Role of Phenolic Phytochemicals in Diabetes Management: Phenolic Phytochemicals and Diabetes [1st ed. 2019] 978-981-13-8996-2, 978-981-13-8997-9

Table of contents :
Front Matter ....Pages i-xi
Diabetes: Its Implications, Diagnosis, Treatment, and Management (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 1-12
Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 13-44
Food Sources of Antidiabetic Phenolic Compounds (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 45-82
Mechanisms of Action of Phenolic Phytochemicals in Diabetes Management (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 83-121
Synergistic Behavior of Phytophenolics with Antidiabetic Drugs (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 123-143
Polyphenol Nanoformulations with Potential Antidiabetic Properties (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 145-157
Pharmacokinetics and Pharmacodynamics of Polyphenols (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 159-173
Trends in Research and Development of Phenolic Phytochemicals as Potential Antidiabetic Therapeutics (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 175-184
Conclusions (Muddasarul Hoda, Shanmugam Hemaiswarya, Mukesh Doble)....Pages 185-187

Citation preview

Muddasarul Hoda  Shanmugam Hemaiswarya  Mukesh Doble

Role of Phenolic Phytochemicals in Diabetes Management Phenolic Phytochemicals and Diabetes

Role of Phenolic Phytochemicals in Diabetes Management

Muddasarul Hoda Shanmugam Hemaiswarya Mukesh Doble

Role of Phenolic Phytochemicals in Diabetes Management Phenolic Phytochemicals and Diabetes

Muddasarul Hoda Department of Biotechnology Indian Institute of Technology Madras Chennai, Tamil Nadu, India

Shanmugam Hemaiswarya Department of Biotechnology Indian Institute of Technology Madras Chennai, Tamil Nadu, India

Department of Biological Sciences Aliah University Kolkata, India Mukesh Doble Department of Biotechnology Indian Institute of Technology Madras Chennai, Tamil Nadu, India

ISBN 978-981-13-8996-2    ISBN 978-981-13-8997-9 (eBook) https://doi.org/10.1007/978-981-13-8997-9 © Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

Diabetes is a major chronic disease characterized by hyperglycaemia, polyuria, polydipsia, and polyphagia. According to the seventh edition of the International Diabetes Federation (IDF) Atlas, approximately 415 million people between the ages of 20 and 79 around the globe have been estimated to suffer from diabetes in the year 2015. This count is further expected to rise to 642 million by the year 2040. The ever-changing lifestyle and dietary habits have immensely contributed to the development of not only chronic but also acute diabetic conditions. The current drugs in the market have their associated toxicity and side effects as well as become ineffective after a certain period of treatment. Phytomedications are among the oldest remedies for diabetes that have been practiced around the world under various names including Ayuveda (Indian subcontinent), Unani (West Asia), and Zhōngyī (Central Asia). They are essentially mixtures of a variety of phytochemicals in various proportions. The concentrations of these phytochemicals may vary significantly, depending upon the plant source, or even in various organs within the same plant. As per the US Department of Agriculture (USDA) database, approximately 1200 phytochemicals have been reported to reverse/control diabetic conditions via a number of transcriptional, translational, and epigenetic modulations of major signaling molecules. Some of the limitations of phytomedicine include lack of validations of constituents’ proportions and ambiguous mechanisms of action against diabetes. Among the various types of phytochemicals, phenolic compounds have been of particular interest. It is among the major constituents and active principles in various plant extracts. Phenolic compounds are a group of simple and complex molecules, classified together based on the presence of at least one aromatic ring and a hydroxyl group attached to it. Herbs, fruits, and spices, including bitter gourd, java plum, and turmeric, are among the vast repository of natural resources from which a variety of phenolic compounds, including flavonoids, aromatic acids, phenylethanoids, alkylresorcinols, and capsaicin, have been identified and isolated. These phenolic phytochemicals have been studied for their therapeutic efficacy against various types of diseases, including cancer, diabetes, arthritis, cardiovascular diseases, and some neurodegenerative disorders. This book summarizes the current research trends of phytophenolic therapy against diabetes. It lists the various phenolics reported to possess anti-diabetic activity and their plant sources. It also discusses the various mechanisms of actions of v

