and without abdominal obesity (Doustmohammadian et al. 2022). Likewise, the impact of the Mediterranean diet on liver enzymes among type 2 diabetic patients was also reported (Fraser et al. 2008). Also, it has been indicated that adherence to the Mediterranean diet is greater among healthy children than among those with NAFLD (Cakir et al. 2016). Like a healthy diet, the Mediterranean diet can have protective effects on NAFLD attributed to improving insulin resistance, mitigating inflammation, and reducing weight through its active components (Plaz Torres et al. 2019). This diet contains foods that are an essential source of polyphenols and flavonoids, such as garlic, olives, and spices, enhancing total antioxidant capacity and reducing pro-inflammatory factors (Ortega 2006).

2.7 OTHER DIETS IN THE MIDDLE EAST There are also some diets like the vegetarian diet, which is followed by a small group of people, or the fasting diet, which is followed during a special month or time as part of a religious ceremony. Both of them were shown to be beneficial in the treatment of NAFLD. For instance, adherence to a lacto-ovo-vegetarian diet for 3 months resulted in a more pronounced effect on NAFLD management than a standard weight-loss diet among Iranian adults (Garousi et al. 2021). In addition, during the month of Ramadan, fasting involves avoiding eating and drinking from sunrise until sunset. Documents support the beneficial effect of fasting on NAFLD by improving insulin resistance and fasting glucose levels, decreasing body weight, and mitigating inflammation (Aliasghari et al. 2017). The pros of fasting are suggested to be due to the metabolic shifting of metabolic energy source preferences from glucose to fatty acid–derived ketones, which takes place 12 hours after food consumption and depletion of hepatic glycogen store; as a consequence, the rate of lipolysis raises to make fatty acids (Pugliese et al. 2022). However, it is noteworthy that food choice plays an essential role in the optimum effect of fasting on NAFLD. If consuming a high amount of simple carbohydrate-rich foods such as sweets is the first choice during the non-fasting time, fasting will result in nothing but worsened NAFLD risk factors. In this case, having a balanced diet emphasizing sufficient intake of water and nutrient-enriched foods, including vegetables and fruits, is vital to reach a favorable result. Furthermore, people with NAFLD and other metabolic disorders must consider a fasting diet with caution since its detrimental effects could easily outweigh the benefits it offers. For instance, NAFLD patients with type 2 diabetes are vulnerable to hypoglycemia during fasting periods; therefore, they must check their blood glucose multiple times and be under the supervision of an endocrinologist.

2.8

CONCLUSION

Diet can be a critical factor in the onset, progression, and treatment of NAFLD, and its modification is the best approach to NAFLD management. Nutritional policies can substantially help mitigate the increasing rate of NAFLD and its risk factors, which have already reached an alarming height. Enhancing people’s awareness of the advantages of healthy dietary patterns and the negative consequences of the Western diet could hopefully change the trend of NAFLD prevalence in Middle Eastern countries. Even episodic follow-up or partial adherence to a healthy diet could have substantial effects on public health. However, finding a healthy dietary pattern that is tailored to fit people of a specific region with long-lasting compliance needs to consider people’s culture and preferences and the availability and cost of foods. Given that a paucity of information is available, further investigations, particularly prospective population-based cohort studies and long-duration randomized clinical trials from this geographical area, may help make an evidence-based conclusion and address this issue.

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2.9 SUMMARY POINTS • This chapter focuses on dietary patterns and NAFLD in Middle Eastern countries. • Adherence to the Western dietary pattern can be associated with an increased risk of NAFLD. • Following a healthy dietary pattern can inversely be related to NAFLD risk. • There is no association between traditional dietary patterns and the disease risk in some Middle Eastern countries due to the complex nature of the diet in this region. • The Mediterranean dietary pattern is traditionally the usual diet of some countries in the Middle East and is correlated with a lower risk of NAFLD. • The Mediterranean dietary pattern is one of the best dietary approaches to NAFLD management.

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Huang, Daniel Q, Hashem B El-Serag, and Rohit Loomba. 2021. “Global epidemiology of NAFLD-related HCC: Trends, predictions, risk factors and prevention.” Nature Reviews Gastroenterology & Hepatology 18 (4):223–238. Ismail, Said Ibrahim, Majd Soubani, Jena Monther Nimri, and Ali Hazem Al-Zeer. 2013. “Cancer incidence in Jordan from 1996 to 2009-a comprehensive study.” Asian Pacific Journal of Cancer Prevention 14 (6):3527–3534. Ji, Yun, Yue Yin, Lijun Sun, and Weizhen Zhang. 2020. “The molecular and mechanistic insights based on gutliver axis: Nutritional target for non-alcoholic fatty liver disease (NAFLD) improvement.” International Journal of Molecular Sciences 21 (9):3066. Kastorini, Christina-Maria, George Papadakis, Haralampos J Milionis, Kallirroi Kalantzi, Paolo-Emilio Puddu, Vassilios Nikolaou, Konstantinos N Vemmos, John A Goudevenos, and Demosthenes B Panagiotakos. 2013. “Comparative analysis of a-priori and a-posteriori dietary patterns using state-of-the-art classification algorithms: A case/case-control study.” Artificial Intelligence in Medicine 59 (3):175–183. Leamy, Alexandra K, Robert A Egnatchik, and Jamey D Young. 2013. “Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease.” Progress in Lipid Research 52 (1):165–174. Lupsor-Platon, Monica, Teodora Serban, Alexandra Iulia Silion, George Razvan Tirpe, Alexandru Tirpe, and Mira Florea. 2021. “Performance of ultrasound techniques and the potential of artificial intelligence in the evaluation of hepatocellular carcinoma and non-alcoholic fatty liver disease.” Cancers 13 (4):790. Maersk, M, A Belza, JJ Holst, M Fenger-Grøn, SB Pedersen, A Astrup, and B Richelsen. 2012. “Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: A controlled trial.” European Journal of Clinical Nutrition 66 (4):523–529. Masterjohn, Christopher, and Richard S Bruno. 2012. “Therapeutic potential of green tea in nonalcoholic fatty liver disease.” Nutrition Reviews 70 (1):41–56. Moradi, Fateme, Seyedeh Parisa Moosavian, Farhang Djafari, Azam Teimori, Zahra Faghih Imani, and Amirmansour Alavi Naeini. 2022. “The association between major dietary patterns with the risk of nonalcoholic fatty liver disease, oxidative stress and metabolic parameters: A case-control study.” Journal of Diabetes & Metabolic Disorders:1–11. Mosallaei, Zahra, Mohsen Mazidi, Mohammad Safariyan, Abdolreza Norouzy, Seyed Amir Reza Mohajeri, Habibollah Esmaily, Ali Bahari, Majid Ghayour-Mobarhan, and Mohsen Nematy. 2015. “Dietary intake and its relationship with non-alcoholic fatty liver disease (NAFLD).” Mediterranean Journal of Nutrition and Metabolism 8 (2):139–148. Musaiger, Abdulrahman O. 2002. “Diet and prevention of coronary heart disease in the Arab Middle East countries.” Medical Principles and Practice 11 (Suppl. 2):9–16. Ortega, RM. 2006. “Importance of functional foods in the Mediterranean diet.” Public Health Nutrition 9 (8A):1136–1140. Plaz Torres, Maria Corina, Alessio Aghemo, Ana Lleo, Giorgia Bodini, Manuele Furnari, Elisa Marabotto, Luca Miele, and Edoardo G Giannini. 2019. “Mediterranean diet and NAFLD: What we know and questions that still need to be answered.” Nutrients 11 (12):2971. Pugliese, Nicola, Maria Corina Plaz Torres, Salvatore Petta, Luca Valenti, Edoardo G Giannini, and Alessio Aghemo. 2022. “Is there an ‘ideal’ diet for patients with NAFLD?” European Journal of Clinical Investigation 52 (3):e13659. Rishor-Olney, Colton R, and Melissa R Hinson. 2021. “Mediterranean diet.” In StatPearls [Internet]. StatPearls Publishing. Ronto, Rimante, Jason HY Wu, and Gitanjali M Singh. 2018. “The global nutrition transition: Trends, disease burdens and policy interventions.” Public Health Nutrition 21 (12):2267–2270. Salehi-Sahlabadi, Ammar, Samaneh Sadat, Sara Beigrezaei, Makan Pourmasomi, Awat Feizi, Reza Ghiasvand, Amir Hadi, Cain CT Clark, and Maryam Miraghajani. 2021. “Dietary patterns and risk of non-alcoholic fatty liver disease.” BMC Gastroenterology 21 (1):1–12. Salomone, Federico, Dana Ivancovsky-Wajcman, Naomi Fliss-Isakov, Muriel Webb, Giuseppe Grosso, Justyna Godos, Fabio Galvano, Oren Shibolet, Revital Kariv, and Shira Zelber-Sagi. 2020. “Higher phenolic acid intake independently associates with lower prevalence of insulin resistance and non-alcoholic fatty liver disease.” JHEP Reports 2 (2):100069. Sanai, Faisal M, Faisal Abaalkhail, Fuad Hasan, Muhammad Hamed Farooqi, Nawal Al Nahdi, and Zobair M Younossi. 2020. “Management of nonalcoholic fatty liver disease in the Middle East.” World Journal of Gastroenterology 26 (25):3528.

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3

Fatty Acids in Different Foods of Middle Eastern Diets Implications for Health Ayoub Al-Jawaldeh and Lara Nasreddine

CONTENTS 3.1 3.2

Introduction ...........................................................................................................................28 Traditional Foods in the Middle East and Their Fatty Acid Profiles ...................................28 3.2.1 Olives and Olive Oil .................................................................................................28 3.2.2 Legumes and Nuts .................................................................................................... 29 3.2.3 Milk and Dairy Products .......................................................................................... 29 3.2.4 Fish and Meats .......................................................................................................... 30 3.3 Current Trends in Fatty Acid Intakes in the Middle East..................................................... 30 3.4 Saturated Fatty Acids ............................................................................................................ 31 3.5 Trans-Fatty Acids.................................................................................................................. 32 3.6 Toxicity and Cautionary Notes ............................................................................................. 36 3.7 Health Implications Related to the Shifts in Food Consumption Patterns ........................... 36 3.8 Policy Implications ............................................................................................................... 37 3.9 Conclusion............................................................................................................................. 37 3.10 Summary Points.................................................................................................................... 38 References........................................................................................................................................38

LIST OF ABBREVIATIONS CHD CVD EI FAOSTAT GCC HDL-C KSA LDL-C ME MUFAs NCDs PHO PUFAs SFA TFA UAE WHO

coronary heart disease cardiovascular disease energy intake Food and Agriculture Organization Corporate Statistical Database Gulf Cooperation Council high-density lipoprotein cholesterol Kingdom of Saudi Arabia low-density lipoprotein cholesterol Middle East(ern) monounsaturated fatty acids non-communicable diseases partially hydrogenated oils polyunsaturated fatty acids saturated fatty acids trans-fatty acids United Arab Emirates World Health Organization

DOI: 10.1201/9781003243472-4

27

28

Ancient and Traditional Foods Used in the Middle East

3.1 INTRODUCTION The Middle East (ME) region encompasses countries of various income categories, demographic profiles, and economic development levels. The relative unity of the region is principally cultural, driven by a long historical process of civilization exchange and the spreading of common cultural and religious patterns across countries (McKee et al. 2017). Traditional foods represent an essential component of this culture and the people’s habits, hospitality, and way of life (Savvaidis et al. 2022). The traditional ME diet has been typically characterized by the consumption of wheat, rice, chickpeas and other legumes, olives, pistachios, dates, dried and fresh fruits, vegetables, cheese, yogurt, lamb, and fish (Encyclopedia 2022). This diet has been described as a nutritionally balanced diet given its abundance in fresh fruits, vegetables, and unprocessed grains (Salari 2002). It was also reported to have a healthy fatty acid profile, being low in SFA and high in MUFAs and omega-3 PUFAs (Montagnese et al. 2019). It is well acknowledged that globalization, urbanization, and economic development in countries of the ME have been accompanied by the nutrition transition, with its characteristic shifts away from traditional diets, and toward westernized dietary patterns and eating habits (Sibai et al. 2010). As people in the ME have become more affluent and more exposed to foods from other cultures, local traditional foods have been increasingly sidelined, being progressively replaced by modern or novel food products that are typically higher in fat, especially SFA and TFA (Savvaidis et al. 2022). These shifts in dietary patterns have been paralleled by significant increases in the prevalence and burden of obesity and other non-communicable diseases (NCDs) such as type 2 diabetes and cardiovascular disease (CVD), which are increasingly crippling the economies of countries in the region (Sibai et al. 2010). Given the important role that dietary fats play in the modulation of NCD risk (Billingsley et al. 2018), the objective of this chapter is to shed light on the fatty acid profiles of foods typically consumed in the ME. More specifically, the first part of the chapter reviews the fatty acid profile of foods that once characterized the traditional diets in the ME, and the second part provides an overview of current trends in fatty acid intakes in countries of the region, and their health implications.

3.2

TRADITIONAL FOODS IN THE MIDDLE EAST AND THEIR FATTY ACID PROFILES

Diets in countries of the ME share many characteristics while also reflecting the individual countries’ geographic and historical profiles. Some countries of the ME border the Mediterranean Sea, hence their diets bear many similarities with the so-called Mediterranean diet that is rich in olive oil, fruits, vegetables, pulses, and fish (Naja et al. 2015). Diets in other Middle Eastern countries such as those of the Gulf Cooperation Council (GCC) have been traditionally influenced by trade with India, Iraq, the Mediterranean region, and Africa (Foundations of Restaurant Management and Culinary Arts 2017). Rice is in fact one of the pillars of traditional diets in the GCC countries, and numerous recipes use rice as their main ingredient, such as kabsa (rice mixed with meat, vegetables and spices), maqluba (rice mixed with meat and vegetables), and mandi (rice mixed with meat and saffron) (Foundations of Restaurant Management and Culinary Arts 2017). Traditional diets in Iran have been also influenced by the position of Iran on the ancient Silk Road (between China and modern Italy), resulting in a diet that builds on a mixture of vegetables, fermented dairy products, meat, vegetables, and herbs (Foundations of Restaurant Management and Culinary Arts 2017).

3.2.1

OLIVES AND OLIVE OIL

Olives and olive oil are traditional hallmarks of Middle Eastern diets, particularly those on the Mediterranean basin. Olive oil is typically consumed with salads, dips, cooked vegetables, stews, and fermented dairy products (Tuttolomondo et al. 2019). The majority of fat in olives and olive oil

Fatty Acids in Different Foods of Middle Eastern Diets

29

is in the form of MUFAs, and more specifically in the form of oleic acid (18:1, omega-9), which represent 75% of its fat content, while SFA represents 15% and PUFAs 10% (Berry et al. 2011). Studies have shown that, when replacing SFA, the consumption of MUFAs decreases the levels of serum low-density lipoprotein cholesterol (LDL-C) and its oxidation (Aviram and Eias 1993) and reduces the risk of developing atherosclerotic disease and CVDs (Schwingshackl and Hoffmann 2012). Although olives and olive oil would increase the fat content of the diet, MUFA consumption was shown to raise postprandial fat oxidation, diet-induced thermogenesis, and total energy expenditure (Soares et al. 2004), and hence may not contribute to body weight gain (Berry et al. 2011).

3.2.2

LEGUMES AND NUTS

Legumes are common ingredients of Middle Eastern dishes, such as hummus, foul moudammas, falafel, bean stews, and lentil soup (Clemente and Jimenez-Lopez 2020). Legumes are naturally low in fat and are commonly prepared with olive oil or tahini (a form of sesame paste), the latter being rich in PUFAs that exert cardioprotective effects (Sakketou et al. 2021). The consumption of nuts is also a characteristic of Middle Eastern diets, where nuts are consumed in their raw state with dried fruits or used to garnish meals (such as rice with chicken dishes), or incorporated in desserts (such as baklawah) (Montagnese et al. 2019). Nuts are naturally rich in unsaturated fats: most nuts enclose significant amounts of MUFAs, while walnuts are also rich in omega-6 and omega-3 PUFAs. The healthy fatty acid profile of nuts contributes to the beneficial effects attributed to frequent nut consumption, such as the prevention of diabetes, coronary heart disease (CHD), and sudden death (Ros and Mataix 2006). In short-term feeding trials, the consumption of nuts was associated with lower cholesterol levels, higher LDL-C resistance to oxidation, and improved endothelial function. In this respect, MUFAs in nuts may have an advantage over PUFAs, given that the enrichment of lipoprotein lipids with MUFAs increases their resistance to oxidation (Ros and Mataix 2006).

3.2.3

MILK AND DAIRY PRODUCTS

Milk (cow, goat, sheep, camel) and fermented dairy products such as labneh (i.e., strained yogurt), yogurt, white cheese, butterfat milk, and hard cheese are also considered traditional foods in the ME (Savvaidis et al. 2022). In a recent study, the composition of beneficial fatty acids such as oleic acid, linoleic acid, and stearic acid was investigated in fermented milk products in comparison with unfermented ones, and the percentage yield in fatty acid compounds was calculated (Balakrishnan and Agrawal 2014). The study showed that oleic acid exhibited the highest yield among all of the investigated fatty acids, while also showing that the yield of oleic acid in fermented camel milk was higher compared to that in fermented cow and goat milks, by 1.15 and 1.08 times, respectively (Balakrishnan and Agrawal 2014). Although linoleic and linolenic acids were present in minor amounts in fermented products, the presence of these fatty acids may contribute to the protection against CVDs and ischemic diseases (Sokoła-Wysoczańska et al. 2018). The levels of stearic acid (C18:0) were found to be 1.89, 1.58, and 1.82 times higher in fermented cow, goat, and camel milk, respectively, in comparison with their corresponding unfermented milk (Balakrishnan and Agrawal 2014). Available evidence suggests that, despite being a saturated fatty acid, stearic acid does not raise the levels of LDL-C and does not contribute to atherogenesis risk (Ebringer et al. 2008). The levels of lauric acid (C12:0) were found to be three times higher in fermented goat milk and more than 1.5 times higher in camel milk, in comparison with cow milk products (Balakrishnan and Agrawal 2014). Because of its shorter chain length and lower melting point, lauric acid is associated with lower rigidity in triglyceride and phospholipid molecules as compared to palmitic acid, and hence may exert different effects on hepatic cholesterol metabolism and blood lipid profiles (Eyres et al. 2016). Studies have shown that lauric acid was in fact associated with lower levels of LDL-C in comparison with other SFA (Eyres et al. 2016).