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Preface

these compounds. Each of these pathways may be targeted by the combination of multiple phytophenolics and synthetic drugs, such that their synergistic effects may result in lowering the diabetic conditions or simultaneous lowering of the dependence on synthetic drugs. Phytochemicals have certain shortcomings which include poor aqueous solubility, bioavailability, and shelf life. Nanotechnology-based approaches may overcome some of these problems. The pharmacokinetics, pharmacodynamics, and degradation of phytophenolics also need to be understood for their effective use which is also discussed here. The National Institutes of Health (NIH) and the USDA are among the many agencies that are funding intensive research in phytochemicals as dietary supplements in preventive medicine. The current trends of European markets evidently suggest that phytomedicines are increasingly being preferred as an alternative preventive medicine due to its mild adverse effects and reduced toxicity. This book could be a useful reference to academicians, scientists working in government and industrial labs, dieticians, alternative therapy practitioners, and the common public. Some of the novel photochemicals reported here could also be a lead molecule for the design of novel anti-diabetic drug. Chennai, India  

Muddasarul Hoda Shanmugam Hemaiswarya Mukesh Doble

Contents

1 Diabetes: Its Implications, Diagnosis, Treatment, and Management��������  1 1.1 Introduction������������������������������������������������������������������������������������������  1 1.2 Epidemiology of Diabetes��������������������������������������������������������������������  2 1.3 Types of Diabetes����������������������������������������������������������������������������������  2 1.4 Clinical Implications of Diabetes����������������������������������������������������������  4 1.5 Economic Implications of Diabetes������������������������������������������������������  5 1.6 Diagnosis Criteria for Diabetes������������������������������������������������������������  5 1.7 Diabetes Prevention and Management��������������������������������������������������  8 1.8 Current Drugs and Their Alternatives in Diabetes Management����������  9 1.9 Plant Sources as Alternative Treatment to Synthetic Drugs ����������������  9 1.10 Role of Functional Food in Diabetes Management������������������������������ 10 References������������������������������������������������������������������������������������������������������ 11 2 Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation���������������������������������������������������������������������������������������� 13 2.1 Introduction������������������������������������������������������������������������������������������ 13 2.2 Classification of Phenolic Compounds from Plant Sources ���������������� 15 2.2.1 Flavonoids�������������������������������������������������������������������������������� 16 2.2.2 Phenolic Acids and Phenyl Alkanoids�������������������������������������� 19 2.2.3 Quinones ���������������������������������������������������������������������������������� 19 2.2.4 Stilbenoids�������������������������������������������������������������������������������� 19 2.2.5 Lignans and Neolignans������������������������������������������������������������ 20 2.2.6 Polyphenolic Amides���������������������������������������������������������������� 20 2.2.7 Xanthones and Curcuminoids �������������������������������������������������� 20 2.2.8 Dimeric and Polymeric Polyphenols���������������������������������������� 20 2.3 Biosynthesis of Phenolic Compounds�������������������������������������������������� 21 2.3.1 Biosynthesis of Aglycone Phenolic Compounds���������������������� 21 2.3.2 Functional Group Derivation of Primary Aglycones���������������� 23 2.4 Extraction and Isolation Processes of Phenolic Compounds���������������� 24 2.4.1 Sample Preparation ������������������������������������������������������������������ 24 2.4.2 Phytochemical Extraction and Isolation ���������������������������������� 25 2.4.3 Isolation of Specific Phenolic Compounds ������������������������������ 29

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2.5 Identification and Quantification of Phenolic Compounds������������������ 30 2.6 Structural Elucidation of Phenolic Compounds������������������������������������ 31 References������������������������������������������������������������������������������������������������������ 40 3 Food Sources of Antidiabetic Phenolic Compounds���������������������������������� 45 3.1 Introduction������������������������������������������������������������������������������������������ 45 3.2 Cereals�������������������������������������������������������������������������������������������������� 46 3.3 Vegetables �������������������������������������������������������������������������������������������� 49 3.4 Fruits ���������������������������������������������������������������������������������������������������� 54 3.5 Spices���������������������������������������������������������������������������������������������������� 54 3.6 Beverages���������������������������������������������������������������������������������������������� 55 3.7 Medicinal plants������������������������������������������������������������������������������������ 55 References������������������������������������������������������������������������������������������������������ 74 4 Mechanisms of Action of Phenolic Phytochemicals in Diabetes Management �������������������������������������������������������������������������������������������������� 83 4.1 Introduction to General Mechanisms of Action Against Type 2 Diabetes������������������������������������������������������������������������������������������������ 83 4.1.1 Transcriptional Modulation of Diabetic Regulatory Genes���������������������������������������������������������������������������������������� 85 4.1.2 Modulation of Cell Signaling Pathways of Glucose Homeostasis Regulatory Proteins �������������������������������������������� 85 4.1.3 Modulation of Various Enzymes and Protein Activity Diabetes-­Related Metabolism�������������������������������������������������� 86 4.1.4 Modulation of Epigenetic Factors That Influence Diabetes������������������������������������������������������������������������������������ 87 4.2 Mechanism of Action of Specific Phytophenolic Compounds ������������ 88 4.2.1 Anthocyanins���������������������������������������������������������������������������� 88 4.2.2 Catechins���������������������������������������������������������������������������������� 88 4.2.3 Resveratrol�������������������������������������������������������������������������������� 90 4.2.4 Curcumin���������������������������������������������������������������������������������� 93 4.2.5 Silymarin���������������������������������������������������������������������������������� 99 4.2.6 Capsaicin���������������������������������������������������������������������������������� 99 4.2.7 Emodin������������������������������������������������������������������������������������ 103 4.2.8 Thymoquinone������������������������������������������������������������������������ 103 4.2.9 Chlorogenic Acid�������������������������������������������������������������������� 106 4.2.10 Quercetin�������������������������������������������������������������������������������� 106 4.3 Conclusion������������������������������������������������������������������������������������������ 109 References���������������������������������������������������������������������������������������������������� 111 5 Synergistic Behavior of Phytophenolics with Antidiabetic Drugs���������� 123 5.1 Introduction���������������������������������������������������������������������������������������� 123 5.2 Evaluation of Combinations in Diabetes�������������������������������������������� 124 5.3 Herb-Drug Interactions ���������������������������������������������������������������������� 126 5.3.1 Herb–Biguanide Interaction���������������������������������������������������� 126 5.3.2 Herb–Thiazolidinedione Interaction �������������������������������������� 129 5.3.3 Herb–Sulfonylurea Interaction������������������������������������������������ 131 5.3.4 Interaction Between Herb–Αlpha Glucosidase Inhibitors �������������������������������������������������������������������������������� 133

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5.4 Herb–Herb Interactions���������������������������������������������������������������������� 135 5.5 Food–Drug Interaction������������������������������������������������������������������������ 136 5.6 Mechanism of Herb–Drug Interaction������������������������������������������������ 137 References���������������������������������������������������������������������������������������������������� 138 6 Polyphenol Nanoformulations with Potential Antidiabetic Properties������������������������������������������������������������������������������������������������������ 145 6.1 Introduction���������������������������������������������������������������������������������������� 145 6.2 Curcumin�������������������������������������������������������������������������������������������� 146 6.3 Resveratrol������������������������������������������������������������������������������������������ 151 6.4 Epigallocatechin Gallate (EGCG)������������������������������������������������������ 152 6.5 Green Synthesis of Nanoparticles������������������������������������������������������ 153 6.6 Conclusion������������������������������������������������������������������������������������������ 154 References���������������������������������������������������������������������������������������������������� 154 7 Pharmacokinetics and Pharmacodynamics of Polyphenols�������������������� 159 7.1 Introduction���������������������������������������������������������������������������������������� 159 7.2 Interaction of Polyphenols with Saliva ���������������������������������������������� 160 7.3 Intestinal Transit of Polyphenols�������������������������������������������������������� 160 7.3.1 Transporter Proteins���������������������������������������������������������������� 160 7.3.2 Gut Microbiota-Mediated Metabolism of Polyphenols���������� 162 7.4 Phase 1 and Phase 2 Metabolism of Polyphenols������������������������������ 166 7.5 Pharmacokinetic (PK) Parameters������������������������������������������������������ 167 7.6 Pharmacodynamics ���������������������������������������������������������������������������� 168 References���������������������������������������������������������������������������������������������������� 169 8 Trends in Research and Development of Phenolic Phytochemicals as Potential Antidiabetic Therapeutics������������������������������������������������������ 175 8.1 Introduction���������������������������������������������������������������������������������������� 175 8.2 Status of Research and Development of Phenolic Phytochemicals as Therapeutics �������������������������������������������������������� 177 8.2.1 Phenolic Compounds as Part of Personalized Medicine in Diabetes Management���������������������������������������� 179 8.2.2 Potential Natural Analogs of some Prominent Phenolic Compounds�������������������������������������������������������������� 180 8.2.3 Research and Development of Isolation, Identification, and Drug-Delivery Methods of Phenolic Phytochemicals ���������������������������������������������������������������������� 181 8.3 Challenges and Future of Phenolic Phytochemicals as Potential Antidiabetics�������������������������������������������������������������������� 181 References���������������������������������������������������������������������������������������������������� 183 9 Conclusions�������������������������������������������������������������������������������������������������� 185

About the Authors

Muddasarul  Hoda Currently Assistant Professor, Department of Biological Sciences, Aliah University, Kolkata. His research interests include nanotechnology in drug targeting and therapeutics, and synergism of phytochemicals against glucose homeostasis imbalance and cancer. He received his PhD from Pondicherry University, and postdoctoral degree from the IIT Madras. He has 7 research publications to his credit.  