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3.2.4

FISH AND MEATS

Certain types of fish like hamour, tuna, grouper, barracuda, emperor, and pomfret (FAO 2011) constitute main ingredients in the preparation of seafood-based dishes in countries of the region (Savvaidis et al. 2022). Fish, and especially oily fish, represent an important source of omega-3 fatty acids in the diet, and hence may play a role in the prevention of heart diseases. A longitudinal cohort study where adult participants were followed for 18 years showed that the consumption of one or more portions per week of either fatty or lean fish was associated with a significant reduction in the incidence of ischemic stroke (Hengeveld et al. 2018). Meat (lamb, goat, camel meat) are also essential ingredients of traditional meat-based dishes in region (Savvaidis et al. 2022). Although meats are characteristically rich in SFA, their consumption level was traditionally low in comparison with modern diets (Golzarand et al. 2012). In addition, camel and goat meat have lower total fat and SFA content as compared to beef and lamb (Baba et al. 2021). For instance, the content of SFA in goat meat is of 0.71 g/100 g, compared to 11.8 g/100 g in beef. Camel meat, which is considered an ethnic food in the ME, has also a high content of PUFAs and a low level of cholesterol, which add to the health benefits of camel meat consumption within traditional diets.

3.3 CURRENT TRENDS IN FATTY ACID INTAKES IN THE MIDDLE EAST Traditional diets in countries of the ME are progressively eroding and being replaced by “modern” or westernized dietary habits and patterns. Diets have been shifting, during the past few decades, to diets that are increasing energy-dense, sweeter, and with higher amounts of total fat (Sibai et al. 2010). Analyses of FAOSTAT food supply data in countries of the region document a gradual rise in daily fat per capita over the past few decades. Fat supply has in fact approximately doubled in some countries such as Iran, Iraq, and Jordan, and available food consumption surveys documented a similar increasing trend in fat consumption (FAOSTAT). In the Kingdom of Saudi Arabia (KSA), for example, fat intake was found to contribute approximately 38% of daily energy intake (EI) in adults (Alissa et al. 2006). A study conducted in Egypt showed that around 20% of mothers and more than 30% of children had fat intakes that exceeded 30% of total EI (Hassan et al. 2006). In Lebanon, the intake of fat was reported to increase from 22% in 1965 up to levels ranging between 35 and 39% in 2002 (Nasreddine et al. 2006)

TABLE 3.1 Changes in Dietary Fat Supply (g per Capita per Day) in Selected Countries of the Middle East, Based on FAOSTAT Supply Data   Egypt Iran Iraq Jordan KSA Kuwait Lebanon Oman Syria

1969–1971 1979–1981 1995–1997 2002–2004 2005–2007 2010–2012 2013–2015 2016–2018 2019 46 36 39 51 32 68 67 – –

64 54 55 60 74 87 84 – –

56 67 69 76 76 105 104 73 –

58 67 50 94 84 117 110 71 –

59 70 56 94 84 122 109 74 –

62 73 74 89 99 114 102 84 114

58 78 71 91 108 109 94 80 104

58 78 71 91 106 108 91 79 100

59 79 66 97 106 111 91 79 97

Fatty Acids in Different Foods of Middle Eastern Diets

31

This rise in total fat intake may be explained by the increased availability and consumption of vegetable oils (e.g., sunflower, safflower, soybean, palm oil), meat and meat products, and fast and processed foods (Sibai et al. 2010). Of more concern is the shift in the fatty acid profile of diets in the ME, whereby the intakes of MUFAs and omega-3 fatty acids have decreased while that of SFA and TFA have increased (Afshin et al. 2015). For instance, studies describing current food consumption patterns in countries of the region have reported low levels of olive oil consumption (the main source of MUFAs) and fish (the main source of marine omega-3 fatty acids). In Lebanon, urban adults were reported to consume only 5 g of olive oil per day (i.e., 1 teaspoon) and to have a low consumption of fish (around 20 g/day on average). The study also showed that approximately 74% of subjects consumed less than the recommended two servings of fish per week and 65% less than one serving per week (Nasreddine et al. 2006). Afshin et al. (2015) have investigated dietary risk factors in countries of the ME. They showed that the intakes of marine omega-3 fatty acids were below the optimal level of 250 mg/day in all countries of the ME, the lowest being observed in Levantine countries including Syria, Palestine, and Lebanon (Afshin et al. 2015). This low intake of omega-3 fatty acids (10μM pSMAD2/3, boswellic acid SMAD4, derivatives TGF-β1, TGF-βR1/2, C57BL/6 mice in α-SMA. Increases vivo KLOTHO, SMAD7

References Zhang et al. 2016

Fung et al. 2013

Lin et al. 2013 Ni et al. 2012

Efferth and Oesch 2020; Hakkim et al. 2015 Suhail et al. 2011

Bini Araba et al. 2019 Avula et al. 2021

Suhail et al. 2011

Efferth and Oesch 2020; Liu et al. 2018

(Continued)

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TABLE 12.1 (Continued) Therapeutic Uses of Boswellia sacra Extracts, Essential Oils, and Isolated Compounds, Studies Screening Them, and Mechanisms (Where Known) Therapeutic Use

Preparation and Uses

Extracts and individual triterpene components

Oleoresin essential oil

Oleogum resin

Diabetes

Tested Against

Potency (μg/mL)

CD4+ cells

Not quantified

Indomethacininduced inflammation in rats Platelet lysates

Not quantified

Caco2 cells exposed Noteworthy effects to H2O2, INF and at 1 μg/mL. IC50 TNF-α values were not quantified. HMEC cells Not quantified

Oleoresin methanol extract

Analgesia in mice

Oleoresin essential oil

Human dermal skin cells

Oleoresin extracts BSA antiglycation

Bacterial infection Oleoresin essential oil

Not quantified

DPPH free radical scavenging Propionibacterium acne Staphylococcus aureus Staphylococcus epidermidis Staphylococcus hominis Pseudomonas aeruginosa

Mechanisms (Where Known)

References

Efferth and IL-1β triggered Oesch 2020; IL-17A release. Beghelli et al. Decreased 2017 IL-1β-mediated IRAK1 signaling, Decreased pSTAT3 Decreases LOX Efferth and Oesch 2020; Krieglstein et al. 2001 Efferth and Decreases LOX Oesch 2020; Safayhi et al. 2000 Increases GPx, decreases SOD, Governa et al. NF-KB, iNOS 2018

Decreases TNF-α, Efferth and Oesch 2020; carrageenan, Mbiantcha et al. NO, IL-1β, 2018 PGE2 Not quantified Loeser et al. Decreases acetic 2018; acid and formalin-induced Al-Harrasi et al. 2013 pain Substantial effects Reduced T-cell at 5 μg/mL. IC50 Aldahlawi et al. proliferation. 2020 Enhanced IL-10 not quantified secretion. 5%–55% inhibition Inhibits AGEs Al-Harrasi et al. at 1 mg/mL 2013 5%–33% inhibition Scavenges free at 1 mg/mL radicals MIC = 210–225 μg/ Not examined mL Di Stefano et al. 2020 MIC = 52–210 μg/ mL MIC = 52–420 μg/ mL MIC = 210–225 μg/ mL MIC = 52–210 μg/ mL

Frankincense (Boswellia sacra Flueck.) and Its Usage

161

TABLE 12.1 (Continued) Therapeutic Uses of Boswellia sacra Extracts, Essential Oils, and Isolated Compounds, Studies Screening Them, and Mechanisms (Where Known) Therapeutic Use

Preparation and Uses

Tested Against

Oleoresin extracts Acinetobacter baylyi Escherichia coli Enterococcus faecalis Klebsiella pneumoniae Proteus mirabilis Shigella sonnei Salmonella newport Staphylococcus aureus Pseudomonas aeruginosa Oleoresin Escherichia coli essential oil Enterococcus faecalis Klebsiella pneumoniae Pseudomonas aeruginosa Salmonella paratyphi Staphylococcus aureus Oleoresin Bacillus subtilis essential oil Micrococcus luteus Staphylococcus aureus Pseudomonas aeruginosa Escherichia coli Enterobacter aerogenes Escherichia coli Proteus vulgaris Fungal infections

Oleoresin essential oil

Aspergillus flavus Aspergillus parasiticus

Potency (μg/mL)

Mechanisms (Where Known)

MIC = 805 μg/mL

The extracts also potentiate the MIC = 1165 μg/mL antibacterial MIC = 1165 μg/mL activity of several conventional MIC = 625 μg/mL antibiotics against these MIC = 605 μg/mL MIC = 1348 μg/mL pathogens. MIC = 146 μg/mL MIC = 682 μg/mL

References Rashan et al. 2021; Zhang et al. 2016

MIC = 2250 μg/mL No MIC reported, only ZOIs

Not examined

Javed et al. 2015

MIC = 5 μL/mL MIC = 5 μL/mL MIC = 5 μL/mL

Not examined

Al-Saidi et al. 2012

MIC = 50–60 μL/ mL MIC = 30–40 μL/ mL MIC = 80 μL/mL MIC = 30–40 μL/ mL MIC = 20–70 μL/ mL 43%–96% Not examined inhibition of aflatoxin secretion at 2.5–10 g/100 mL

El-Nagerabi et al. 2013

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Ancient and Traditional Foods Used in the Middle East

12.3 ANTICANCER EFFECTS One of the most extensively studied therapeutic properties of Boswellia sacra oleoresin is its use in the prevention and treatment of some cancers and numerous studies have reported on its cytotoxicity toward a broad spectrum of solid carcinomas (including bladder, breast, cervix, fibrosarcoma, glioblastoma, liver, lung, meningioma pancreas prostate), as well as leukemias and myelomas in vitro and in vivo (Efferth and Oesch 2020). Essential oils prepared from Omani B. sacra oleoresin are potent potentiators of apoptosis in MDA-MB-231 human breast cancer cells, although the authors of that study did not examine the pro-apoptotic mechanism(s) (Hakkim et al. 2015). Further studies reported that local application of B. sacra essential oil was effective in the treatment of basal cell carcinoma (Fung et al. 2013) and invasive urothelial carcinoma (Xia et al. 2017). Ni et al. (2012) reported that B. sacra essential oil induces apoptosis in human pancreatic cancer via activation of caspase-dependent apoptosis and Akt and Erk1/2 pathways. The authors of that study also reported that the essential oil also had cytostatic effects via suppression of cyclin D1 cdk4 expression in cultured pancreatic cancer cells. Similarly, another study demonstrated that B. sacra essential oil activates caspase-3 dependent apoptosis in CD133+ and CD133− colorectal cancer cell lines and highlighted the involvement of the volatile terpenoid components (Becer et al. 2021). Furthermore, apoptosis was induced in three human breast cancer cell lines (T47D, MCF7 and MDA-MB-231) by B. sacra essential oil (Suhail et al. 2011). The authors of that study determined that the essential oil induced DNA fragmentation and modulated the levels of caspases-8 and 9, as well as activating caspase-3. Furthermore, the essential oil also downregulated the expression of cdk4, cyclin D1, pAkt, and pERK12. Therefore, the essential oil induces both cytotoxic and cytostatic pathways. B. sacra oleoresin extracts also have good anticancer activity against Caco2 human colorectal cancer and HeLa cervical cancer cell lines, with IC50 values down to 1500 μg/mL (Zhang et al. 2016). While the authors of that study did not examine the anticancer mechanisms, they did highlight multiple mono- and sesquiterpenoid components. Another study reported that B. sacra extracts have proapoptotic activities and inhibit proliferation of murine skin cancer (Huang et al. 2005). The anticancer properties of isolated components (especially boswellic acids, as well as mono- and sesquiterpenoids) have also been extensively reported and will be discussed separately later in this report.

12.4 ANTIBACTERIAL ACTIVITY There is considerable evidence that demonstrates the effectiveness of Boswellia sacra extracts, essential oils, and isolated phytochemicals in the inhibition the growth of many bacterial pathogens (Table 12.1). Early studies showed that aqueous B. sacra extracts produce moderate to strong inhibition of Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Salmonella typhi, Klebsiella pneumonia, Streptococcus pneumoniae, Enterobacter aerogenes, and Proteus vulgaris on agar media (Ismail et al. 2014). However, extracts were only screened at high concentrations, with microdilution broth assays revealing MIC values of 50–100 mg/mL for most of these strains, with other strains uninhibited by the extracts. Notably, most studies define noteworthy activity as 0.95 was reported at all concentrations indicating the ability of the previously mentioned extract to inhibit kidney stones formation (Kachkoul et al. 2018). Additionally, A. visnaga extract has modified the nucleation rate of calcium oxalate monohydrate (1.54 × 1029 nuclei/cm3 vs. 3.14 × 1029 nuclei/cm3) as well as the crystalline size (25 nm vs. 93 nm) (Abdel-Aal, Yassin, and El-Shahat 2016). Ability of A. visnaga seed extract (500 mg/kg) to treat oxalate nephrolithiasis was assessed on male Wistar rats following laboratory-induced kidney stones (Khan et al. 2001). The findings were reduction in calcium oxalate renal deposit after 4 weeks of oral treatment with a proposed mechanism of action via diuretic activity elicited by the seed extract (Khan et al. 2001). Calcium channel blocking effect was previously reported following treatment of depolarized guinea-pig aortic strips with A. visnaga fruit extract. The main constituent which proved to have the highest effect in this model was visnadin, compared to khellin and visnagin (Rauwald, Brehm, and Odenthal 1994). Khellin treatment stimulated cell proliferation in cultured normal human melanocytes and Mel-1 melanoma cells at the concentrations of 1 nmol/L and 0.5 mmol/L, whereas treating fibroblasts inhibited cellular proliferation at all investigated concentrations (Carlie et al. 2003). In pigmented cells, Khellin combined with solar irradiation (KUVA) therapy (0.01 mmol/L khellin with

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250 mJ cm−2 UVA) improved melanogenesis via stimulating melanogenic enzyme activity (Carlie et al. 2003). Antitumor activity of A. visnaga whole methanolic extract and isolated constituents (i.e., khellin and visnagin) was investigated using sulforhodamine B (SBR) assay deploying cervical carcinoma cell line (HeLa cells), liver carcinoma cell line (Hep-G2), colon carcinoma cells (HCT 116), and breast carcinoma cells (MCF7) (Beltagy and Beltagy 2015). The highest antitumor activity was encountered in Hep-G2 cells treated with visnagin with IC50 = 10.9 ± 0.68 μg/mL compared to 4.13 μg/mL in the positive control group treated with doxorubicin, while khellin had higher antitumor activity in MCF7 cells with IC50 = 13.3 ± 0.94 μg/mL compared to 3.68 μg/mL in the MCF7 doxorubicin treatment group (Beltagy and Beltagy 2015).

13.4.2

CLINICAL TRIALS

A case study report of a 50-year-old patient who was admitted to the hospital to perform surgery for resistant kidney stones coupled with hyperlipidemia, found that treatment with A. visnaga seeds twice daily for 10 days helped passing the kidney stones with symptom improvement (Bhagavathula et al. 2015). Additionally, high-density lipoprotein (HDL) level was elevated during the treatment period (32 to 56 mg/dL), which indicates a potential benefit of improving the lipid profile (Bhagavathula et al. 2015). Similarly, Harvengt and Desager reported a cholesterol-HDL elevation following 4 weeks of treatment with 50 mg of khellin three times daily (n = 20) (Harvengt and Desager 1983). However, side effects such as nausea and vomiting were reported (n = 4), as well as serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) elevation (n = 2) leading to treatment withdrawal (Harvengt and Desager 1983). A double-blind clinical trial to investigate the efficacy of a single oral dose of 100 mg khellin followed by 15-minute exposure to sunlight in treating psoriasis compared to placebo has demonstrated variable improvement in psoriasis condition (Abdel-Fattah et al. 1983). Eight patients out of ten who received the treatment showed variable responses, with three of them experiencing significant clearing of psoriatic lesions after 4 months of therapy (Abdel-Fattah et al. 1983). Description of clinical trials and investigations that were performed on A. visnaga and its constituents is summarized in Table 13.2.

13.5 OTHER FOODS, HERBS, SPICES, AND BOTANICALS USED IN THE MIDDLE EAST Many plants that are indigenous to the Middle East exhibit various pharmacological activities and are used in traditional medicine. For example, dates (Phoenix dactylifera), meswak (Salvadora persica), and figwort (Scrophularia striata) have antimicrobial properties (Varijakzhan et al. 2020). In addition, savory of Crete (Satureja thymbra) has been reported to have antiviral activity and is used traditionally to treat gastrointestinal disorders, such as indigestion and cramps (Varijakzhan et al. 2020). Moreover, plants with antifungal properties are also found in the Middle East, such as chicory (Cichorium intybus), which is a plant that originates from Iran. The aforementioned plants are also rich in phytochemicals with antioxidant properties and also have antitumor properties (Varijakzhan et al. 2020). Cactus (Opuntia ficus-indica) is another plant that is commonly found in Middle Eastern deserts and was found to possess gastroprotective properties (Varijakzhan et al. 2020). Garlic (Allium sativum) is known in Unani medicine and was proved to have antimicrobial, antifungal, antiviral, antiparasitic, antidiabetic, antioxidant, antihypertensive, and cardioprotective properties; it is considered an important plant within the Middle Eastern culture (Alam, Hoq, and Uddin 2016). Aloe vera is also found in Mediterranean countries and was reported to have antimicrobial, antifungal, antiviral, anti-inflammatory, moisturizing, and wound healing properties, as well as laxative activity (Sahu et al. 2013). Other important plants with medicinal properties that are found in the Middle East include clove (Eugenia caryophyllata), which has antimicrobial,

Country

Intervention (Dose/ Method of Population (n) Application)

Comparison(s)

Outcome(s)

Egypt

Double-blind clinical trial (n = 20)

100 mg once daily Treatment group Eight cases khellin and 15 minutes’ (n = 10) was compared responded exposure to sunlight for to placebo (n = 10) positively 21 days followed by 9 days’ cessation

Austria

Interventional (n = 28)

Italy

Interventional (n = 36)

Oral dose of 100 mg Assessment of vitiligo (n = 25) preceded by every 6 months 2.5 hours UVA exposure at least 2.5 hours prior to treatment three times weekly or 2% topical solution (n = 3) khellin 1 hour before UVA exposure. Control group was vitiligo areas that was covered during treatment 1% khellin gel Re-pigmentation formulation skin assessment between application vs. control treatment and control (water/2-propanol/ groups propylene glycol). This was foregone by 30 minutes’ UVA exposure

Various skin re-pigmentation between 8 and 24 months’ treatment. Improved tolerance to natural light

Improved re-pigmentation in >10% of application areas (p < 0.01)

Method of Testing

Duration

Four-points rating scale 4 months (scales gradual diminution, lesions flattening, decrease in erythema, and psoriatic skin clearance) Skin re-pigmentation Up to 24 months

Re-pigmentation assessment

6 months

Part Used

Reference

Oral preparation of khellin

Abdel-Fattah et al. 1983

Khella (Ammi visnaga )

TABLE 13.2 Clinical Trials on the Use of Ammi visnaga to Treat Different Clinical Conditions

Hard gelatin capsule of Ortel et al. khellin or glycerol 1988 formol 2% solution

Khellin gel

Orecchia et al. 1998

187

(Continued)

188

TABLE 13.2 ( Continued) Clinical Trials on the Use of Ammi visnaga to Treat Different Clinical Conditions

Country

Intervention (Dose/ Method of Population (n) Application)

Netherlands Case study (n = 74)

Hungary

Pilot study (n = 33)

Outcome(s)

Method of Testing

Duration

Part Used

Reference

Re-pigmentation assessment between treatment and control groups KUVA treatment group compared to psoralen UVA (n = 17)

72% had improved re-pigmentation

Re-pigmentation assessment

12 months (range 10–14 months)

KPLUV

de Leeuw et al. 2003

Planimetry methods to Average= 7 5% khellin in water/oil Valkova et al. Percentage re-pigmentation assess re-pigmentation months (25–30 emulsion 2004 was comparable to in vitiligo-affected skin procedures) the PUVA group but longer treatment period and number of procedures (p < 0.001) Boiling 10 g of seeds in The patient was No kidney stone on Ultrasound 10 days twice Bhagavathula Seeds 200 mL water admitted to the hospital day 10 daily et al. 2015 with two treatmentresistant kidney stones

Ancient and Traditional Foods Used in the Middle East

UAE, Jordan Case study (n = 1)

Liposomal khellin and UVA/B treatment compared to UVA/B treatment (control) Khellin and solar irradiation (KUVA). Khellin was applied 1 hour prior to the phototherapy session

Comparison(s)

Khella (Ammi visnaga)

189

antioxidant, antifungal, antiviral, anti-inflammatory, cytotoxic, insect repellent and anesthetic properties (Saganuwan 2010); ginger (Zingiber officinale), which has anti-inflammatory, cardiovascular stimulant, and gastrointestinal relief properties in addition to having cancer preventive effects; and olive (Olea europaea), which has antimicrobial, antiviral, antioxidant, cardioprotective, hypoglycemic, hypolipidemic, and emollient effects (Saganuwan 2010). Additionally, wild thyme (Thymus serpyllum) is a common plant used in Mediterranean traditional medicine and is reported to have antimicrobial and carminative properties (Saganuwan 2010). A juice that is popular in Middle Eastern countries and made of licorice (Glycyrrhiza glabra) possesses antibacterial, antioxidant, antimalarial, antispasmodic, anti-inflammatory, and hypoglycemic properties (Saganuwan 2010). Finally, henna (Lawsonia inermis), which is traditionally used as a hair and skin dye was reported to have antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, and hepatoprotective properties (Saganuwan 2010).

13.6 TOXICITY AND CAUTIONARY NOTES Ethanolic extract of A. visnaga did not show any acute or subacute toxicity on rat tissues including liver, brain, kidney, spleen, heart, testes, and ovaries following oral administration of 150, 300, and 600 mg/kg for 2 weeks (Koriem, Arbid, and El-Attar 2019). Hydrogel formulation of khellin showed no toxicity in rats during skin treatment (Risaliti et al. 2021). Oral administration of 100 mg khellin resulted in liver enzymes elevation; aspartate aminotransferase (AST), alanine aminotransferase (ALT), SGOT, SGPT, and gamma glutamyltransferase (GGT) (25%, n = 25) that returned to normal 5 to 12 weeks after treatment cessation (Ortel, Tanew, and Hönigsmann 1988). Additionally, the aforementioned treatment increased the likelihood of nausea (21%, n = 25) and orthostatic issues (7%, n = 25) that subsided during the treatment period (Ortel, Tanew, and Hönigsmann 1988). Another case report of a woman who was treated with KUVA (UVA exposure 2.5 hours after 100 mg oral khellin) for vitiligo showed a ninefold elevation of liver enzymes that returned to normal 6 weeks after treatment discontinuation (Duschet et al. 1989). Because khellin has uterine stimulant activity, A. visnaga should be avoided during the early stages of pregnancy (Abosalah 2004).

13.7

SUMMARY POINTS

• This chapter focuses on the medicinal uses of Ammi visnaga, which is commonly known as khella in the Middle East. • A. visnaga is native to Mediterranean regions and is also distributed in other countries around the world. • A. visnaga has been used from ancient times in the Mediterranean countries to treat various ailments including kidney diseases, respiratory diseases, cardiovascular diseases, abdominal spasms, and several skin conditions. • The most important phytochemicals found in A. visnaga include khellin and visnagin which were investigated in various preclinical and clinical trials. • The use of A. visnaga can lead to elevation of liver enzymes and photosensitivity, and it should be avoided during pregnancy.

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14

French Marigold (Tagetes patula L.) Phytochemical and Bioactive Targets of Secondary Metabolites Ausama Abdulwahab Safar

CONTENTS 14.1 Introduction ....................................................................................................................... 194 14.2 Morphology and Occurrence ............................................................................................ 195 14.3 Background (Ethnomedicinal and Traditional Uses) ........................................................ 195 14.4 Phytochemical Constituents from Tagetes patula L. ........................................................ 196 14.5 Essential Oils .................................................................................................................... 197 14.6 Thiophenes ........................................................................................................................ 199 14.7 Flavonoids ......................................................................................................................... 199 14.8 Other Compounds .............................................................................................................200 14.9 Antimicrobial Activity ......................................................................................................200 14.10 Antioxidant and Cytotoxic Activity .................................................................................. 203 14.11 Biocidal Activity (Insecticide, Acaricide, Larvicide, and Nematicide) ............................204 14.12 Toxicity..............................................................................................................................206 14.13 Summary ...........................................................................................................................206 References......................................................................................................................................206

LIST OF ABBREVIATIONS ABTS AcOCH2BBT AIT α-terthieny AQF BBT BBT(OAc)2 BBTOAc BBTOH DAD DDM DPPH EAF EC50 EHT EOs GC-MS

2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid 5-methylaceto-5-(3-buten-1-ynyl)-2,2-bithienyl adult immersion test l2,2′:5′,2″-terthienyl aqueous fraction 5-(3-buten-1-ynyl)-2,2-bithienyl 5-(3,4-diacetoxy-1-butynyl)-2,2-bithienyl 5-(4-acetoxy-1-butynyl)-2,2-bithienyl 5-(4-hydroxy-1-butynyl)-2,2-bithienyl diode array detector disk diffusion method 2,2-diphenyl-1-picrylhydrazyl ethyl acetate half of the effective concentration egg hatch test essential oils gas chromatography–mass spectrometry

DOI: 10.1201/9781003243472-16

193

194

HPLC IC50 IL-10 IPDT LC50 LD50 LDT LME LWE MDR MeBBT MIC PE PBT SME TC TD50 TNFα TPF TPR TPS TPSF TPSV

Ancient and Traditional Foods Used in the Middle East

high-performance liquid chromatography Half of the inhibitory concentration interleukin-10 impregnated paper disk test half of the lethal concentration half of the lethal dose larval development test leaves methanol extract leaves water extract multidrug-resistant 5-methyl-5-(3-buten-1-ynyl)-2,2-bithienyl minimum inhibition concentrations petroleum ether 5-(3-penten-1-ynyl)-2,2′-bithiophene stem methanol extract total carotenoid median toxic dose tumor necrosis factor alpha 2,2:5, 2″ marigold flowers marigold root marigold foliage marigold shoot at flowering stage marigold shoot at vegetative stage

14.1 INTRODUCTION Asteraceae plant family (Compositae), which is called sometimes the sunflower family, is known as one of the largest vascular plant families; it consists of about 1900 genera and more than 32,000 accepted species distributed in 13 subfamilies. The family has a great concentration of species in different areas of Mediterranean. Tagetes, which is a botanical identification of marigold, is an important genus belonging to the Asteraceae family (tribe Heliantheae), native to Central and South America, as well as to the Middle East, and now is widely naturalized to tropical and subtropical countries and the Middle East (Moghaddam et al. 2021, Salehi et al. 2018, Ayub et al. 2017). In addition, T. patula, T. erecta, T. minuta, and T. tenuifolia are extensively grown as ornamental plants. However, the studies showed that the different parts of the genus are traditionally has been exploited for the treatment of several diseases including rheumatism, dental, eye problem, stomach, muscular pain, and intestinal (Gupta and Vasudeva 2012, Armas et al. 2012) due to their anti-inflammatory, antihemorrhagic, diaphoretic, anthelmintic, and antimalarials properties (Salehi et al. 2018, Fabrick, Yool, and Spurgeon 2020). Tagetes patula L., which is a cosmopolitan ornamental plant thrives in varied agroclimates, is commonly known as Jaafari or Qadifa, and its English name is French marigold. The species has a long record of human use for the treatment of several pathogens (Riaz et al. 2020, Martínez et al. 2009). The different parts of the plant are known to possess secondary metabolites with multibiological activities, namely antioxidant and antimicrobial (Villada-Ramos et al. 2021, Latifian et al. 2021, Safar, Ghafoor, and Dastan 2020); biocidal (Siddiqi et al. 2015); and larvicidal (Krzyzaniak et al. 2017, Munhoz et al. 2014, Dharmagadda et al. 2005) activities. Several factors can influence the composition of the phytochemicals including geographic region, the development stage of the plant, the plant parts, habitat, and climatic conditions (Safar, Ghafoor, and Dastan 2020, Atteya and El Gendy 2018). Recently, the alcoholic extract of the whole plant and its essential oils (EOs) were reported to be the possible source of anticancer agents (Azhar et al. 2019, Politi et al. 2016, Kashif et al. 2015). In addition, the normal roots are capable to produce heterocyclic aromatic compounds

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195

called thiophenes with a strong biocidal efficacy to inhibit nematodes, and thus can be considered a good alternative of pesticides (Deineka et al. 2014, Szarka 2010). The present review provides data about the pharmaceutical activity of T. patula as well as its biocidal uses.

14.2

MORPHOLOGY AND OCCURRENCE

The marigold plant is applied to several species with large beautiful golden or yellow inflorescence and alternate leaves. There are many species of Tagetes genus; however, the French marigold (T. patula) and the African marigold (T. erecta) are the most commonly distributed species in the Middle East (Ayub et al. 2017). T. patula L. is an annual bushy plant native to South America. The species reaches a height of 30–90 cm (1 to 3 ft) with an upright stem and has a beautiful orange, golden, and bicolored radiate capitulum (head) containing ray and disc florets. The leaves are dark green, odd pinnately with dentate margins; the plant has an unpleasant aromatic fragrance. T. patula L. is frost sensitive and prefers growing in well-drained soil. The flowering of the plant occurs from July to December (Hassanpouraghdam et al. 2011).

14.3 BACKGROUND (ETHNOMEDICINAL AND TRADITIONAL USES) The remedial efficiency of traditional herbal medicines in the Middle East has been realized since ancient times. The genus Tagetes is one of the most ornamental known plants that has been exploited in different traditional systems of the world (Gupta and Vasudeva 2012). In ancient Egyptians, the plant was considered as a revitalized herb, the flower petals are utilized by Persians and Greeks for decorating food. It is used to garnish temple altars by Hindus. Tagetes was used in folk medicine for treating angina, high blood pressure, cough, diarrhea, diuresis, fever, inflammation, and rheumatism by Caribbean, Chinese, and Peruvian cultures. During the American Civil War, doctors were healing wounds with marigold leaves as antiseptic. Furthermore, it has been applied to insect

FIGURE 14.1

The whole plant of (Tagetes patula L.) with blooming flowers.

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and snake bites by medieval monks (Al-Saadi 2009). In Guatemala, the genus is used for curing respiratory problems like pneumonia, asthma, wound healing, and immune system stimulation, as well as against headache, tetanus, and various parasites (Salehi et al. 2018). French marigold is a cosmopolitan medicinal plant that is widely introduced as a therapeutic herb having multiple potentials as mentioned in folk medicine by local communities (Riaz et al. 2020). Different parts of the plant including leaves are given as a remedy for antiseptic, swellings, kidney troubles, muscular pain, skin irritating, piles, as well as applied to boils, earache, and ophthalmia (Chkhikvishvili et al. 2016). The flowers are used in eczema, cut and injury healing, stomachic, inflammation, fever, liver complaints, and are also employed in diseases of the eyes and rheumatism by different societies (Salehi et al. 2018, Chkhikvishvili et al. 2016). Moreover, T. patula is also used as a yellow to orange food colorant, for instance, in salad dressings, ice cream, dairy products, and other foodstuffs (Riaz et al. 2020). Its fresh and dry flowers are used to dye wool, silk, and cellulose fibers into shades of golden-yellow to orange (Atteya and El Gendy 2018). Folk healers from the Garo tribal of Netrakona district, Bangladesh, have used a paste of the whole plant of T. patula for treating cuts and stopping blood in wounds (Rahmatullah et al. 2009). In Pakistan, both leaves and flowers are collected and used for the treatment of fever (Salehi et al. 2018). Moreover, the roots and seeds act as a purgative (Gupta and Vasudeva 2012). Riaz et al. (2020) asserted that different communities and cultures have used T. patula for its spiritual attributes. Moreover, it was used in western India during worship to decorate their temples and holy places. They also used it during their marriage ceremonies. Muslims also sprinkle the flowers of the plant on the tombs of their relatives. Nowadays, flowers are the most commonly used part of T. patula in funeral ceremonies throughout Mexico and Guatemala (Kaplan 1960).

14.4

PHYTOCHEMICAL CONSTITUENTS FROM TAGETES PATULA L.

Phytochemicals are secondary metabolites produced by plants that have biological activity. French marigold has been screened for various phytochemicals ranging from phenolic compounds (flavonoids and phenolic acids) in hydrophilic extracts until thiophenes, fatty acids, terpenes, and terpenoids in lipophilic extracts (Riaz et al. 2020, Politi et al. 2016, Chkhikvishvili et al. 2016). Furthermore, the relative concentration of these compounds is dependent on the plant growth stage, plant organ, extraction method, and climatic conditions (Martínez et al. 2009). There is much data concerning the chemical composition of cultivated T. patula throughout the world. The flower extract of the plant has been found to contain biologically useful flavonoids and carotenoids which are responsible for the mitigation of oxidative stress that caused disorders such as cardiovascular diseases, inflammation, and cancer (Azhar et al. 2019, Kashif et al. 2015, Yasukawa and Kasahara 2013). Likewise, most phytoconstituents such as fatty acids, benzofurans, thiophenes, phenols, and steroids have been evaluated and used as a good source of pesticide and allelopathic ingredients (Fabrick, Yool, and Spurgeon 2020, Siddiqi et al. 2015). Although EOs are used in the perfumery industry, they also exhibited some pharmacological activities, namely antimicrobial, antioxidant, anti-inflammatory, hepatoprotective, and cytotoxic (Villada-Ramos et al. 2021, Moghaddam et al. 2021, Politi et al. 2016, Gupta and Vasudeva 2012). α-Terpinolene, (Z)-β-ocimene, indole, sylvestrene, (E)-ocimenone, β-caryophyllene, 4,6,6-trimethyl, (Z)-ocimenone, piperitone, piperitenone, and (E)-caryophyllene are the major EO components of T. patula and are classified as terpenes. These compounds are found prolifically in both the leaves and flowers (Moghaddam et al. 2021, Salehi et al. 2018). Moreover, EOs are effective in the field of biocidal activity (Fabrick, Yool, and Spurgeon 2020, Gupta and Vasudeva 2012, Dharmagadda et al. 2005). T. patula, which are described herein (Table 14.1) for their phytochemical components, have been collected from the different geographical regions of the Middle East.

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TABLE 14.1 Major Phytochemical Components of Different Parts of Tagetes patula L. Isolated by Different Extraction Techniques Major Compounds

Plant Organ

Extraction Method

Origin (Country) Reference

4.1.5′-Hydroxymethyl-5-(3-butene-1-ynyl)2,2′-bithiophene Methyl-5-[4-(3-methyl-1-oxobutoxy)-1butynyl]-2,2′-bithiophene Cholesterol, β-Sitosterol (24-R-stigmast-5ene-3β-ol), Stigmasterol [24-(S)-stigmast-5,22E-dien-3β-ol] α-terthienyl, methyl protocatechuate, patuletin, patulitrin, tetracosanol

Root part

Ethanol

Pakistan

(Bano et al. 2002)

Flower part

Ethanol

Petroleum ether, Pakistan methanol, methanol70% Petroleum ether Pakistan Roots, Seeds, Leaves, Flowers (P.E)

(Faizi et al. 2008)

Flowers

Petroleum ether Pakistan (P.E)

(Bano et al. 2019)

Leaves

Ethanol70%

Egypt

(Ismail et al. 2019)

Petals

n-hexane, methanol

Pakistan

(Ayub et al. 2017)

Flowers

Petroleum ether Pakistan (P.E)

(Faizi et al. 2011)

Roots

Methanol

(Saleem et al. 2004)

E-Ocimenone, Tagetone, Z-Ocimenone, Methyl eugenol 1-Pentadecyne, Tetradecanoic acid, Methyl palmitate, Methyl 9,12,15 Octadecatrienoate, Nonacosane Tetradecanoic acid, Hexadecanoic acid, Octadecanoic acid, Stigmast-4-en-3-one, N,N-bis(5-ethylhexyl) cyclopenten-, 3,7,11,15-Tetramethyl-2-hexadecen-1-ol Hexadecanoic acid, or palmitic acid ethyl ester Phytol Ethyl linoleate, or linoleic acid ethyl ester – Docosene Gallic acid, Chromotropic acid, Caffeic acid, Syringic acid, p-coumaric acid, Ferulic acid, Sinapic acid, Chlorogenic acid, Quercetin β-carotene R-tocopherol, 14-methylpentadecanoic acid, methyl ester, 9,12-octadecadienoic acid, methyl ester, 9,12-eicosadienoic acid, 1-(3-methoxyphenyl) ethenone, 4-(3-hydroxy-1-propenyl)-2-methoxyphenol, (Z)-3-decen-1-ol, 7,7-diethylnonadecane Citric acid, Trimethyl citrate, Dimethyl citrate, pyridine hydrochloride, 2,2′,5′,2‴-terthiophene, dimethyl mallate, malic acid, 2-formyl, 5-hydroxymethyl furan, 2-Hydroxy, 5-hydroxymethyl furan

Roots, Flowers, Involucres

Pakistan

(Siddiqi et al. 2015)

14.5 ESSENTIAL OILS EOs are also known as volatile oils and are complex mixtures of compounds extracted from plants. The compounds are considered natural products and represent an important part of both traditional and modern pharmacopeia. The whole Tagetes plant possesses EOs; however, the amount of oil varies depending upon plant parts and method of isolation (Martínez et al. 2009). However, the content of

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essential leaf oil (isolated by different methods, such as hydrodistillation) using Clevenger apparatus or pharmacopeia distillation apparatus ranged from 0.06% to 0.15% v/w; in flowers it ranged from 0.02% to 0.18% v/w; in fruits it ranged from 0.02% to 0.15% v/w; and in the root part it ranged from 0.012% to 0.20% v/w (Safar, Ghafoor, and Dastan 2020, Armas et al. 2012, Hassanpouraghdam et al. 2011). In addition, Atteya and El Gendy (2018) reported that treating T. patula with different fertilizers and nutrients in the open field could improve the EOs yield both qualitatively and quantitatively. Many studies have been carried out on the chemical composition and yields of the EOs of T. patula, particularly those from Asia including the Middle East (Table 14.2). However, the major constituents of T. patula were varied according to different climatic regions. For instance, from Egyptian species, piperitone, caryophyllene, α-terpinolene, D-limonene, and caryophyllene oxide were the principal constituents for plants collected from EL-Behira (Atteya and El Gendy 2018). In another study, components such as caryophyllene oxide, β-caryophyllene, and spathulenol were found to be major compounds of the EO collected from Beni Suef (Ali et al. 2016). TABLE 14.2 Major Essential Oil Components, as Percentages, of Tagetes patula Aerial Parts from Middle East Countries Molecule Limonene Piperitone Sylvestrene D-Limonene (Z)-β-Ocimene Terpinolene α-Terpinolene (E)-Caryophyllene Germacrene D Caryophyllene β-Caryophyllene Caryophyllene oxide Acetic acid, octyl ester α-Terthienyl (Z)-epoxy-ocimene Nerolidol-Epoxy acetate (E)-tagetone (Z)-tagetone (Z)-ocimenone (E)-ocimenone β-bisabolene (E)-β-farnesene Cyperene Neophytadiene Heneicosane Spathulenol Tricosane Piperitenone Reference

Note: Tr, trace ( 5000 mg/kg), with no adverse behavioral changes and toxicity symptoms observed. Other Pelargonium species were also evaluated for their antioxidant activity. For example, Şeker Karatoprak and coworkers investigated the chemical composition and biological properties of the decoction root extracts of Pelargonium endlicherianum Fenzl. cultivated in Turkey and used for the treatment of intestinal parasite (Şeker Karatoprak et al. 2017). The 70% methanol and ethyl acetate extracts displayed the highest antioxidant activities. The ethyl acetate extract increased the levels of endogenous antioxidant enzymes such as glutathione peroxidase and superoxide dismutase in a cell culture setup. Ouedrhiri et al. evaluated the antioxidant activity of the essential oil of Pelargonium asperum grown in Morocco (Ouedrhiri et al. 2018). The oil exhibited weak antioxidant potential in the DPPH assay with IC50 of 14.62 ± 0.19 mg/mL. The authors noted that despite the richness of the oil in compounds with proved antioxidant activity such as linalool, geraniol, and citronellol, the observed moderate activity suggested that some minor constituents might act antagonistically to diminish the activity of the antioxidant components.