Shanmugam Hemaiswarya Project Officer, Department of Biotechnology, Indian Institute of Technology, Madras. Her research interests include phytomedicine and studying combinations of phytochemicals with synthetic drugs as effective antibacterial and anticancer agents. She was engaged in a two-year postdoctoral stay at the University of Algarve, Portugal and a three-year research fellowship under Women Scientist Scheme A (DST) at Anna University, Chennai (SR/WOS-A/ LS-1231/2014 G). She has 19 research publications to her credit.  

Mukesh Doble is a Professor (Emeritus) at the Department of Biotechnology, IIT Madras, Chennai, India. His areas of interest include drug design, natural products and biomaterials. He has previously worked for 23 years in Imperial Chemical Industries (ICI) and General Electric (GE) Technology centres. He holds BTech and MTech degrees in Chemical Engineering from the IIT Madras, a PhD from the University of Aston, UK, and postdoctoral degrees from the University of Cambridge, UK, and Texas A&M, USA. He has authored 310 technical papers, 10 books, and filed 12 patents. He is a fellow of the Royal Society of Chemistry and a recipient of the Herdillia Award for “Excellence in Basic Research” from the Indian Institute of Chemical Engineers. He received the 5th National Award for Technology Innovation in the Field of Petrochemicals and Downstream Plastic Processing Industry, Govt of India for his innovations in “Antimicrobial Food Wrap” (Runner up, 2015). He is also the Director of two biotech start-ups.  

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1

Diabetes: Its Implications, Diagnosis, Treatment, and Management

Abstract

Diabetes is a major noncommunicable disease, along with cancer and cardiovascular ailment, affecting millions in the developed and developing world. It is generally known to develop as a result of malfunctioned glucose homeostasis triggered by a number of genetic and nongenetic factors. This chapter deals with the basics of diabetes, its various types, and their symptoms, diagnosis, and implications. Prevention and management of diabetes have also been briefly discussed. Keywords

Diabetes mellitus · Noncommunicable disease · Diabetes diagnosis · Diabetes management

1.1

Introduction

Diabetes is considered among the most prevalent chronic diseases, along with cancer and cardiovascular ailment. Until the beginning of twentieth century, it was rarely identified. However, with the advent of industrial revolution, there have been significant changes in the lifestyle and food habits of the general population which have contributed to abnormal glucose homeostasis, resulting in diabetes mellitus (DM) (Education 2017). Though, DM is the prevalent form of diabetes, a second type of diabetes, known as diabetes insipidus (DI), is another severe disorder. While the former mainly deals with abnormal glucose homeostasis, the latter is known for excessive urinary output mainly due to abnormal functioning of antidiuretic hormone, vasopressin. DM may be triggered by exogenous factors such as diet, physical exercise, occupational hazards, and environment; however, endogenous factors, such as gene alteration, and malfunctioning of various receptors and proteins play a key role in its establishment (Education 2017). A number of diabetes-related genes © Springer Nature Singapore Pte Ltd. 2019 M. Hoda et al., Role of Phenolic Phytochemicals in Diabetes Management, https://doi.org/10.1007/978-981-13-8997-9_1

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1  Diabetes: Its Implications, Diagnosis, Treatment, and Management

have been identified which generally get altered during the lifetime of an individual or are inherited by birth. Today, diabetes can be easily predicted in an individual even before its actual onset, a condition recognized as prediabetes (Alberti and Zimmet 1998). Unattended prediabetic conditions can lead to diabetes which is a health hazard.

1.2

Epidemiology of Diabetes

World Health Organization (WHO) has recognized diabetes as a pandemic, that is, spread across all the continents of the planet (World Health Organization 2016). As per their reports, globally 422 million individuals have suffered from diabetes in 2014 as compared to 180 million in 1980, i.e., a rise from 4.7% to 8.5%, of the total population. Each year, approximately 1.5 million deaths occur due to high blood glucose alone, while approximately 2 million deaths occur due to increased risk of diabetic implications such as cardiovascular diseases, cancer, kidney failure, and tuberculosis (World Health Organization 2016). In addition, International Diabetes Federation (IDF) has estimated an additional 175 million diabetes cases that have remained undiagnosed due to the lack of basic healthcare infrastructure. It has been estimated that the number of diabetes cases could cross over 590 million by 2025 (IDF 2013). East-Mediterranean region has the highest cases of deaths related to diabetes, followed by Southeast Asia (World Health Organization 2016). European region has the least number of cases of diabetes due to efficient primary healthcare infrastructure, in addition to simple dietary habits. Majority of the cases of diabetes are reported among the age group 50–69, though a significant number of cases are reported among every age group starting from 20 years (World Health Organization 2016). There are also reports of diabetes among infants and children below the age of 10 (Alberti and Zimmet 1998). In terms of gender, statistics suggest that females are more prone to diabetes when compared to males. This is due to hormonal changes triggered by menopause, in addition to gestational diabetes that is triggered during pregnancy (Woodward et al. 2015). Economic conditions of individuals play a significant role in the development of diabetes. Low-middle income group has the highest mortality rate due to diabetes, followed by low-income group. High-income group has least mortality, due to access of high-quality diabetes treatment and management (World Health Organization 2016).