Pelargonium Species and Their Usage as Medicinal Herbs

16.5.2

233

ANTIMICROBIAL ACTIVITY

Essential oils are ideal candidates to deter the emergence of drug-resistant microorganism. Due to its lipophilic nature, essential oils, including those of Pelargonium, exert its antimicrobial action by binding and disrupting the cell membrane of the microorganisms, thus increasing its permeability and inducing the leakage of vital cellular components resulting in cell death. Furthermore, essential oils can inhibit the synthesis of vital biomacromolecules in the cell such as RNA, DNA, proteins, and polysaccharides (Kalemba and Kunicka 2003). The antimicrobial characteristics of the essential oils and extracts of Middle Eastern Pelargonium plants are well established in scientific literature that validated the traditional use of the plant in cosmetics, perfumery, food industry, and as agents to combat microbial and parasitic infections. In herbal medicine, Pelargonium species are widely used to treat several bacterial infection-related diseases such as diarrhea, dysentery, fever, respiratory tract infections, wounds, and gastroenteritis (Saraswathi et al. 2011). In a study that evaluated the antibacterial activity of Lebanese rose geranium essential oil against Staphylococcus epidermis CIP 444 (gram-positive) and Escherichia coli (gram-negative), Fayoumi et al. found that the oil displayed bactericidal effects on both microorganisms with MIC value of 22.8 mg/mL (Fayoumi et al. 2022a). The antibacterial activity of the essential oils was attributed to the presence of high levels of oxygenated monoterpenes such as citronellol, geraniol, citronellyl formate, geraniol formate and linalool which act synergistically and antagonistically to augment bioactivity (Boukhris et al. 2015). The Lebanese geranium oil was more potent against gram-positive than gram-negative bacteria, which has a hydrophilic polysaccharide chain that acts as a barrier to the hydrophobic essential oil (Ben Hsouna and Hamdi 2012, Hamidpour et al. 2017). Such observation is recurrent in most reports. Boukhatem and colleagues assessed the antimicrobial activity of Algerian rose geranium essential oil against 23 food spoilage microorganisms (Boukhatem et al. 2013). The authors noted that the oil was effective against all gram-positive bacteria with Staphylococcus aureus ATCC 6538 and Enterococcus faecalis ATCC 29212 being the most sensitive, and three gram-negative bacteria with the strongest activity against Escherichia coli. The oil also showed strong inhibitory effect against Candida strains. Elansary and coworkers studied the antimicrobial activity of Egyptian P. graveolens essential oil on six fungal and seven bacterial strains (Elansary et al. 2018). The minimum inhibition concentration (MIC) against the fungi ranged between 0.21 ± 0.01 (against Penicillium ochrochloron) and 0.83 ± 0.05 mg/mL (against Candida albicans), and the minimum fungicidal concentration (MFC) ranged between 0.47 ± 0.01 (against Aspergillus flavus) and 1.92 ± 0.10 mg/mL (against Candida albicans). On the other hand, the essential oil displayed the strongest antibacterial activity against Micrococcus flavus with MIC and MBC values of 0.15 ± 0.01 and 0.33 ± 0.01 mg/mL, respectively. Several studies tested the antimicrobial activity of the Pelargonium essential oil from Morocco. Sadiki et al. examined the antibacterial potential of P. graveolens essential oil against five clinical pathogenic bacteria (Sadiki et al. 2019). The oil displayed bactericidal effect against all microorganisms with E. coli being the most sensitive at MIC of 1.25 μL/mL. Moutaouafiq and colleagues confirmed that P. graveolens essential oil inhibited the growth of all fungi with EC50 between 0.255 and 1.022 mg/ mL, thus highlighting the potential use of P. graveolens essential oils for wood protection against wood decay fungi (Moutaouafiq et al. 2019). El Aanachi and coworkers studied the antimicrobial effects of organic extracts of P. graveolens growing in Morocco. The methanolic extract showed the strongest effect with MIC values 1000 mg/kg. At 100 mg/kg oral dosage, the oil caused a reduction in paw edema comparable to that observed for diclofenac sodium (50 mg/kg) (73.1% vs. 80.8%, respectively). In the croton oil-induced ear edema assay, the topically applied essential oil reduced ear edema by 88% at 400 μL/kg. Such effect was not statistically different from that of diclofenac sodium. These findings highlighted the therapeutic potential of rose geranium essential oil for topical applications as in aromatherapy and body massage, and can be used to treat inflammatory conditions such as rheumatoid arthritis, aphthous stomatitis, and bacterial or fungal infections.

16.5.5 ANTI-ACETYLCHOLINESTERASE ACTIVITY Alzheimer disease (AD) is a progressive, irreversible common neurodegenerative disorder characterized by the gradual loss of memory and the ability to learn, comprehend, and perform daily life activities (Cummings 2004). The pathogenesis of AD is attributed in part to the loss of cholinergic neurons and the high uncontrolled activity of acetylcholinesterase (AChE), leading to decreased levels of the neurotransmitter acetylcholine (ACh) and inducing detrimental effects on the patient’s ability to learn and memorize. Currently available treatments for AD are dominated by AChE inhibitors such as donepezil, rivastigmine, tacrine, and galantamine. Unfortunately, these medications exhibit modest activity and are not devoid of side effects such as nausea, vomiting, and diarrhea (Schulz 2003). Two of the currently available drugs for AD, namely rivastigmine and galantamine, are of natural origin. Therefore, the development of novel natural AChE inhibitors holds huge promise for AD treatment. Plant-derived essential oils demonstrated strong AChE inhibitory activity probably due to the adequate size and lipophilicity of the bioactive constituents that enable them to cross the blood brain barrier into the brain (Dos Santos et al. 2018). Several groups investigated the AChE inhibitory action of Pelargonium plants grown in Middle Eastern countries. Fayoumi et al. tested the ability of Lebanese rose geranium essential oil to inhibit AChE activity, and reported a dose-dependent inhibition with IC50 value of 10.5 mg/mL. Maximum inhibition of about 72% was achieved at 47 mg/mL of the oil (Fayoumi et al. 2022a). The anti-AChE activity was attributed to the presence of phytochemicals with proven inhibitory action such as (S)(−)-citronellol, linalool, α-pinene, menthone, and isomenthone. In regard to extracts, the ethanol leaves and stem extracts

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demonstrated the highest anti-AChE activity with IC50 values of 0.63 ± 0.151 and 0.65 ± 0.05 mg/mL, respectively (Fayoumi et al. 2022b). Ben ElHadj Ali and coworkers evaluated the anti-AChE activity of the essential oils, methanol, ethanol and aqueous extracts of flower and leaves of Tunisian P. graveolens. Overall, the essential oils were more active than the extracts with IC50 values of 272 ± 3.43 and 294 ± 1.91 μg/mL for the leaves and flower oils, respectively. The IC50 of the extracts ranged between 877 ± 2.6 μg/ mL for the leaves methanol extract and 3289 ± 4.6 μg/mL for the flowers aqueous extract (Ben ElHadj Ali et al. 2020). Ennaifer et al. reported that the decoction water extracts of rose geranium cultivated in Tunisia possessed good anti-AChE activity with 93% inhibition achieved at 2.5 mg/mL (Ennaifer et al. 2020). Jazayeri et al. reported that the maceration extract of rose geranium in aqueous methanol was a strong AChE inhibitor with IC50 of 196.9 ± 7.25 μg/mL (Jazayeri et al. 2014).

16.5.6

MISCELLANEOUS ACTIVITIES

The traditional use of P. graveolens essential oil for the treatment of diabetes was validated by Boukhris and coworkers in alloxan-induced diabetic rat model (Boukhris et al. 2012). Effective hypoglycemic effects were observed at 150 mg/kg by body weight associated with a significant reduction in the liver and kidney thiobarbituric acid reactive substances (TBARS) levels thus highlighting the oil’s protective potential to alleviate oxidative stress induced by peroxidative damage. Furthermore, P. graveolens essential oil is traditionally used to reverse reproductive damage and treat sterility. Such application was validated by Ben Slima et al., who tested the ability of P. graveolens essential oil to combat reprotoxicity induced by deltamethrin in healthy, male, virgin mice (Ben Slima 2013). Interestingly, the oil exhibited positive effects on the animals’ reproductive system. At a daily dose of 67 mg/kg, the oil increased the sperm count and motility, normalized the abnormal morphology of the sperm, and improved the levels of testicular enzymatic antioxidants such as catalase and superoxide dismutase levels.

16.6 TOXICITY AND CAUTIONARY NOTES The pharmacological and medicinal profiles of Pelargonium plants are remarkable and encompass a broad spectrum of diseases and medical conditions. The outstanding adaptability of the plants to diverse environmental conditions, the ease of cultivation and propagation, the good yield of essential oil per hectare, and the high market value render Pelargonium plants attractive crops for large-scale cultivation and production as a supportive measure for the fragile economies particularly in developing Middle Eastern countries. Despite the large body of research dedicated to the address the therapeutic and industrial benefits of the plants, it is only the surface that has been scratched and much needed work is required to investigate previously unexplored species, improve the quality and yield of essential oil possibly by directing the plants to produce specific terpenes through gene biotechnology, and address the short, medium, and long term toxicological profile. While P. graveolens oil is classified as generally recognized as safe (GRAS) between 1.6 and 200 ppm by the FDA, and the ethanol extract of Pelargonium roots is commercialized in Germany for acute and chronic respiratory tract infections, enormous studies are still needed to establish a comprehensive toxicity profile for the different species. In addition, the contradicting reports on the therapeutic activities of the same Pelargonium species cultivated in the same country were mainly attributed to marked differences in the chemical composition of the extracts, and therefore the establishment of standardized assessment protocols correlated to the plant’s phytochemical profile becomes a necessity.

16.7

SUMMARY POINTS

• This chapter provided a comprehensive assessment of the herbal use of Pelargonium plants in Middle Eastern countries.

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• The traditional use of Pelargonium plants was validated by evidence-based scientific research. • Extracts of Pelargonium plants are approved to treat respiratory tract infections. • Pelargonium plants exhibited remarkable pharmacological profile with noted antioxidant, antimicrobial, antiproliferative, anti-AChE, antidiabetic activities, to name a few. • More research is needed particularly to mechanistically explore the mode of action at the molecular level and establish a full toxicological scheme for the plants.

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El Aanachi, S., Gali, L., Nacer, S.N., Bensouici, C., Dari, K., Aassila, H. 2020. Phenolic contents and in vitro investigation of the antioxidant, enzyme inhibitory, photoprotective, and antimicrobial effects of the organic extracts of Pelargonium graveolens growing in Morocco. Biocatalysis and Agricultral Biotechnology 29:101819–101827. Elansary, H.O., Abdelgaleil, S.A.M., Mahmoud, E.A., Yessoufou, K., Elhindi, K., El-Hendawy, S. 2018. Effective antioxidant, antimicrobial and anticancer activities of essential oils of horticultural aromatic crops in northern Egypt. BMC Complementary and Alternative Medicine 18:214–223. El-Garawani, I., El Nabi, S.H., Nafie, E., Almeldin, S. 2019. Foeniculum vulgare and Pelargonium graveolens essential oil mixture triggers the cell cycle arrest and apoptosis in MCF-7 cells. Anti-Cancer Agents in Medicinal Chemistry 19:1003–1113. Ennaifer, M., Bouzaiene, T., Messaoud, C., Hamdi, M. 2020. Phytochemicals, antioxidant, anti-acetylcholinesterase, and antimicrobial activities of decoction and infusion of Pelargonium graveolens. Natural Product Research 34:2634–2638. Fayed, S.A. 2009. Antioxidant and anticancer activities of Citrus reticulate (Petitgrain Mandarin) and Pelargonium graveolens (Geranium) essential oils. Research Journal of Agriculture and Biological Sciences 5:740–747. Fayoumi, L., Khalil, M., Ghareeb, D., Chokr, A., Bouaziz, M., El-Dakdouki, M.H. 2022a. Phytochemical constituents and therapeutic effects of the essential oil of rose geranium (Pelargonium hybrid) cultivated in Lebanon. South African Journal of Botany 147:894–902. Fayoumi, L., Khalil, M., Ghareeb, D., El-Dakdouki, M.H. 2022b. Chemical composition and therapeutic activity of Lebanese rose geranium (Pelargonium hybrid) extracts. Farmacia 70:477–490. Hamidpour, S., Marshall, V., Hamidpour, R., Hamidpour, M., Hamidpour, R. 2017. Pelargonium graveolens (rose geranium): A novel therapeutic agent for antibacterial, antioxidant, antifungal and diabetics. Archive in Cancer Research 5:1–5. Ibrahim, M.M., Abd El Ghani, S., Abd El-Moez, S.I. 2018. Phytochemical analysis and antimicrobial activities of different callus extracts of Pelargonium sidoides DC. against food borne pathogenic bacteria. Journal of Applied Pharmaceutical Science 8:109–118. ISO. 2012. International Organization for Standardization (ISO). Essential oil of geranium (Pelargonium x ssp.) (ISO Standard No. 4731:2012). www.iso.org/standard/52144.html. Jazayeri, S.B., Amanlou, A., Ghanadian, N., Pasalar, P., Amanlou, M. 2014. A preliminary investigation of anticholinesterase activity of some Iranian medicinal plants commonly used in traditional medicine. DARU Journal of Pharmaceutical Sciences 22:1–5. Juliani, H.R., Koroch, A., Simon, J.E., Hitimana, N., Daka, A., Ranarivelo, L., Langenhoven, P. 2006. Quality of geranium oils (Pelargonium species): Case studies in southern and eastern Africa. Journal of Essential Oil Research 18:116–121. Kalemba, D., Kunicka, A. 2003. Antibacterial and antifungal properties of essential oils. Current Medicinal Chemistry 10:813–829. Kolodziej, H. 2000. Traditionally used Pelargonium species: Chemistry and biological activity of umckaloabo extracts and their constituents. Current Topics in Phytochemistry 3:77–93. Labat-Robert, J., Robert, L. 2014. Longevity and aging: Role of free radicals and xanthine oxidase: A review. Pathologie Biologie 62:61–66. Lis-Balchin, M. 2002. History of nomenclature, usage and cultivation of Geranium and Pelargonium species, in: Lis-Balchin, M. (Ed.), Geranium and Pelargonium Species: Medicinal and Aromatic Plants: Industrial Profiles, CRC Press, London, pp. 17–22. Lis-Balchin, M., Hart, S.L., Deans, S.G., Eaglesham, E. 1996. Potential agrochemical and medicinal usage of essential oils of Pelargonium species. Journal of Herbs, Spices & Medicinal Plants 3:11–22. Lis-Balchin, M., Roth, G. 2000. Composition of the essential oils of Pelargonium odoratissiumum, P. exstipulatum, and P. x fragrans (Geraniaceae) and their bioactivity Flavour and Fragrance Journal 15:391–394. Moutaouafiq, S., Farah, A., Ez zoubi, Y., Ghanmi, M., Satrani, B., Bousta, D. 2019. Antifungal activity of Pelargonium graveolens essential oil and its fractions against wood decay fungi. Journal of Essential Oil Bearing Plants 22:1104–1114. Moyo, M., Van Staden, J. 2014. Medicinal properties and conservation of Pelargonium sidoides DC. Journal of Ethnopharmacology 152:243–255. Narnoliya, L.K., Jadaun, J.S., Singh, S.P. 2019. The phytochemical composition, biological effects and biotechnological approaches to the production of high-value essential oil from Geranium, in: Malik, S. (Ed.), Essential Oil Research: Trends in Biosynthesis, Analytics, Industrial Applications and Biotechnological Production, Springer Nature, Switzerland, pp. 327–352.

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17

Saffron (Crocus sativus) as a Middle East Herb Traditional and Modern Medicinal Applications Mehrnaz Shojaei, Mohammad Bagherniya, Gholamreza Askari, Babak Alikiaii, Seyed Ahmad Emami, Eric Gumpricht and Amirhossein Sahebkar

CONTENTS 17.1 17.2 17.3

Saffron ............................................................................................................................... 242 Phytochemical Components of Saffron ............................................................................. 242 Health Benefits of Saffron ................................................................................................. 243 17.3.1 Saffron and Gastrointestinal Diseases..................................................................243 17.3.2 Saffron and Diabetes Mellitus..............................................................................250 17.3.3 Saffron and Mental Health ...................................................................................252 17.3.4 Saffron and Sleep .................................................................................................253 17.3.5 Saffron and Other Human Conditions .................................................................254 17.4 Other Foods, Herbs, Spices, and Botanicals Used in the Middle East .............................. 255 17.5 Toxicity and Cautionary Points .......................................................................................... 255 17.6 Conclusion.......................................................................................................................... 256 17.7 Summary Points................................................................................................................. 256 References......................................................................................................................................256

LIST OF ABBREVIATIONS ALP ALT AMD AST BCVA BDI-II BMI BUN CMT DAS28 DPPH ESR FPG HbA1c HPA hs-CRP

alkaline phosphatase alanine aminotransferase age-related macular degeneration aspartate aminotransferase improved best-corrected visual acuity Beck Depression Inventory–II body mass index blood urea nitrogen central macular thickness disease activity score diphenylpicrylhydrazyl erythrocyte sedimentation rate fasting plasma glucose hemoglobin A1c (glycosylated hemoglobin) hypothalamus-pituitary-adrenal high-sensitivity C-reactive protein

DOI: 10.1201/9781003243472-19

241

242

IL-6 ISQ MADRS MDA NAFLD NF-κB PGA PSQI T2DM TAC TG TNF-α

Ancient and Traditional Foods Used in the Middle East

interleukin-6 Insomnia Symptom Questionnaire Montgomery-Åsberg Depression Rating Scale malondialdehyde nonalcoholic fatty liver disease nuclear factor-kappa B physician global assessment Pittsburgh Sleep Quality Index type 2 diabetes mellitus total antioxidant capacity triglyceride tumor necrosis factor-alpha

17.1 SAFFRON The genus Crocus, with 249 accepted species, is a member of Iridaceae. Saffron (C. sativus) is a popular spice belonging to the saffron crocus related to the mentioned family, which has been used for thousands of years (Kamalipour and Akhondzadeh 2011; Mzabri et al. 2019). Saffron is one the most expensive spice, originating in the Middle East, Central Asia, the Mediterranean region, and Greece (Kamalipour and Akhondzadeh 2011). Saffron is native to Greece and cultivated in Iran, the largest spice producer (Moghaddasi 2010). Saffron, with chemicals picrocrocin and safranal shows a bitter taste and an iodoform- or hay-like fragrance (Kamalipour and Akhondzadeh 2011). Crocin, a carotenoid dye, is another principal saffron component that causes a golden-yellow hue in foods. With these unique traits, saffron has become a much-sought ingredient in diverse foods globally. Due to the specific taste and color that saffron adds to foods, as a favorable spice, it is extensively used in several distinct places of the world, including Central Asian, Persian, Arab, Indian, European, Moroccan, and Cornish cuisines. Saffron is also used in cosmetics, confectionery, and liquors (Figure 17.1) (Kamalipour and Akhondzadeh 2011; Mzabri et al. 2019). Saffron application in human health has been a research focus for many years (Javadi et  al. 2013a). In traditional and modern medicine, saffron is considered a unique herb with enormous health benefits. With its antioxidant, anti-inflammatory, immuno-modulating, antidepressant, anticonvulsant, anticarcinogenic, antimutagenic, and antidiabetic properties, saffron has attracted significant attention to prevent and treat several human conditions, including cancer, diabetes, metabolic syndrome, neurological disorders, psychological conditions, cardiovascular disease (CVD), gastrointestinal disorders, and other diseases (Kamalipour and Akhondzadeh 2011; Mzabri et al. 2019; Khorasany and Hosseinzadeh 2016b; Samarghandian and Borji 2014; Singletary 2020; Javadi et al. 2013b; Pourmasoumi et al. 2019; Rahiman et al. 2018; Riazi et al. 2017; Shafiee et al. 2018a; Yaribeygi et al. 2019b; Nikbakht-Jam et al. 2015; Yaribeygi et al. 2018a; Yaribeygi et al. 2018b). In this chapter, we discuss applications of saffron in different aspects of human health and diseases, considering both traditional and modern medicine. In Table 17.1, a summary of the included randomized, double-blind controlled trials is illustrated.

17.2 PHYTOCHEMICAL COMPONENTS OF SAFFRON A total of 150 volatile and non-volatile components are found in saffron by chemical analysis, but less than 50 components have been identified (Winterhalter and Straubinger 2000). The three components of saffron that are considered the most important biologically active compounds are crocin, picrocrocin, and safranal. The yellow-orange color of the saffron is attributed to crocin (C44H64O24), a carotenoid pigment with a high level of solubility in the water. Another major component of saffron is crocetin (C20H24O4), an apocarotenoid dicarboxylic acid also responsible for the saffron color. Picrocrocin (C16H26O7), responsible for the bitter taste and flavor of the spice, and safranal (C10H14O) is a volatile and aromatic aldehyde that causes saffron’s specific aroma and smell (Mzabri

Saffron (Crocus sativus) as a Middle East Herb

FIGURE 17.1

243

Saffron and its health applications.

et al. 2019). Anthocyanins, flavonoids (such as kaempferol), amino acids, proteins, vitamins, minerals, starch, gums, and other ingredients of saffron (Mzabri et al. 2019). Carotenoids such as α- and β-carotenes and zeaxanthin and lycopene are non-volatile active constituents of saffron. More than 34 volatile constituents with a very strong odor also exist in saffron (Mzabri et al. 2019).

17.3 HEALTH BENEFITS OF SAFFRON 17.3.1

SAFFRON AND GASTROINTESTINAL DISEASES

Due to the several unique properties of saffron, including chemopreventive, cell proliferation inhibition, apoptosis induction, anti-inflammatory effects, radical scavenging, antioxidant properties, and

244

TABLE 17.1 Characteristics of Included Clinical Trials First Author, Year, Country (Reference)

Daily Intervention Number of (mg Unless Subjects Otherwise Stated)

Treatment Duration

Subjects

Kaviani Pour et al. 2020, Iran (Kaviani Pour et al. 2020)

RCT, parallel

Nonalcoholic fatty liver disease (NAFLD)

76

100 mg saffron

12 weeks

Tahvilian et al. 2021, Iran (Tahvilian et al. 2021)

RCT, parallel

Ulcerative colitis

75

100 mg saffron

8 weeks

Tajaddini et al. 2021, Iran (Tajaddini et al. 2021)

RCT, parallel

Overweight/obese patients with type 2 diabetes mellitus (T2DM)

60

100 mg saffron

8 weeks

Main Outcomes

Adverse Events

High sensitivity C-reactive protein (hs-CRP) ↓ Leptin ↓ Malondialdehyde (MDA) ↓ Total antioxidant capacity (TAC) ↑ Alanine aminotransferase (ALT) ↔ Aspartate aminotransferase (AST) ↔ Adiponectin ↔ Tumor necrosis factor-alpha (TNF-α) ↔ Anthropometric indices ↔ Visceral fat level ↔ Mean score of simple clinical colitis activity index ↑ Total antioxidant capacity ↑ Superoxide dismutase ↑ Glutathione peroxidase ↑ MDA ↔ Fasting plasma glucose (FPG) ↓ Insulin ↓ Triglyceride (TG) ↓ ALT ↓ AST ↓ Beck Depression Inventory–II (BDI-II) ↑ Pittsburgh Sleep Quality Index (PSQI) ↑

Allergic reaction (n = 1)

Not mentioned

No adverse effects

Ancient and Traditional Foods Used in the Middle East

Study Design

RCT, parallel

T2DM

50

15 mg crocin (two times a d providing 30 mg total)

12 weeks

Mobasseri et al. 2020, Iran (Mobasseri et al. 2020)

RCT, parallel

T2DM

60

100 mg saffron

8 weeks

Karimi-Nazari et al. 2019 (Karimi-Nazari et al. 2019)

RCT, parallel

Overweight/obese prediabetic

75

100 mg saffron

8 weeks

Moravej Aleali et al. 2019, Iran (Moravej Aleali et al. 2019)

RCT, parallel

T2DM

64

30 mg saffron

3 months

Sepahi et al. 2018, Iran (Sepahi et al. 2018)

RCT, parallel

Refractory diabetic macular edema (DME)

60

5 or 15 mg crocin

3 months

No adverse effects

Not mentioned

No adverse effects

Allergy to saffron (n = 2)

Increased appetite, foot swelling, stomachache, subconjunctivalhemorrhage, swelling, redness, and burning of the eyes

245

hs-CRP ↓ TNF-α ↓ Nuclear factor-kappa B (NF-κB) ↓ Interleukin 6 (IL-6) ↔ MDA↔ FBG ↓ TNF-α ↓ TNF-α mRNA expression ↓ IL-6 mRNA expression ↓ Serum IL-10 and IL-10 mRNA expression ↔ FBG ↓ Glycosylated hemoglobin (HbA1c) ↓ Diphenylpycrylhydrazyl (DPPH) ↑ Lipid profile ↔ Anthropometric measures ↔ Renal markers ↔ FPG ↓ Cholesterol ↓ LDL-c ↓ LDL/HDL ↓ Blood urea nitrogen (BUN) ↔ Creatinine ↔ HbA1c ↔, TG ↔, HDL-C ↔ Results for 15 mg crocin compared with placebo: FPG ↓ HbA1c ↓ Central macular thickness (CMT) ↓ Improved best-corrected visual acuity (BCVA) ↓ Lipid profile ↔ Renal markers ↔

Saffron (Crocus sativus) as a Middle East Herb

Behrouz et al. 2021, Iran (Behrouz et al. 2021)

(Continued)

246

TABLE 17.1 (Continued) First Author, Year, Country (Reference)

Daily Intervention Number of (mg Unless Subjects Otherwise Stated)

Treatment Duration

Main Outcomes

Adverse Events

A starch-based gel containing 1% saffron

1 month

Erectile dysfunction ↓

No adverse effects

78

30 mg crocin

4 months

Not reported

52

30 mg Crocus sativus

12 weeks

28 mg saffron extract (affron)

8 weeks

57

30 mL saffron (two 15 mL capsules of saffron)

8 weeks

Anxiety ↓ Depression ↓ Hypersensitivity reaction ↓ Neurological disorders ↓ Leucopenia ↑ Depression ↓ Food craving ↔ Appetite ↔ Depressive symptoms based on Montgomery-Åsberg Depression Rating Scale (MADRS) ↓ Adverse effects of antidepressants ↓ self-rated MADRS ↔ Quality of life ↔ Depression ↓

68

28 mg saffron extract (affron)

8 weeks

Subjects

MohammadzadehMoghadam et al. 2015, Iran (MohammadzadehMoghadam et al. 2015) Salek, et al. 2021, Iran (Salek et al. 2021)

RCT, parallel

Diabetic men

50

RCT, parallel

Breast cancer

Akhondzadeh et al. 2020, Iran (Akhondzadeh et al. 2020) Lopresti et al. 2019, Australia (Lopresti et al. 2019)

RCT, parallel

Overweight women with mild to moderate depression Persistent depression

Jalali et al. 2018, Iran (Jalali and Hashemi 2018)

RCT, parallel

Consumers of methamphetamine living with HIV/ AIDS

Lopresti et al. 2018, Australia (Lopresti et al. 2018)

RCT, parallel

Youth (12–16 years) with mild to moderate anxiety and depression

RCT, parallel

139

Internalizing symptoms ↓ Separation anxiety ↓ Social phobia ↓ Depression ↓

Hives (n = 1)

No adverse effects

Anxiety (n = 1), increased appetite (n = 2), drowsiness (n = 4), nausea (n = 1), and headache (n = 1) Increased frequency of headaches (n = 1)

Ancient and Traditional Foods Used in the Middle East

Study Design

RCT, parallel

Mothers with mild to moderate postpartum depression

60

30 mg saffron

8 weeks

Depression ↓ Remission rate ↓

Nikbakht Jam et al. 2017, Iran (Jam et al. 2017) Mazidi et al. 2016, Iran (Mazidi et al. 2016) Lopresti et al. 2021, Australia (Lopresti et al. 2021)

RCT, parallel

Patients with metabolic syndrome Patients with anxiety and depression Adults with poor sleep

33

30 mg crocin

8 weeks

Depression ↓

60

50 mg saffron

12 weeks

120

14 and 28 mg saffron extract (affron)

28 days

Pachikian et al., Belgium 2021 (Pachikian et al. 2021)

RCT, parallel

66

Saffron extract (15.5 mg)

6 weeks

Depression ↓ Anxiety ↓ Saffron (at both doses): Quality of sleep ↑ Mood ratings after awakening ↑ Insomnia Symptom Questionnaire (ISQ) total score ↑ ISQ-insomnia classifications ↑ Evening melatonin ↑ Restorative sleep questionnaire ↔ Functional outcomes of sleep questionnaire ↔ Evening cortisol ↔ Time in bed ↔ Getting to sleep became easier ↔ Sleep quality ↔ Duration of sleep ↑ Sleep latency ↔ Global scores ↔

RCT, parallel RCT, parallel

Individuals with mild to moderate sleep disorder associated with anxiety

Low breast milk supply (6.2%), bleeding gums (probably platelet disorders) (3.3%), which should be considered. Gastrointestinal disorders (6.2%), lack of sleep (3.3%), and oversleeping (3.3%) Allergic symptoms (n = 1) Allergic symptoms (n = 1) No adverse effects

Saffron (Crocus sativus) as a Middle East Herb

Tabeshpour et al. 2017, Iran (Tabeshpour et al. 2017)

Palpitations in the evening (n = 1)

(Continued)

247

248

TABLE 17.1 (Continued) First Author, Year, Country (Reference)

Daily Intervention Number of (mg Unless Subjects Otherwise Stated)

Treatment Duration

Subjects

Umigai et al. 2018, Japan (Umigai et al. 2018)

RCT, crossover

Healthy adults with mild sleep complaints

30

Crocetin 7.5 mg

Two intervention periods of 14 days each

Kashani et al. 2013, Iran (Kashani et al. 2013)

RCT, parallel

Women treated with fluoxetine with sexual dysfunction

34

Saffron 30 mg

4 weeks

Safarinejad et al. 2011, Iran (Safarinejad et al. 2011)

RCT, parallel

Infertile men

260

Saffron 60 mg

26 weeks

Zilaee et al. 2019, Iran (Zilaee et al. 2019)

RCT, parallel

Patients with mild and moderate allergic asthma

80

Saffron 100 mg

8 weeks

Main Outcomes

Adverse Events

Objective sleep parameter (delta power) ↑ Sleep latency ↔ Sleep efficiency ↔ Total sleep time ↔ Wake after sleep onset ↔ Subjective scores including sleepiness on rising and feeling refreshed ↑ Female Sexual Function Index (FSFI) ↑ Arousal ↓ Lubrication ↓ Pain ↓ Desire satisfaction ↔ Orgasm ↔ Semen parameters (sperm density, morphology, and motility) ↔ Total seminal plasma antioxidant capacity ↔

Pollen allergy (n = 3), cold-like symptoms (n = 3), headache (n = 2)

Shortness of breath frequency ↓ Usage of salbutamol spray ↓ Waking up because of asthma symptoms ↓ Limitation of activity ↓ Systolic and diastolic blood pressure ↓ Triglycerides ↓ LDL ↓

Increased appetite (n = 2), decreased appetite (n = 2), headache (n = 1), insomnia (n = 1), sedation (n = 1), nausea (n = 2) Reduced platelet count, leukocyte count, red blood cell count, appetite, increased appetite, headache, nausea, sedation, hypomania Feeling of warming up

Ancient and Traditional Foods Used in the Middle East

Study Design

RCT, parallel

Multiple sclerosis patients

40

Crocin 30 mg

28 days

Abbaszadeh-Mashkan et al. 2021, Iran (Abbaszadeh-Mashkani et al. 2021) Hamidi et al. 2020, Iran (Hamidi et al. 2020)

RCT, parallel

Subjects under MMT programs

60

Crocin 30 mg

12 weeks

RCT, parallel

Patients with active rheumatoid arthritis

61

Saffron 100 mg

12 weeks

Broadhead et al. 2019, Australia (Broadhead et al. 2019)

RCT, crossover

Patients with mild/ moderate agerelated macular degeneration (AMD) with age 50

100

Saffron 20 mg

3 months

Peroxidation of lipid ↓ DNA damage ↓ TNF-α ↓ IL-17 ↓ TAC ↑ Total thiol groups (TTG) ↔ Craving score ↓ Withdrawal symptoms score ↓ Cognitive function parameters ↔

Not reported

Tender and swollen joints ↓ Intensity of pain using a visual analog scale ↓ disease activity score (DAS28) ↓ Physician global assessment (PGA) ↓ Erythrocyte sedimentation rate (ESR) ↓ TNF-α ↔ IFN-γ ↔ hs-CRP ↔ ESR ↔ MDA ↔ Mean best-corrected visual acuity (BCVA) ↓ Changes in multifocal electroretinogram (mfERG) ↓

Stomach pain (n = 1)

No adverse effects

Saffron (Crocus sativus) as a Middle East Herb

Ghiasian et al. 2019, Iran (Ghiasian et al. 2019)

Death (urinary sepsis) (n = 1), fall (n = 2), neovascular AMD (n = 2), cataract progression (n = 1), bowel cancer (n = 1)

249

250

Ancient and Traditional Foods Used in the Middle East

reduction of lipid peroxidation, it is hypothesized that saffron might have favorable effects on various digestive system disorders (Khorasany and Hosseinzadeh 2016a). It is proposed that saffron might have potential therapeutic effects against fatty liver, hepatotoxicity, liver cancer, stomach cancer, peptic ulcer, colon cancer, ulcerative colitis, pancreas cancer, and ileum contractions (Khorasany and Hosseinzadeh 2016a). However, most of the studies on the effects of saffron on gastrointestinal diseases were performed on animals, with very few clinical studies performed. Considering potential antidiabetic and anti-inflammatory effects of saffron, Kaviani Pour et  al. performed a recent placebo-controlled study to evaluate the effects of saffron in patients with non-alcoholic fatty liver disease (NAFLD) (Kaviani Pour et al. 2020). The subjects consumed 100 mg saffron daily for 12 weeks. Results indicated that high-sensitivity C-reactive protein (hs-CRP), leptin, and malondialdehyde (MDA) significantly decreased while total antioxidant capacity (TAC) significantly increased in the intervention group compared with the placebo group. However, alanine aminotransferase (ALT), aspartate aminotransferase (AST), adiponectin, tumor necrosis factor-alpha (TNF-α), anthropometric indices, and visceral fat level did not notably change. Relatedly, Hasani et al. performed a systematic review and meta-analysis including eight clinical trials and observed saffron supplementation significantly reduced AST while not affecting either ALT or alkaline phosphatase (ALP) (Hasani et al. 2021). Tahvilian et al. hypothesized that since oxidative stress is elevated in patients with ulcerative colitis, saffron’s antioxidant properties could improve the health status of ulcerative colitis patients (Tahvilian et al. 2021). Therefore, these patients were supplemented with 100 mg saffron daily for 8 weeks. Results showed that disease severity decreased as indicated by increases in the mean score of the simple clinical colitis activity index questionnaire. In addition, the blood levels of superoxide dismutase, glutathione peroxidase, and total antioxidant capacity significantly increased in patients receiving saffron compared to the control group (Tahvilian et al. 2021). Although the current evidence is insufficient, saffron might have beneficial effects on gastrointestinal diseases.