1.3

Types of Diabetes

Gene alteration, insulin deficiency, insulin resistance, impaired glucose tolerance, and low β-cell count are among the major factors that trigger diabetes (Thomas and Philipson 2015). However, secondary factors like tuberculosis, various pancreatic diseases, and drug side effects are also responsible for triggering diabetes (Thomas and Philipson 2015). Hence, diabetes may be broadly classified into primary and

1.3  Types of Diabetes

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Table 1.1  Types, epidemiology, implications, and management of diabetes mellitus Types of diabetes

Epidemiology of diabetes

Implications of diabetes

Diabetes prevention and management

Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes mellitus Monogenic diabetes – MODY, neonatal diabetes, syndromic diabetes Majority of the cases are reported in individuals >40 years of age Worldwide, female diabetic patients exceed their male counterparts High-income countries have higher cases of diabetes compared to low-income countries Diabetic morbidity is higher in developing countries compared to developed countries Clinical implications - Dementia, stroke, renal failure, blindness, cardiovascular disease, sleep disorder, reproductive infertility, tuberculosis, compromised bone health and periodontitis, and nocturnal hypoglycemic shock Economic and social implications – financial burden, poor productive life, low self-esteem, and social stigma Diet management under medical nutritional therapy Physical exercises including brisk walk, regular participation games involving aerobic activity Disciplined and punctual lifestyle in sync with biological clock Regular self-monitoring of glucose level under self-management education

secondary diabetes. The former are of several types, ranging from monogenic types, such as maturity onset of diabetes of the young (MODY), neonatal diabetes mellitus, and syndromic diabetes, to polygenic types that include Type 1 and Type 2 diabetes mellitus (Thomas and Philipson 2015). The latter may include diabetes developed due to diseases like cystic fibrosis of pancreas or due to genetic anomalies such as Cushing’s syndrome (Nomiyama and Yanase 2015). Among the primary diabetes, monogenic diabetes is the rare form that is generally detected at birth or in the early phase of life (Savova and Slavcheva 2015). However, Type 2 diabetes mellitus (T2DM) is the most prevalent form accounting for approximately 90% of diabetes cases, followed by Type 1 diabetes mellitus (T1DM) (Thomas and Philipson 2015) (Table 1.1). T2DM is also known as non-insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. Being a progressive and chronic disorder, it may take several years before showing its implications. Impaired glucose tolerance is among the primary symptoms of T2DM (Poretsky 2010). It is characterized by abnormally elevated blood glucose level due to insulin resistance in glucose-storing tissues such as muscle, liver, and adipose tissue. This resistance is the loss of ability of insulin receptors to respond to insulin binding on the surface of the glucose-storing tissues, resulting in inhibition of insulin-dependent glucose uptake of the body. Some of the prominent risk factors of T2DM include genetic anomaly, metabolic disorders like obesity, limited physical exercise, and unhealthy diet (Poretsky 2010).

4

1  Diabetes: Its Implications, Diagnosis, Treatment, and Management

T1DM is an insulin-dependent diabetes mellitus (T1DM) characterized by excessive urination, thirst, weight loss, blurred vision, and fatigue. Loss of insulin secretion is the primary reason behind T1DM (Alberti and Zimmet 1998). It may be due to various underlying factors including nonfunctional β cells and their decreased count in islets of Langerhans. The loss of β cells is generally caused by diabetes-­ associated antibodies (DAA) such as glutamic acid decarboxylase 65 antibody (GADA), zinc transport 8 antibody (ZnT8), Islet cell cytoplasmic antibody (ICA), intracytoplasmic domain of tyrosine phosphatase-like protein (IA-2A), and insulin antibody (IAA) (Burn 2010). These antibodies are generally expressed during early childhood and juvenile phase, hence also known as juvenile or childhood-onset diabetes. T1DM is relatively easy to control when compared to T2DM. The treatment regime includes injection of recombinant insulin and their analogs, in well-­regulated dosages. Gestational diabetes mellitus (GDM) occurs exclusively in pregnant women. It is considered to be a mild form of diabetes, generally triggered in the first trimester of pregnancy. It is a temporary form of diabetes which generally subsides soon after pregnancy period. However, it runs high risk of developing into T2DM, if not monitored well during and after the pregnancy (Alberti and Zimmet 1998). Prediabetes is a physiological condition that does not meet the clinical criteria for diabetes, yet the fasting glucose level and hemoglobin A1C (HbA1C) are constantly above the recommended normal concentration. It helps in prediction and control of the development of diabetes in individuals (Perreault and Færch 2014).