17.3.2

SAFFRON AND DIABETES MELLITUS

The antidiabetic effects of saffron are one of the most salient properties of this spice, making it a unique choice for preventing or treating diabetes as complementary medicine. However, the number of clinical trials in this field is limited to date. Mechanistically, saffron may have a hypoglycemic effect via its carotenoid content. For example, insulin sensitivity can be induced by crocin, safranal, and crocetin through induction of insulin-dependent tissues resulting in a hypoglycemic response (Yaribeygi et al. 2019a). Peripheral insulin sensitivity is significantly increased through acetyl-CoA carboxylase phosphorylation (AMPK/ACC) and mitogen-activated protein kinases, though PI3kinase/Akt is not involved (Figure 17.2) (Kang et al. 2012). Administration of crocetin in diabetic rats downregulated adiponectin, TNF-α, and leptin expression in white adipocytes at protein and mRNA level, which resulted in insulin sensitivity (Xi et al. 2007). In addition, several other antidiabetic mechanisms are suggested including β-cell function improvement, GLUT-4 expression/localization induction, and prevention and suppression of oxidative stress and inflammation (Yaribeygi et al. 2019a). Moreover, Giannoulaki et al. showed that saffron supplementation had a favorable effect on fasting plasma glucose (FPG) in a systematic review (Giannoulaki et  al. 2020). Additionally, supplementation with 100 mg saffron daily for 8 weeks resulted in significantly decreased FPG, insulin, triglyceride (TG), ALT, and AST in overweight and obese subjects with type 2 diabetes mellitus (T2DM) with significant improvements found in Beck Depression Inventory–II (BDI-II) and Pittsburgh Sleep Quality Index (PSQI) assessments (Tajaddini et al. 2021). In another study, using 15 mg crocin twice daily for 12 weeks in T2DM patients caused a significant reduction in hs-CRP, TNF-α, and nuclear factor-kappa B (NF-κB) compared with the control group, although neither interleukin 6 (IL-6) nor MDA levels significantly changed (Behrouz et al. 2021). In another clinical trial, Mobasseri et al. reported T2DM patients

Saffron (Crocus sativus) as a Middle East Herb

251

Acetyl-CoA carboxylase phosphoryla on

Mitogen-ac vated protein kinases Insulin sensi vity

Adiponec n

An diabe c effects

TNF-α

Improve func on of B cell

GLUT-4 expression/ localiza on induc on

Stress oxida ve

Inflammation

FIGURE 17.2 Schematic summary of pathways depicting antidiabetic effects of saffron and its potential related mechanisms.

consuming 100 mg saffron daily for 8 weeks resulted in significant decreases in serum FBG, TNFα, and IL-6 mRNA expression (Mobasseri et al. 2020). In another clinical trial, overweight/obese prediabetic subjects received 15 mg of saffron daily for 8 weeks, FBG and glycosylated hemoglobin (HbA1c) significantly reduced in the saffron group compared to the placebo (Karimi-Nazari et al. 2019). Saffron also displays free radical scavenging activity without impacting lipid profiles, anthropometric measures, or renal markers (Karimi-Nazari et al. 2019). In another study, T2DM patients received 30 mg of saffron daily for 3 months, in which FPG, cholesterol, LDL-c, and LDL/HDL ratio significantly reduced in the saffron group compared with the control group; however, blood urea nitrogen (BUN), creatinine, HbA1c, TG, and HDL-C did not significantly change (Moravej Aleali et al. 2019). In another trial, 101 eyes of 60 patients with refractory diabetic maculopathy received 5 or 15 mg crocin daily for 3 months. Crocin 15 mg daily meaningfully reduced FPG, HbA1c, and central macular thickness (CMT) and improved best-corrected visual acuity (BCVA) in comparison to the placebo, although 5 g crocin daily failed to affect these outcomes (Sepahi et al. 2018). In a topical administration study, Mohammadzadeh-Moghadam et  al. reported that a 1% saffron-based gel improved erectile dysfunction in diabetic men based on the International Index of Erectile Function Questionnaire (Mohammadzadeh-Moghadam et al. 2015). To summarize, saffron has several potential benefits to diabetic individuals. The effect of saffron or crocin was assessed on several biomarkers in T2DM patients, with promising outcomes. Nevertheless, due to the heterogeneity of the studies, making a broad conclusion is difficult, which indicates that more studies will be required.

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17.3.3 SAFFRON AND MENTAL HEALTH Depression and anxiety are common psychological problems with a high prevalence and economic costs. Antidepressant drugs, psychotherapy, and electroconvulsive therapy are some therapies to treat depression and anxiety, and due to unfavorable adverse effects, limited efficacy, and low tolerability, finding a novel treatment strategy is warranted (Shafiee et al. 2018b). Saffron is identified as a natural agent with antidepressant properties. It is revealed that several mechanisms might justify antidepressant effects of saffron, including anti-inflammatory, antioxidant, serotonergic, hypothalamus-pituitary-adrenal (HPA) axis-modulating, and neuroprotective properties (Figure 17.3) (Lopresti and Drummond 2014). Previous systematic reviews and meta-analyses showed that saffron might be used to treat anxiety and depression (Lopresti and Drummond 2014; Marx et al. 2019; Khaksarian et al. 2019; Dai et al. 2020). In one recent clinical trial, 30 mg crocin daily was administrated during doxorubicin-based breast cancer chemotherapy. Anxiety, depression, hypersensitivity reaction, and neurological disorders significantly decreased, whereas leucopenia dramatically increased in the crocin group compared with the placebo (Salek et al. 2021). In a study, women with body mass index (BMI) > 25 and mild to moderate depression were supplemented with 30 mg of Crocus sativus capsules (15 mg twice daily) for 12 weeks. At the end of the study, the score of depression significantly decreased in the saffron group compared with the placebo group though saffron did not affect food craving (Akhondzadeh et al. 2020). In another study, adults with persistent depression taking an antidepressant drug were asked to take a placebo or a saffron extract (affron, 14 mg twice daily). After 8 weeks, depressive symptoms based on Montgomery-Åsberg Depression Rating Scale (MADRS) were reduced in more patients in the saffron group than placebo. Adverse effects

FIGURE 17.3 Schematic summary of pathways depicting potential beneficial effects of saffron on anxiety and depression, sleep quality, and quality of life. As illustrated in the figure, saffron’s anti-inflammatory, antioxidant, serotonergic, hypothalamus-pituitary-adrenal (HPA) axis-modulating, and neuroprotective properties may reduce depression and anxiety, resulting in improved sleep quality and quality of life.

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of antidepressants were fewer in the saffron group compared with placebo. However, there were no significant differences between groups regarding self-rated MADRS and quality of life (Lopresti et al. 2019). In another trial, patients with HIV/AIDS who took methamphetamine (depression usually occurred after taking this drug) received 30 mL of saffron daily. After 8 weeks, depression was significantly reduced in the intervention group compared with a control group (Jalali and Hashemi 2018). In a study conducted on youth aged 12–16 years having mild to moderate anxiety or depression, supplementation with saffron extract (affron, 14 mg twice daily) resulted in improvements in internalizing symptoms, separation anxiety, social phobia, and depression (Lopresti et al. 2018). In their study, Tabeshpour et al. assessed the effects of saffron (15 mg twice daily) on mothers with a maximum score of 29 on the Beck Depression Inventory–II (BDI-II). After 8 weeks, the BDI-II score significantly decreased in the saffron group compared with the placebo group. The remission rate was 96% in the saffron group compared with the 43% in the placebo group (Tabeshpour et al. 2017). In another study, supplementation with 30 mg of crocin for 8 weeks resulted in a significant decrease in depressive symptoms compared with placebo in patients with metabolic syndrome (Jam et al. 2017). In a study, 50 mg saffron capsules for 12 weeks resulted in a significant decrease in anxiety and depression in adults with anxiety and depression (Mazidi et al. 2016). To sum up, based on several studies conducted of patients with depression, it seems that saffron or crocin can be considered as a novel and practical treatment for mild and moderate depression and anxiety. Only a very few adverse effects were reported by some studies, indicated safety of saffron use in mental disorders. Almost all of the studies were conducted in Iran, more studies will be needed in different area of the world. In addition, it is necessary to focus on differences between saffron and crocin and the optimum dose and duration.

17.3.4

SAFFRON AND SLEEP

The prevalence of insomnia is estimated at 5%–15%, with approximately 30%–43% of adults reporting at least one symptom of insomnia (Morin et al. 2006; Ohayon and Reynolds III 2009; Walsh et al. 2011). Considering that insomnia is not a homogenous disorder and has multifaceted pathophysiology, its treatment is one of the main challenging issues globally (Riemann et al. 2010). Recently, herbal medicine, particularly saffron, has attracted significant attention as a novel and safe treatment approach for decreasing the rate of insomnia and increasing sleep quality. Several potential mechanisms are suggested for the potential sleep-enhancing qualities of saffron though its main mechanisms are unclear. For example, saffron influences several factors related to sleep quality and insomnia such as serotonergic, glutaminergic, and γ-aminobutyric acid (GABA)-ergic systems (Meyerhoff et al. 2014; Gottesmann 2002; Carmassi et al. 2020; Hosseinzadeh and Sadeghnia 2007; Georgiadou et al. 2012). In addition, as it has been shown that inflammation and insomnia have a direct association (Slavish et al. 2018), saffron’s anti-inflammatory properties might be important in sleep enhancement and sleep restoration. Animal studies showed that saffron constituents such as crocin, safranal, and crocetin caused increases in non–rapid eye movement sleep (Masaki et al. 2012; Liu et al. 2012). Moreover, saffron’s antidepressive and anxiolytic properties might improve sleep quality. In a recent clinical trial, adults with inadequate sleep were asked to consume saffron extract (affron) (14 or 28 mg) 1 hour before bed. After 28 days of supplementations, saffron (at both doses) caused a greater improvement in the quality of sleep, mood ratings after awakening, the Insomnia Symptom Questionnaire (ISQ) total score, and ISQ insomnia classifications. However, compared to the placebo, saffron had no significant effects on restorative sleep questionnaires and the functional outcomes of sleep questionnaires. Evening melatonin concentrations significantly increased after saffron supplementation; however, evening cortisol did not significantly change (Lopresti et  al. 2021). As mentioned above, saffron (100 mg daily) for 8 weeks increased the sleep quality in overweight and obese diabetic patients as assessed with PSQI (Tajaddini et al. 2021). In another study, individuals with mild to moderate sleep disorders associated with anxiety were supplemented with

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saffron extract (15.5 mg daily). After 6 weeks, actigraphy data indicated that time in bed increased, while getting to sleep became easier based on the LSEQ questionnaire, and sleep quality, duration of sleep, sleep latency, and global scores improved according to the PSQI questionnaire in the saffron group compared with baseline. Interestingly, however, only an increase in sleep duration was significantly higher than in the placebo group (Pachikian et al. 2021). In another crossover study in healthy adults with mild sleep complaints, 7.5 mg crocetin daily for two intervention periods of 14 days each was associated with increases in objective sleep parameter (delta power) compared with placebo. However, no significant differences were found in sleep latency, sleep efficiency, total sleep time, or wake after sleep onset. Moreover, a significant improvement was observed in subjective scores, including sleepiness on rising and feeling refreshed in crocetin compared to the placebo (Umigai et al. 2018). To sum up, saffron or its constituents has favorable effects on sleep quality, though the number of the study is relatively low, and considering their heterogeneity in terms of sample size, dose, and duration of the studies, making a broad conclusion is difficult.

17.3.5

SAFFRON AND OTHER HUMAN CONDITIONS

Saffron may also provide some mild effects on sexual health. For example, Kashani et al. studied women who had major depression using 40 mg fluoxetine daily for at least 6 weeks with sexual dysfunction who co-supplemented with saffron (30 mg daily) for 4 weeks (Kashani et al. 2013). These researchers noted a significant improvement in the Female Sexual Function Index (FSFI), arousal, lubrication, and pain in the saffron group compared to fluoxetine alone. However, in another clinical trial, infertile men with idiopathic oligoasthenoteratozoospermia (OAT) supplemented with saffron (60 mg daily) for 26 weeks failed to impact semen parameters and total seminal plasma antioxidant capacity (Safarinejad et al. 2011). Asthma and chronic airway inflammation have a direct association, and it is hypothesized that saffron with anti-inflammatory properties might be a potential treatment strategy. Saffron has also been investigated as a potential therapeutic avenue for asthma. In a study in patients with mild and moderate allergic asthma, saffron (100 mg daily) for 8 weeks resulted in improvement in the frequency of the subjects’ clinical symptoms, such as the shortness of breath frequency, usage of salbutamol spray, waking up because of asthma symptoms, and limitation of activity compared with placebo (Zilaee et al. 2019). Systolic and diastolic blood pressure, triglycerides, and LDL were significantly reduced in the intervention group compared with the placebo (Zilaee et al. 2019). Recently, saffron’s primary constituent crocin was also investigated in patients with multiple sclerosis. In one study, patients received 30 mg crocin daily for 28 days. Results showed that lipid peroxidation, DNA damage, TNF-α, and IL-17 significantly decreased, whereas serum total antioxidant capacity significantly increased in the crocin group compared to the placebo group (Ghiasian et al. 2019). Crocin has also been investigated in mitigating withdrawal symptoms. Since methadone maintenance treatment (MMT) programs make patients susceptible to a range of problems such as withdrawal syndrome, craving, and cognitive deficits, one clinical trial used crocin to reduce these unfavorable complications of MMT. This study used 30 mg crocin daily for 12 weeks in subjects under MMT programs. Compared to the placebo, crocin led to a reduction in craving and withdrawal symptoms scores. However, crocin did not affect cognitive function parameters (Abbaszadeh-Mashkani et al. 2021). In another clinical trial, the effects of saffron on rheumatoid arthritis were assessed. In this study, patients received 100 mg saffron daily for 12 weeks. Results showed that saffron significantly decreased the number of tender and swollen joints, pain intensity using a visual analog scale, and disease activity score (DAS28) in rheumatoid arthritis patients (Hamidi et al. 2020). Moreover, there was a significant improvement in physician global assessment (PGA) and erythrocyte sedimentation rate (ESR). In another study, adults with mild to moderate age-related macular degeneration (AMD) were supplemented with saffron (20 mg daily) for 3 months followed by crossover for 3 months. Finally,

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there was a significant reduction in mean BCVA and changes in multifocal electroretinogram (mfERG) in the saffron group compared with the placebo (Broadhead et al. 2019). It seems that saffron can be used as complementary medicine to improve a wide range of conditions though more studies will be required.

17.4

OTHER FOODS, HERBS, SPICES, AND BOTANICALS USED IN THE MIDDLE EAST

Turmeric and its main polyphenol curcumin are widely used in the Middle East. A large body of evidence showed the unique properties of curcumin to prevent and combat a wide range of diseases (Mohseni et  al. 2021; Bagherniya, Soleimani, et  al. 2021; Bagherniya, Askari, et  al. 2021; Atefi et al. 2021). It has been shown that curcumin plays a beneficial role in human health through its antidiabetic, antihyperlipidemic, anti-inflammatory, antioxidant, antitumor, anticoagulant, antiviral, and antibacterial effects (Rafiee et al. 2021; Mahdavi et al. 2021; Alikiaii, Bagherniya, Askari, Sathyapalan, et al. 2021; Alikiaii, Bagherniya, Askari, Johnston, et al. 2021; Miryan et al. 2021; Bagherniya et  al. 2018). Several clinical trials conducted in the Middle East using curcumin to improve human health, and their results were summarized in recent systematic reviews; in almost all of them, curcumin showed promising effects on different aspects of human health (ShokriMashhadi et al. 2021; Shirban et al. 2021; Safari et al. 2021; Rafiee et al. 2021; Mohseni et al. 2021; Mahdavi et  al. 2021; Bagherniya, Soleimani, et  al. 2021; Bagherniya, Askari, et  al. 2021; Atefi et al. 2021; Alikiaii, Bagherniya, Askari, Sathyapalan, et al. 2021; Alikiaii, Bagherniya, Askari, Johnston, et al. 2021). Another herb is cinnamon, which is widely used in the Middle East as a safe and inexpensive complementary medicine for prevention and treatment of diseases. It has been shown that cinnamon has antioxidant, anti-inflammatory, and antiviral properties (Zareie et al. 2020; Zareie et al. 2021; Rao and Gan 2014). In addition, several studies indicated that cinnamon has beneficial effects on the metabolic profile among patients with non-communicable diseases (Shirzad et al. 2021; Keramati et al. 2022; Jamali, Kazemi, et al. 2020; Jamali, Jalali, et al. 2020; Atazadegan et al. 2021). Resveratrol is another phytochemical which is used widely in the Middle East as an adjunct therapy to improve human health. Antioxidant and anti-inflammatory properties of resveratrol play a significant role in neutralizing liver tissue damage, kidney, and brain caused by oxidative stress and inflammation. As oxidative stress and inflammation have a salient role in pathogenesis of several diseases such as diabetes, CVD, cancer, and other metabolic diseases, it seems that supplementation with resveratrol may result in attenuating or preventing the progression of these diseases (Bagherniya et  al. 2018). Findings of recent meta-analyses confirmed beneficial effects of resveratrol on CVD risk factors including glycemic parameters, lipid profile and inflammatory factors (Zhang et al. 2021; Zeraattalab-Motlagh et al. 2021; Koushki et al. 2018). Moreover, several other herbs such as propolis, berberine, ginseng, ginger, garlic, and so on were used for centuries as spices, food additives, flavoring, and medicinal purposes in the Middle East. Almost all of these agents showed promising effects on a wide range of diseases (Falzon and Balabanova 2017; Guo et al. 2021; Samadi et al. 2022; Gheflati et al. 2021).

17.5 TOXICITY AND CAUTIONARY POINTS Saffron has been used for a long time as a safe and favorable spice and food flavoring. It is indicated that ingestion of 5 g saffron is toxic and using saffron with dose of 20 g daily can be lethal (Moshiri et al. 2015). On the other hand, in clinical trials, saffron was usually supplemented in considerably lower dose (30–100 mg daily) with a wide therapeutic index. The most common side effects of mild toxicity with saffron are dizziness, vomiting, nausea, and diarrhea. Numbness, tingling in the hands and feet, yellowish skin and eyes, and spontaneous bleeding are common side effects of severe toxicity with saffron (Moshiri et al.