1.4

Clinical Implications of Diabetes

Implications of diabetes are extremely diverse, which directly and indirectly impacts most of the vital organs including heart, liver, brain, and kidney (Table  1.1). However, blood vessels of the body are among the primary physiological systems where implications of diabetes are observed. Based on vasculature, it is generally classified into microvascular and macrovascular implications (Fowler 2011). Microvascular implications include three major clinical conditions, namely, retinopathy, nephropathy, and neuropathy. Retinopathy is a clinical condition of damaged blood vasculature of retina caused by hypertension and excessive oxidative stress. Similarly, nephropathy leads to renal failure, resulting in several renal diseases. Neuropathy impacts the nervous system which in turn causes multiple complications including nervous breakdown (Fowler 2011). Chronic diabetes triggers of a number of macrovascular complications such as cardiovascular diseases (CVD), cerebrovascular diseases, and atherosclerosis. A number of other vascular diseases are also triggered by diabetes because of induced endothelial dysfunction as a result of impairment of nitric oxide synthase. It is an enzyme involved in the synthesis of nitric oxide, an essential vasodilator that maintains blood vessel homeostasis. Diabetes also triggers cardiac remodeling which adversely impacts the cardiac rhythms, blood flow and pumping. Similarly, diabetes-­ triggered endothelial dysfunction also results in aberrant neovascularization of

1.6  Diagnosis Criteria for Diabetes

5

blood vessels, especially in cerebral region of the brain. These aberrant blood vessels have poor endothelial wall formation, resulting in increased permeability and reduced number of pericytes (Fowler 2011). A number of other diseases that are triggered or aggravated due to impact of diabetic conditions include sleep disorder, lowered male fertility, tuberculosis, periodontitis, delayed wound healing, and compromised bone density and metabolism (Wojciechowska et al. 2016). Other diseases like nonalcoholic fatty liver diseases (NAFLD) and thyroid disorder are also linked to diabetes.

1.5

Economic Implications of Diabetes

Diabetes incurs significant financial loss for individual and the state alike. Individuals with diabetes are burdened with direct medical expenditure on diagnosis and treatment. Though preliminary diagnosis may be simple and cost-effective, treatment regimes can include expensive drugs that have to be consumed for extended time periods. Indirect loss equally contributes to financial burden on an individual. It may include inability to perform everyday task as efficiently as a normal individual, resulting in low productivity and quality of life. The state also incurs significant financial burden in terms of unsustainable health-care projects including prevention and treatment, prediabetes awareness, and education on diabetes self-care management (McAdam Marx 2013). From 2011 to 2030, net loss of gross domestic product worldwide has been estimated to cost approximately $1.7  trillion, of which the high-income countries contribute to approximately $900  billion loss, while low-­ income countries bear an approximate loss of $800 billion (Bloom et al. 2011).

1.6

Diagnosis Criteria for Diabetes

WHO has laid out parameters for preliminary diagnosis and confirmatory tests for classical diabetes and its various types (Table 1.2). Standard parameters of preliminary diagnosis include performing oral-glucose tolerance test (OGTT) for estimation of glucose concentration of fasting plasma glucose (FPG) and 2-hour postprandial glucose (2  h-PG), and percentage of glycated hemoglobin A1C (HbA1C). Estimation of glucose and HbA1C significantly depends on age, gender, and ethnicity. Prediabetes test may be initiated for an asymptomatic individual if the following criteria are observed: (i) BMI ≥23 kg/m2 (for Asians) and ≥ 25 kg/m2 (for Caucasians); (ii) identification of two or more risk factors of diabetes; (iii) identification of two or more major implications related to diabetes; (iv) no risk factors but attended age of 45 years; (v) reported history of diabetes in family; and (vi) history of GDM during pregnancy (World Health Organization 2016). Presence of DAAs ascertains T1DM, while the absence of it ascertains development of T2DM (Drouin et al. 2009). However, the DM that has absence of DAA may not always be T2DM; further gene analysis is needed for confirmation. Specific gene alterations (both autosomal dominant and autosomal recessive) are identified

6

1  Diabetes: Its Implications, Diagnosis, Treatment, and Management

Table 1.2  Diagnosis and treatment of various types of diabetes No. Type 1. Prediabetes

Symptoms/criteria (i) ≥25 kg/m2 BMI (ii) Two or more risk factors of diabetes

2.

Diabetes (all types)

3.

T1DM

4.

T2DM

(iii) Two or more observed implications of diabetes (iv) Normal individual >45 years age (v) History of GDM/ diabetes in family (i) Criteria/symptoms similar to prediabetes (ii) Confirmed history of prediabetes

(i) Confirmed test for diabetes (ii) Excessive urination, thirst, and weight loss (iii) Age of onset of diabetes is 25 years

Diagnosis/confirmation FPG^ 110–125 mg/dL or 5.6–6.9 mmol/L∗ OR 2 h-PG between 140–199 mg/dL or 7.8–11.0 mmol/L # AND/OR

Current drugs No drugs recommended Multi-nutritional therapy and physical exercises recommended

HbA1C concentration between 5.7–6.4% (39–47 mmol/Mol) ∆ FPG^ ≥126 mg/dL (≥7.0 mmol/L) ∗ OR 2 h-PG ≥200 mg/dL or ≥ 11.1 mmol/L # OR HbA1C concentration ≥ 6.5% (48 mmol/Mol) ∆ OR Random plasma glucose of ≥200 mg/dL or ≥ 11.1 mmol/L Similar to basic clinical diagnosis as mentioned above AND Presence of DAAs (GADA, ICA, ZnT8, IAA, and IA-2A) OR Β-cell count in Islets of Langerhans Basic clinical diagnosis as mentioned above AND Absence of DAAs or normal β-cell count AND

Biguanides, e.g., Metformin

Insulin shots

Insulin sensitizers, e.g., Rosiglitazone, Pioglitazone Secretagogues, e.g., sulfonylurea (glimepiride)

Enhanced insulin resistance (IR) and impaired glucose tolerance (IGT) (continued)

1.6  Diagnosis Criteria for Diabetes

7

Table 1.2 (continued) No. Type 5. GDM

Symptoms/criteria (i) Individuals with high BMI (>25 kg/m2) (ii) Women who attend pregnancy >35 years of age (iii) Women with family history of diabetes (iv) Test for undiagnosed diabetes at the first prenatal visit (v) Test for GDM at 24–28 weeks after pregnancy

Diagnosis/confirmation One-step (75 g-OGTT) method FPG^ ≥92 mg/dL (≥5.1 mmol/L) ∗ OR

Current drugs Insulin shots

1 h-PG ≥180 mg/dL or ≥10 mmol/L # OR 2 h-PG ≥153 mg/dL or ≥8.5 mmol/L # Two-step (50 g-GLT and 100 g-OGTT) method   (A.) 50 g-GLT step- Ω If 1 h-PG ≥130 mg/dL or ≥7.2 mmol/L, THEN proceed to 100 g-OGTT step   (B.) 100 g-OGTT step- μ. FPG^ ≥105 mg/dL (≥5.8 mmol/L) ∗ OR 1 h-PG ≥190 mg/dL or ≥10.6 mmol/L OR 2 h-PG ≥165 mg/dL or ≥9.2 mmol/L OR 3 h-PG ≥145 mg/dL or ≥8.0 mmol/L

Fasting plasma glucose (FPG) condition is defined as per WHO standard of minimal 8 hours of zero calorie intake ∗ This glucose concentration of prediabetes suggests impaired fasting glucose (IFG) # This glucose concentration is based on OGTT of 75 g glucose dissolved in water ∆ Should be performed by NGSP certified method that is standardized to DCCT assay Ω Glucose-load test (GLT) – this test is performed in nonfasting conditions at 24–28 weeks of pregnancy μ 100 g-OGTT step is performed based on criteria recommended by National Diabetes Data Group (NDDG)

^

8

1  Diabetes: Its Implications, Diagnosis, Treatment, and Management

as MODYs, while multiple gene alterations, insulin resistance of tissues, and impaired glucose tolerance (IGT) confirm diagnosis of T2DM (Alberti and Zimmet 1998). The symptoms and diagnosis of prediabetes and all major types of diabetes are summarized in Table 1.2.