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2015). Saffron at dose of 200 mg daily caused a reduction in platelet counts (Modaghegh et al. 2008) though other studies did not find similar finding (Moshiri et al. 2015). In a study, supplementation with 200 and 400 mg daily of saffron for 1 week resulted in increasing in creatinine and blood urea nitrogen levels (Modaghegh et al. 2008).

17.6 CONCLUSION This review discusses the potential beneficial effects of saffron and its constituents, particularly crocin, on various aspects of human health and disorders. Overall, randomized clinical trials suggest saffron as a natural, safe, and accessible agent to treat several conditions, especially mental disorders. Evidence also suggests that saffron can treat mild to moderate depression. Likewise, it can be used as a safe agent to increase the quality of sleep and life. Recently, due to saffron’s antioxidant, anti-inflammatory, and antidiabetic properties, it is considered an herb with potential beneficial effects on various metabolic dysfunctions. However, the beneficial effects of saffron on different parameters related to the metabolic status of patients, like those with diabetes, will require additional studies to best elucidate the exact mechanisms involved in modulating its specific effects. In rare cases, gastrointestinal adverse effects have been reported. Future studies should focus on an optimum dose, differences between saffron and crocin, the best duration for intervention, and identify the potential adverse effects regarding supplementation with saffron/crocin in different diseases.

17.7 • • • • • •

SUMMARY POINTS This chapter focuses on the effectiveness of saffron and crocin on human health. Crocin, picrocrocin, and safranal are the most important constitutes of saffron. Saffron has promising effects on mental health, reduction of depression, and anxiety. Saffron has beneficial effects on patients with diabetes mellitus. Saffron can improve sleep quality. Saffron in doses of less than 1.5 g is safe and without significant adverse effects.

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Sage Plants (Salvia sp.; Lamiaceae) in the Middle East Phytochemistry, Ethnopharmacology, and Traditional Use Salar Hafez Ghoran, Fatemeh Taktaz, Ali Akbar Mozafari, Armin Saed-Moucheshi and Ali Hosseini

CONTENTS 18.1 18.2 18.3

Introduction.........................................................................................................................264 Uses of Salvia Species in Middle East Traditional Medicine .............................................264 Phytochemistry ...................................................................................................................266 18.3.1 Monoterpenoids and Sesquiterpenoids................................................................267 18.3.2 Diterpenoids ........................................................................................................268 18.3.3 Sesterterpenoids...................................................................................................268 18.3.4 Triterpenoids and Phytosterols ............................................................................268 18.3.5 Flavonoids ...........................................................................................................268 18.3.6 Caffeic Acid Derivatives......................................................................................269 18.4 Pharmacological and Biological Activities .........................................................................269 18.4.1 Antioxidant Activity ............................................................................................269 18.4.2 Anti-Inflammatory Activity .................................................................................270 18.4.3 Antibacterial Activity ..........................................................................................270 18.4.4 Antifungal Activity ..............................................................................................271 18.4.5 Antiviral Activity .................................................................................................271 18.4.6 Anti-Parasite Activity ..........................................................................................272 18.4.7 Cytotoxic and Antiproliferative Activity .............................................................272 18.4.8 Antidiabetic Activity............................................................................................273 18.4.9 Anti-Alzheimer Activity ......................................................................................273 18.4.10 Insecticidal Activity .............................................................................................273 18.5 Toxicity and Cautionary Points ...........................................................................................274 18.6 Summary Points ..................................................................................................................274 References......................................................................................................................................274

LIST OF ABBREVIATIONS Acetyl-CoA AChE CHCl3 CH2Cl2 DMAPP

acetyl-coenzyme A acetylcholinesterase chloroform dichloromethane dimethylallyl diphosphate

DOI: 10.1201/9781003243472-20

263

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EtOAc FC FPP GC-FID GC-MS GGPP GPP HPLC HSV-1 HSV-2 IPP LPS MeOH MIC n-BuOH NF-κB NO PI-3 SDA SRB TAS TNF-α

ethyl acetate Folin-Ciocalteu reagent farnesyl diphosphate gas chromatography–flame ionization detector gas chromatography–mass spectrometry geranylgeranyl diphosphate geranyl diphosphate high-performance liquid chromatography herpes simplex virus type 1 herpes simplex virus type 2 isopentenyl diphosphate lipopolysaccharide methanol minimal inhibition concentration n-butanol nuclear factor-kappa B nitric oxide parainfluenza type 3 Sabouroud dextrose agar sulphorhodamine B total antioxidant status tumor necrosis factor-alpha

18.1 INTRODUCTION The genus Salvia L. (Lamiaceae), commonly known as sage, includes over 1000 species distributed across the world. These species are mainly shrubby and odorous perennial plants that are grown in America, the Mediterranean, the Middle East, the Pacific Islands, and tropical Africa (Figure 18.1). In Mexico, approximately 300 species have been recorded. Therefore, Mexico is considered the host of the greatest diversity regarding the genus Salvia. After Mexico, Turkey has a high diversity of Salvia plants with more than 100 reported species, followed by China (about 84) and Iran (about 62). Since ancient times, Salvia species have been used not only for therapeutic approaches but also for use in the food industry especially as a spice to flavor meats like pork, sausage, and poultry (Hafez Ghoran et al. 2022; Wu et al. 2012). In addition to S. officinalis L., which is used in the Middle East traditional and commercial products, there are some other important Salvia plants that are of particular interest in folk medicine and pharmacological attitudes, including S. aegyptiaca L., S. aethiopis L., S. fruticosa Mill., S. hydrangea DC. Ex Benth., S. indica L., S. libanotica Boiss. & Gaill, and S. reuterana Boiss. (Kintzios 2000). Sage plants have been used by local people of the Middle East to treat common human disorders/symptoms such as gastrointestinal disorders (abdominal pain, colic, indigestion, and diarrhea); respiratory dysfunctions (cough, colds, and sore throat); infection disorders (bacterial, parasitic, tuberculosis, and influenza); pain (headache and stomachache); and miscellaneous complications (liver diseases, diabetes, barrenness, and hemorrhage). This chapter explores current knowledge of traditional and ethnopharmacological uses of sage plants in the Middle East.

18.2

USES OF SALVIA SPECIES IN MIDDLE EAST TRADITIONAL MEDICINE

The traditional uses of sage plants include the treatment of a variety of diseases, ranging from a simple stomachache to highly complicated inflammation and diabetic disorders. In the south and central parts of Iran, the aerial parts of S. mirzayanii Rech. f. & Esfand. are commonly consumed in a form of infusion or decoction to treat diarrhea, gastrointestinal disorders,

Sage Plants (Salvia sp.; Lamiaceae) in the Middle East

FIGURE 18.1

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The Middle East nations.

hypercholesteremia, infections, and diabetes (Ayatollahi et al. 2015). In Iranian traditional medicine, the aerial parts of S. hydrangea are used in the south of Iran for the treatment of carminative, insomnia, anti-inflammatory, and antispasmodic disorders (Bahadori and Mirzaei 2015). The plant’s infusion is also capable of anti-leishmanial and anthelmintic activities used by the people in Fars Province (Sairafianpour et al. 2003). A variety of species, including S. multicaulis Vahl, S. nemorosa L., S. aegyptiaca L., S. hypoleuca Benth., S. leriifolia Benth., S. reuterana Boiss., S. sahendica Boiss. & Buhse, S. sharifii Rech.f. & Esfand., S. spinosa L., and S. urmiensis Bunge, grow wild in different regions of Iran and are consumed traditionally for their ability to treat dyspepsia, diarrhea, skin, carminative, digestive, purgative, sedative, urinary disorders, hemorrhoids, hypoglycemic, anti-inflammatory, antidiabetic, antibacterial, antiseptic, and insecticide effects (Askari et al. 2021). In different locations of Iran, the decoction, infusion, macerated extracts and the grinded roots and aerial parts of other sage plants including S. aethiopis L. (Mediterranean sage), S. bracteata Banks & Sol, S. macrosiphon Boiss., S. macilenta Boiss., S. sclarea L., and S. viridis L., have been locally prescribed by traditional healers not only in respiratory and nervous system complications, cardiovascular and eye disorders, antiseptic, antibiotic, and antiparasite effects but also in cosmetics, sanitation, and the food industries as spices. S. indica L., S. microstegia Boiss. & Balansa, S. russellii Benth., and S. syriaca L. have also been consumed in Turkish and Lebanese traditional medicine (Hatipoğlu et al. 2016). People of Central Anatolia use the aerial parts of some sage species like S. russellii, S. dichroantha Stapf., and S. verticulata L. spp. amasiaca Bornm. as a tea or decoction for treatment of common cold and abdominal pains (Sezik et al. 2001). In the western Mediterranean region in Turkey, the infusion of aerial parts such as shoots, flowers, and leaves of S. viridis (red-topped sage), S. sclarea (clary sage), and S. tomentosa Miller are commonly consumed in folk medicine for sore throat, throat inflammation, bronchitis, asthma, antitussive, ulcer, intestinal spasms, gynecological disorders, and respiratory tract diseases (Sharifi-Rad et al. 2018). Due to the rich traditional culture, Turkish people use different parts of Salvia plants. For instance, the infusions, decoctions, powdered and plant preparations of following Salvia species have been utilized in folk medicine, S.

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wiedemannii Boiss. for the treatment of peptic ulcers and relieving pain; S. cryptantha Montbert & Aucher ex Benthan and S. triloba L. (Eastern Mediterranean sage) for the treatment of stomach symptoms, wound disinfectant, cough and cold; S. tomentosa (balsamic sage; syn.: S. grandiflora) and S. chrysophylla Stapf (golden leaf sage) for relieving the abdominal and rheumatic pains and teeth strength; S. aethiopis and S. nemorosa (woodland sage) for wound healing and hemorrhage, S. russellii, S. dichroantha, and S. verticillata (lilac sage) for the treatment of catarrh, cold, stomachache, and abdominal pain (Ustun and Sezik 2011). In the Kurdistan region of Iraq, infusion and decoction of different plants belonging to the Salvia genus such as S. officinalis flowers, S. limbata C.A.Mey. aerial parts, S. euphatica Montbret & Aucher flowers, S. indica leaves, S. smyrnaea Boiss. leaves, and S. adenocaulon P.H.Davis leaves, have been locally used for the treatment of colds, fever, stomach, intestinal, gastrointestinal disorders, hypoglycemic, antibacterial, and reduction of cholesterol (Amin et al. 2016). In the Tafila region of Jordan, decoction or infusion of S. fruticosa Mill. leaves, locally known as Meirameieh, are utilized for hair tonic, antidandruff, weight loss, improve memory, colic problems, and nervous system disorders (Abdelhalim et al. 2017). A survey on the ethno-botanical plant species used by local Jordanian people showed that three or four daily doses of decoction, cold or hot beverage of S. triloba leaves is used orally for reliving the stomach, abdominal, and colic pain. The plant has also an antispasmodic ability that is very popular among people who live in central part of country (Oran and Al-Eisawi 2015). In Lebanese traditional medicine especially in the Beirut region, the leaves of S. triloba are applied to relieve the nervous system conditions, asthma, rheumatism, and diabetes (Salah and Jäger 2005). Moreover, it has been documented that Lebanon traditional healers have prescribed the decoction of aerial parts of S. acetabulosa L. for blood glucose and blood pressure reduction, menstrual disorders, insomnia, pain reduction in joints, coronary heart disease, antimicrobial, antianxiety, antidepressive effects, eupeptic, and antihydrotic properties (Loizzo et al. 2008). In the West Bank regions of Palestine, traditional healers have orally prescribed the Salvia plants for human cancer treatment. For instance, the infusion of S. palaestina Benth. leaves is used to treat brain cancer (given twice a day) and a decoction of aerial parts of S. fruticosa is applied for the treatment of colon and liver cancers (given four times daily) (Jaradat et al. 2016). S. fruticosa, known as Greek sage, is the most significant Salvia species in Cyprus that its infusion along with its volatile oil is used traditionally to treat cough, throat, skin, respiratory system, and digestive complications (González-Tejero et al. 2008). According to a comprehensive ethnobotanical survey of the medicinal plants wildly grown in the central Abyan governorate of Yemen, the whole parts of S. merjamie are traditionally used for the treatment of fever. Interestingly, cutting the fresh pieces of the plant followed by tying the plant materials under feet is also popular among local people for relieving inflammation of feet soles (Al-Fatimi 2019). Gali-Muhtasib and his colleagues have reviewed the traditional uses of S. libanotica Boiss. & Gaill, known as Eastern Mediterranean sage. A decoction of the plant has been extensively used in Lebanese, Syrian, Palestinian, Turkish, and Jordan folk medicine, so herbalists and pharmacists consider the plant a universal drug for the relief of stomachache, headache, ulcer, and abdominal pain. Infusion of the plant and inhaling its essential oils are recommended for healing fractured bones. S. libanotica has more advantages in the treatment of heart disorders and respiratory symptoms including colds, coughs, and influenza (Gali-Muhtasib et al. 2000).

18.3 PHYTOCHEMISTRY Scientists all over the world have investigated the chemical composition and biological and pharmacological activities of Salvia plants, which are containing a large number of secondary metabolites. According to various studies, these chemical compositions are more effective on different ailments in order to be extracted from the species of Salvia (Hafez Ghoran et al. 2022, Wu et al. 2012).

Sage Plants (Salvia sp.; Lamiaceae) in the Middle East

18.3.1

267

MONOTERPENOIDS AND SESQUITERPENOIDS

Monoterpenoids, the C10 secondary metabolites, are produced from two isoprene units through a combination of dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP) leading to geranyl diphosphate (GPP) production. In addition to monoterpenoids, the predominant Salvia compounds are sesquiterpenoids with C15 carbon backbone derived from a farnesyl diphosphate (FPP) (Dewick 2002). In general, the essential oil compositions of the Middle East sage plants are rich of mono- and sesquiterpenoids with acyclic, monocyclic, and bicyclic structures. The highly significant components of these plants, which have positive effects on human health, are linalool (1), linalool acetate (2), limonene (3), terpinen-4-ol (4), 1,8-cineole (5), α- and β-pinene (6, 7), borneol (8), bornyl acetate (9), β-farnesene (10), germacrene-D (11), α-bisabolol (12), β-elemene (13), β-eudesmol (14), cadinadiene (15), β-caryophyllene (16), bicyclogermacrene (17), α-bourbonene (18), α-gurjunene (19), and spathulenol (20) (Figure 18.2) (Wu et al. 2012).

O OH

O

OH

O

OH 1

2

4

3

O OH

H

21

H

H OH CH2OH

23

COOH

H

O

HO

O

H

H

O HO

OH

27

H

O

H

O

H HO

26

O

HO HO

O

HO

H

28

H

HO H

H

O

H

O

31

H

OH

HO

O

HO HO

O

O

H O

O

H

29

H

COOH

H

25 24

HO

OH H

20

O

O

H 22

OH

O OH

OH HOOC

12

19

O

HO

H

11

18

17

16

OH

10

O

H

H

15

14

9

8

7

OH

H 13

O

O 6

5

O

32

30

OH

OH O

HO HO

O

O

OH

OH

33

OH O

OH

O

34

OH O

O HO HO

O

OH

HO

O

HO COOH HO

O OH

O 36

HO

O

OH

OH

OH

OH

37

OH

O

OH OH

HO

OH

HO O

35

O

HO

HO

HO

O OH

O

O OH

O HO 38

OH

O OH

FIGURE 18.2 Chemical structures of some main phytochemicals reported from the sage plants grown in the Middle East regions.

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18.3.2

Ancient and Traditional Foods Used in the Middle East

DITERPENOIDS

Diterpenoids, derived from a DMPP as precursor and three molecules of IPP as extenders, have a C20 carbon skeleton. The formation processes of geranylgeranyl diphosphate (GGPP) followed by various cyclization induce the construction of diterpenoids (Dewick 2002). Literature survey demonstrate that the content of diterpenoids in the roots of sage plants are higher than that of the aerial parts. Ferruginol (21; an abietane diterpenoid), isopimaric acid (22; a pimarane diterpenoid), and sclareol (23; a labdane diterpenoid) are some examples of diterpenoids that are reported from the Middle East Sage plants (Figure 18.2) (Wu et al. 2012).

18.3.3 SESTERTERPENOIDS Salvia sesterterpenoids are bioactive C25 metabolites that originated from a GGPP as a precursor along with a nucleophilic addition of one IPP leading to build a prenyllabdane core skeleton which are sometimes bearing a γ-lactone ring (Guo et al. 2021). These compounds not only are biosynthesized in the fungi, bacteria, lichens, insects, and marine organisms, but also are derived in the plant kingdom especially the Lamiaceae family. To date, these uncommon compounds have been reported in ten Salvia plants, seven of which (S. aethiopis, S. hypoleuca, S. syriaca, S. sahandica, S. mirzayanii, S. palaestina, and S. lachnocalyx Hedge) are mostly growing in the Middle East regions. Salvisyriacolide (24) and lachnochalyxolide C (25) (Figure 18.2) are two bicyclic and tricyclic examples of Salvia sesterterpenoids (Hafez Ghoran et al. 2022).

18.3.4

TRITERPENOIDS AND PHYTOSTEROLS

Triterpenoids are C30 secondary metabolites derived from a combination of two FPP molecules joined tail-to-tail leading to the formation of squalene followed by cyclization. It is noteworthy mentioning that the Sage triterpenoids are belonging to the ursanes, oleanes, dammaranes, lupanes, and a novel carbon skeleton consisting a condensation of a diterpene plus a monoterpene through a Diels-Alder reaction. It is well-documented that the Middle East sage plants contain all of these triterpenoids types, for example ursolic acid (26), oleanolic acid (27), russelliinoside A (28), lupeol (29), and hydrangenone (30) (Figure 18.2), are reported to be available in the aerial parts of S. russellii, S. palaestina, and S. hydrangea (Hafez Ghoran et al. 2021; Hafez Ghoran et al. 2022). Phytosterols or plant sterols are steroid alcohols that are found in the Salvia seed oils, as well to the aerial parts of Salvia species. These metabolites are chemically similar to cholesterol with few changes in their chemical structures. β-sitosterol (31) and daucosterol (32) (Figure 18.2) are two examples of sage steroids reported from the aerial parts of S. limbata, which grows wild in Iran, Turkey, and Afghanistan. Also, the availability of stigmasterol and stigmasterol-3-O-glucoside has been previously reported (Saeidnia et al. 2011).

18.3.5

FLAVONOIDS

The plants of Salvia genus are also produce the bioactive flavonoid components derived from phenylalanine and three acetyl-coenzyme A (Acetyl-CoA) molecules. Flavonoids possess a C6-C3-C6 carbon skeleton showing a key role in the prevention of different kinds of human diseases via scavenging toxic oxidants (Dewick 2002). Salvia flavonoids are in two types, glycosylated flavonoids and their aglycones (Lu and Foo 2002). Approximately, all the Middle East sage plants contain both classes for instance, salvigenin (33) and cynaroside (34) (Figure 18.2) in the aerial parts of S. dracocephaloides Boiss. (Hafez Ghoran et al. 2020; Wu et al. 2012).

Sage Plants (Salvia sp.; Lamiaceae) in the Middle East

18.3.6

269

CAFFEIC ACID DERIVATIVES

Phenolic acids are other prominent phytochemicals that are distributed in Salvia plants. These compounds are including caffeic acid monomers (with C6 -C3 building block) and their related oligomers originating from a variety of condensation reactions. Like flavonoids, caffeic acid derivatives have been more considered because they act as potential non-enzymatic antioxidants. Caffeic acid (35), chlorogenic acid (36; a caffeic acid dimer), salvianolic acid K (37; a caffeic acid trimer), and sagerinic acid (38; a caffeic acid tetramer) (Figure 18.2) are examples of caffeic acid derivatives recorded in S. officinalis (Lu and Foo 2002), which is commercially cultivated in the Middle East countries.

18.4

PHARMACOLOGICAL AND BIOLOGICAL ACTIVITIES

Apart from a comprehensive investigation of secondary metabolites in the Salvia genus, there is a broad spectrum of scientific and ethnopharmacological studies dealing with the various types of herbal preparations, extracts, and chemical compositions that are guaranteed human health. Reported the outstanding pharmacological effects of S. officinalis called the researchers for in-deep investigations on Salvia plants for their health benefits, such as antioxidant, anti-inflammatory, antimicrobial, antiparasite, anticancer, antidiabetic activities, in addition to anti-Alzheimer and cognitive enhancer ability (Figure 18.3) (El-Feky and Aboulthana 2016). The following can be described as a pharmacological overview of Salvia plants wildly grown in the Middle East habitats.

18.4.1

ANTIOXIDANT ACTIVITY

A variety of investigations has been carried out on the Middle East Salvia plants to evaluate the antioxidant potential and modulation of the induced-oxidative stress in plant cells causing DNA damage. On this occasion, the sage bioactive phytochemical compounds, particularly caffeic acid derivatives and flavonoids have been recognized as antioxidant agents. In order to investigate the antiglycation and antioxidant activity of four Iranian medicinal plants, including S. hydrangea, Safari et al. (2018) evaluated the phenolic, flavonoids contents and antioxidant activities. Examined extracts in this study showed a high effective activity scavenging the free radicals (DPPH•) and glycation inhibition, which were significantly correlated with total phenolic and flavonoids contents. Furthermore, the

FIGURE 18.3 Sage plants (Salvia sp.; Lamiaceae) in the Middle East: ethnopharmacology use, phytochemistry, and pharmacology.

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Ancient and Traditional Foods Used in the Middle East

anti-DPPH• activities of various S. fruticosa extracts collected in Beirut, Lebanon were evaluated, including chloroform (CHCl3), ethyl acetate (EtOAc), methanol (MeOH), and n-butanol (n-BuOH). In this study, the total phenolic contents were measured by using Folin-Ciocalteu (FC) reagent; the phenolic constituents were identified by the high-performance liquid chromatography (HPLC) method. Accordingly, the antioxidant ability had a correlation with total phenolic contents, where the most abundant secondary metabolites were rutin and luteolin. All extracts exerted antioxidant activity; however, the EtOAc extract of roots and shoots showed potent and weak radical scavenging activity, respectively (Boukhary et al. 2016). Previously, the antioxidant effect of the essential oil and methanolic extract of S. eremophila, collected in the Kashan area of Iran, were investigated using both DPPH• and β-carotene-linoleic acid assays. Although the plant essential oils displayed a weak antioxidant activity, the methanolic extract had a considerable activity in both DPPH• scavenging (IC50 value of 35.19 μg/mL) and β-carotene-linoleic acid bleaching activities (inhibition percentage: 72.42%) (Ebrahimabadi et al. 2010). Yuce et al. (2014) investigated the total antioxidant status (TAS) of ethanol, n-hexane, and aqueous extracts of Turkish S. sclarea leaves, using Rel assay diagnostics TAS assay kit (Lot.RL024). The ethanolic extract exhibited the highest TAS levels among the obtained extracts (4.4 mmol Trolox equiv./L.). Esmaeili et al. (2010) examined in vitro the antioxidant activity of MeOH extracts obtained from three Iranian endemic Salvia plants including S. sahandica, S. lachnocalyx, and S. reuterana. The extract of the last plant showed the potent antioxidant activity, which was correlated with the total flavonoids and phenolic content.

18.4.2

ANTI-INFLAMMATORY ACTIVITY

Abu-Darwish et al. (2013) concluded that in concentrations up to 0.64 μL/mL, the essential oil of common sage (S. officinalis, collected from the several parts of Jordan) showed a significant in vitro anti-inflammatory activity through inhibition of nitric oxide (NO) production induced by lipopolysaccharide (LPS) in mouse macrophages, without any changes on cell viability. The most abundant essential compositions were 1,8-cineole (39.5–50.3%) and camphor (8.8–25.0%) characterized by gas chromatography–flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS) techniques. Boukhary et al. (2016) have also evaluated the anti-inflammatory activity of roots and aerial parts of Eastern Mediterranean sage crude extracts, using an adopted carrageenan-induced mouse paw edema model. In agreement with the positive control diclofenac, the promising anti-inflammatory activity was also recorded for both S. fruticosa crude extracts (0.9 and 0.8, respectively). Analyzed the crude extracts, rutin and luteolin were the major flavonoids correlating with the total phenolic contents tested by FC method. Ziaei et al. (2015) reported that a sesquiterpene metabolite isolated from S. mirzayanii (teuclatriol) had anti-inflammatory activity against human macrophage-like and endothelial cells (at a dose of 312 μM). Consequently, higher dosage of 390 μM not only showed an inhibitory effect on nuclear factorkappa B (NF-κB) signaling but also decreased the generation of tumor necrosis factor-alpha (TNF-α). Alonazi et al. (2021) examined the anti-inflammatory effects of the ethanolic and aqueous extracts of S. lanigera, collected from Al-Mariah area north of Riyadh, Saudi Arabia, using calculating the membrane stabilization of human red blood cells along with the percentage inhibition of the COX-1, COX-2, 5LOX, and sPLA2-V enzymes. Interestingly, the ethanolic extract of the plant displayed the highest membrane stabilization (≤91% at a concentration of 100 μg/mL) and equal to the standard drug diclofenac sodium (90.75%), while the aqueous extracts showed moderate activity (≤45%). Meanwhile, the ethanolic extract potently inhibited the COX-1 and 5LOX enzymes at a concentration of 100 μg/mL.

18.4.3

ANTIBACTERIAL ACTIVITY

There are several scientific reports dealing with Salvia essential oils as the effective antibacterial agents rather than their extracts. The essential oil of S. tomentosa aerial parts, collected

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in the Zorkun Plateau region of Turkey, was assayed toward seven gram-positive and gramnegative pathogenic bacteria. Enterobacter aerogenes (inhibition zone of 21 mm; MIC of 10 mg/mL) and Bacillus subtilis (inhibition zone of 20 mm; MIC of 10 mg/mL) were the most sensitive strains, followed by Micrococcus luteus (inhibition zone of 18 mm; MIC of 20 mg/ mL). Despite β-pinene (37.28%) and α-pinene (5.73%) as the predominant components, transpinocarveol (3.05%), myrtenol (2.81%), caryophyllene oxide (2.68%), and camphor (2.08%) were the major volatile compositions (Ulukanli et al. 2013). In order to confirm the traditional claims, Cardile et al. (2009) evaluated the antimicrobial activity of essential oils from aerial parts of S. bracteata and S. rubifolia, collected in Lebanon, against ten bacterial species causing respiratory, gastrointestinal, skin, and urinary disorders. Results showed that the S. bracteata essential oil was more active against gram-positive bacteria than S. rubifolia essential oil, as evidenced by the lower MIC values of 50 μg/mL for all the gram-positive bacterial strains. The petroleum ether and dichloromethane (CH2Cl2) fractions obtained from S. tebesana roots, collected from South Khorasan Province, Iran, possessed a significant antibacterial activity against gram-positive bacteria especially Bacillus cereus (for both MIC values of 1.25 mg/mL) (Eghbaliferiz et al. 2019). In case of detection of antibacterial components in the S. pachystachys essential oil, collected from North Khorasan Province, Iran, a bioautography assay was performed leading to find five volatile compounds (camphor, 1,8-cineole, borneol, spathulenol, and caryophyllene oxide) that are in charge of antibacterial activity toward Staphylococcus aureus (Shakeri et al. 2018).

18.4.4 ANTIFUNGAL ACTIVITY Abu-Darwish et al. (2013) examined the antifungal activity of common sage essential oil, collected from various Jordan regions, using in vitro cultivation method, against a panel of strains including yeasts and filamentous fungi strains (Aspergillus spp. and dermatophytes). Results demonstrated that the dermatophyte strains, especially Trichophyton rubrum and Epidermophyton floccosum were more sensitive to the Sage essential oil with the MIC values of 0.64 μL/mL when compared with Candida and Aspergillus strains. The more sensitive yeast was also Cryptococcus neoformans with a MIC value of 0.64 μL/mL. These findings proposed that the bioactive plant essential oils have no influence on keratinocytes viability. Hence, the essential oil preparations are indeed highly suitable in the combinations of skincare formulations for cosmetic and pharmaceutical goals. Yuce et al. (2014) have studied the antifungal activity of ethanol, n-hexane, and aqueous extracts of S. sclarea leaves, collected from Tunceli, Turkey, against two pathogen fungi, Epicoccum nigrum and Colletotrichum coccodes. Among various extracts assayed, the ethanol extract showed significant inhibition activities toward the mycelial growth of E. nigrum (65.2%) in Sabouroud dextrose agar (SDA) medium, while the low activity was recorded for n-hexane extract (32.1%).

18.4.5

ANTIVIRAL ACTIVITY

The antiviral activity of essential oils and various fractions of S. limbata and S. sclarea collected from Eastern Anatolia, Turkey, were assessed against influenza virus and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). In vitro findings exhibited that CH2Cl2 extract of S. sclarea and methanolic extract of S. limbata had prominent anti-influenza activities against both tested strains, A/Weybridge and A/Aichi. Interestingly, just the MeOH extract of S. sclarea effectively inhibited the HSV-1 and HSV-2 replication with EC50 values of 0.12 and 0.5 mg/mL, respectively (Öğütçü et al. 2008). In another research, the antiviral activity of the CHCl3 and MeOH extracts of 14 Turkish Salvia plants were evaluated against HSV-1 and parainfluenza type 3 (PI-3). In vitro outcomes showed that the CHCl3 extracts of S. cyanescens and S. microstegia were the best inhibitors on both viruses (Özçelik et al. 2011).

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18.4.6

Ancient and Traditional Foods Used in the Middle East

ANTI-PARASITE ACTIVITY

Following the traditional use of Iranian S. hydrangea as an anthelmintic and antileishmanial agent, Sairafianpour et al. (2003) purified the abietane-type diterpenoids along with oleanolic acid from the plant roots. The moderate antiplasmodial activity of S. hydrangea flowers was due to the presence of oleane-type triterpenoids, especially oleanolic acid, adversely affecting the Plasmodium falciparum growth through the erythrocyte membrane. The authors realized that oleanolic acid transformed the erythrocytes into stomatocytes in the concentration range where the in vitro antiplasmodial activity was detected (Sairafianpour et al. 2003). Currently, infection with the Echinococcus granulosus larval stage is a crucial zoonotic helminthic problem that Egyptians are dealing with. For this reason, an antiparasite study was designed under in vitro condition regarding the effects of ethanolic extracts of S. officinalis and Thymus vulgaris on the viability of cystic hydatid protoscolices, Echinococcus granulosus. Both plant extracts had a dose-dependent protoscolicidal activity at concentrations of 500 μg/mL on day 6 and day 7 posttreatment, respectively, when compared to the reference albendazole drug, which did not inhibit the parasites before day 10 posttreatment (Yones et al. 2011).

18.4.7

CYTOTOXIC AND ANTIPROLIFERATIVE ACTIVITY

The antiproliferative effects of essential oils of two Lebanon Salvia species, S. bracteata and S. rubifolia, were assessed against M14 human melanoma cells using MTT assay. In vitro findings of two examined essential oils exhibited an inhibitory activity on the human cancer cells together with induction of apoptotic cell death. Indeed, in a dose-dependent behavior, the oil of S. rubifolia was significantly (p < 0.001) more active as compared to the oil of S. bracteata. GC-FID and GC-MS analysis revealed that caryophyllene oxide (16.6%) and (E)-caryophyllene (4.1%) were the major component in the S. bracteata essential oil, while γ-muurolene (11.8%), trans-pinocarvyl acetate (5.5%), and γ-cadinene (5.5%) were the predominant compositions in the S. rubifolia essential oil (Cardile et al. 2009). The cytotoxic evaluation of petroleum ether, CH2Cl2, n-BuOH, and water fractions prepared from the methanolic extract of S. tebesana roots represented that both non-polar and semi-polar fractions of the plant showed cytotoxicity against A2780 (ovarian), MCF-7 (breast), and DU 145 (prostate) cancer cell lines as evidenced by IC50 values less than 50 μg/mL. Furthermore, results showed that the petroleum ether fraction had also a substantial antiproliferative activity toward DU 145 cell lines (IC50 of 6.25 μg/mL) (Eghbaliferiz et al. 2019). In another research, the growth of MCF-7 cells was inhibited by S. russellii dichloromethane extract with an IC50 13.62 μg/mL. Furthermore, russelliinosides A and B isolated from the plant had toxicity against MCF-7 and A549 cell lines (Hafez Ghoran et al. 2021). The antitumor activity of methanol extracts of six Jordanian Salvia species (S. domenica, S. lanigera, S. menthaefolia, S. palaestina, S. sclarea, and S. spinosa) were tested by MTT assay on a panel of human cancer cell lines including DBTRG-05MG, T98G, and U-87MG (glioblastoma), WiDr and HT-29 (colorectal adenocarcinoma), MDA Pca2b (prostate adenocarcinoma), JEG-3 (choriocarcinoma), HEC-1A (endometrium adenocarcinoma), and B lymphoblast (CIR). Among these species, S. menthaefolia showed a pronounced antiproliferative activity against all of the assayed cancer cell lines with the lower IC50 values. S. palaestina extract exhibited a moderate antiproliferative effect only against HEC-1A, JEG-3, and CIR (Fiore et al. 2006). In continuing on the antiproliferative potential of Salvia plants, Al-Kalaldeh et al. (2010) selected some spices used in the traditional medicine of Jordan, including S. triloba along with three other plants species, to evaluate the antiproliferative activity against MCF-7 cell lines, human adenocarcinoma breast cancer, using sulphorhodamine B (SRB) assay. Among the essential oil, ethanol and water extracts, the ethanolic extract of S. triloba exhibited antiproliferative activity to MCF-7 with IC50 of 25.25 μg/mL. In another study, performed by Al-Zereini (2017), the cytotoxic effects of ethyl acetate extracts of two Jordanian medicinal plants, S. verbenaca and Ononis natrix, was investigated on the growth of breast cancer

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MDA MB-231 cells. The results indicated that both plants were cytotoxic against MDA MB-231 cells with IC50 of 41.3 and 28.75 μg/mL, respectively.

18.4.8

ANTIDIABETIC ACTIVITY

The α-amylase and α-glucosidase are two important gastrointestinal tract enzymes digesting the polysaccharides leading to an increase of postprandial glucose levels in diabetic patients needing insulin therapy (Xu et al. 2018). Bahadori et al. (2017) examined the antidiabetic activity of essential oil, n-hexane, CH2Cl2, and MeOH extracts of aerial parts of S. syriaca, collected from Northwest Iran, through inhibition of α-amylase and α-glucosidase. Results displayed that both essential oil and all extracts moderately inhibited the α-amylase activity, while a potent α-glucosidase inhibition was recorded. On the other hand, the S. syriaca essential oil possessed the strongest effect on both assayed enzymes with IC50-α-amylase value of 1.54 mg/mL and IC50-α-glucosidase value of 1.18 mg/mL. Spathulenol (87.4%), isospathulenol (7.6%), and bornyl acetate (2.7%) were the major essential oil compounds. In another research, Rouzbehan et al. (2017) evaluated the inhibition of α-glucosidase effects of various fractions of Iranian S. mirzayanii, Zataria multiflora Boiss., and Otostegia persica (Burm.) Boiss., all belonging to the Lamiaceae family. Among these, the petroleum ether fraction of S. mirzayanii had the highest α-glucosidase inhibitory activity (noncompetitive-uncompetitive inhibition; IC50 of 0.4 mg/mL) when compared to acarbose as the positive control (IC50 of 7 mg/mL). Nickavar et al. (2010) studied in vitro the α-amylase inhibitory activity of the ethanolic extracts of six Iranian Salvia species including S. hydrangea, S. hypoleuca, S. officinalis, S. reuterana, S. verticillata, and S. virtiga, all collected from Tehran Province. Results demonstrated that the extracts of S. verticillata and S. virtiga significantly inhibited the α-amylase activity in a concentrationdependent manner (IC50 values were 19.73 and 16.34 mg/mL, respectively).

18.4.9

ANTI-ALZHEIMER ACTIVITY

One of the most important enzymes in the pathogenesis of Alzheimer’s disease is acetylcholinesterase (AChE). A comprehensive anti-AChE screening was carried out on the CH2Cl2, EtOAc, and MeOH extracts prepared from 55 Turkish Salvia plants at concentrations of 25, 50, and 100 μg/mL. Interestingly, among the 165-screened Salvia extracts, just CH2Cl2 extract of S. fruticosa inhibited AChE at the concentration of 100 μg/mL (inhibition percentage: 51.07%), followed by EtOAc extracts of S. pomifera (36.39%) and again S. fruticosa (34.27%) (Şenol et al. 2010). The essential oil of Turkish S. wiedemannii showed a moderate AChE and butyrylcholinesterase inhibitory activity (55.95% and 50.97%, respectively), while none of S. dicroantha and S. verticillata subsp. amasiaca demonstrated the inhibitory activity against both enzymes. The major compositions of S. wiedemannii essential oil were germacrene D (36.6%), α-pinene (36.2%), and caryophyllene oxide (22.4%) (Kunduhoglu et al. 2011). Akhondzadeh et al. (2003) conducted a clinical trial on affecting the S. officinalis extract (using a fixed-dose; 60 drops/day) in the treatment of 30 patients with mild to moderate Alzheimer’s disease. After 4 months, the authors realized that S. officinalis extract had an efficient outcome on cognitive functions than the placebo group.

18.4.10 INSECTICIDAL ACTIVITY In order to assess the insecticidal potential, the essential oil extracted from aerial parts of S. tomentosa collected in Zorkun Plateau region of Turkey, was examined against two important pest insects, the bean weevil Acanthoscelides obtectus (Say) and red flour beetle Tribolium castaneum (Herbst). The adults of two insects (