1.7

Diabetes Prevention and Management

An integrated program for prevention and management is essential for diabetes patients. In spite of extensive efforts being made in drug discovery, conventional antidiabetic drugs only intend to maintain the glucose level under control. Hence, its prevention and self-management becomes utmost important (Poretsky 2010). Diabetes prevention and management programs essentially depend on the type of diabetes an individual suffers from. Control of T1DM requires regular insulin shots. A number of insulin analogs with enhanced efficacy are also undergoing advanced level clinical trials. In the case of T2DM, IR and IGT develops over an extended time period, under the influence of various genetic and nongenetic factors. However, these can be reversed by various drugs such as biguanides, thiazolidinediones, sulfonylurea, and non-sulfonylurea, though they have significant adverse effects. T2DM can be easily prevented or managed at initial stages even without antidiabetic drugs. Since it is chronic in nature, it develops late in the lifetime of an individual. In the case of GDM, mild hyperglycemia occurs; hence, it may be easily controlled by self-management and mild insulin shots (Poretsky 2010). Once prediabetes is diagnosed, the individual should take preventive measures to control or reverse these conditions. The most significant among the self-care management is dietary habit. A planned diet that includes limited fats and high quantities of green leafy vegetables including spinach, broccoli, bitter gourd, and Brussels sprouts (Platel and Srinivasan 1997). Physical activity is essential for burning excessive calories from the body. It is especially recommended for obese individuals, since obesity is the major risk factor of T2DM.  This is highly recommended for people with sedentary occupations, since they are prone to develop excess oxidative stress which also contributes to the development of T2DM (American Diabetes Association 2013). Other factors such as alcohol and cigarettes also aggravate diabetic complications. Global Diabetes Scorecard survey published by IDF in 2014 suggests that only about 50% of 125-member countries have a national diabetes plan that is being implemented fully or partially. Among them, 37 countries have adopted the global monitoring framework as set under United Nations’ resolution on prevention and control of noncommunicable diseases (NCD), which includes cancer, cardiovascular diseases, and chronic respiratory diseases. Only 14 countries have a well-­ integrated diabetes self-management education program (IDF 2013).

1.9  Plant Sources as Alternative Treatment to Synthetic Drugs

1.8

9

 urrent Drugs and Their Alternatives in Diabetes C Management

Diabetes cannot be cured permanently; however, it may be managed through various means such as regular physical exercise, a planned diet, and medications. T1DM develops due to lack of insulin production in β-cells; hence, subcutaneous injection of exogenous insulin is effective in reversing the T1DM conditions. Recombinant insulin from yeast is frequently used as an injection, and the dosage depends on the hypoglycemic response of an individual. The standard anti-T2DM drugs include secretagogues such as sulfonylureas (SU) (e.g., glimepiride) and others such as repaglinide and nateglinide (Table 1.2) (Simó and Hernández 2002). The former triggers second phase insulin secretion from β-cells, while the latter triggers first phase insulin secretion. Secretagogues are followed by insulin sensitizers that include thiazolidinediones (TZD) such as rosiglitazone and pioglitazone. These TZDs increase the insulin sensitivity of insulin-receptor cells such as hepatocytes, myocytes, and lipocytes, thus enhancing glucose uptake. Third in the line include enzyme inhibitors such as acarbose, miglitol, sitagliptin, and linagliptin. While the former two are α-glucosidase inhibitors (Simó and Hernández 2002), the latter two belong to dipeptidyl peptidase-IV (DPP-IV) inhibitors (Simó and Hernández 2002). However, since the causal factor of T2DM is unpredictable or the therapeutic response of other class of drugs may begin to fade; biguanides, especially Metformin, may be considered as the ultimate choice of anti-T2DM drug. Primarily, metformin reverses glycogenolysis and gluconeogenesis; however, they can also potentially elevate insulin production, secretion, and sensitivity by enhancing proliferation of β-cell mass and upregulation of GLUT-4 receptors (Simó and Hernández 2002). All the above-mentioned standard antidiabetic drugs are initially recommended as monotherapy; however after ~3 months of treatment, their therapeutic response tends to get subdued by ~30% (DeFronzo 1999). Hence, to enhance the therapeutic response, they are recommended as combinational therapy, where multiple classes of drugs are administered, in various doses. Combinational therapy of these drugs enhances therapeutic response by multifold due to synergism; however, adverse side effects also increase significantly (Zhang et al. 2014).

1.9

 lant Sources as Alternative Treatment to Synthetic P Drugs

Among the limitations of synthetic drugs are limited bioavailability, adverse effects, toxicity issues, and narrow therapeutic window. Alternatively, natural sources as therapeutics are significantly capable of overcoming a number of these limitations. Plants, as a natural source of remedy against various diseases, have been established

10

1  Diabetes: Its Implications, Diagnosis, Treatment, and Management

through several generations of traditional treatment methods. Concepts of Ayurveda and Unani system of medicine are based on preparation of optimal concoction of several plants and their various parts, which targets multiple molecular pathways, thus synergistically inhibiting disease conditions. The bioavailabilities of bioactive components of concoctions are believed to be enhanced significantly, when compared to synthetic single molecule treatments. Conceptually, diabetes, being a multifaceted disease, ought to be more effectively controlled or reversed by more than one bioactive ingredient, when compared to synthetic drugs. Though multiple synthetic drugs are also prescribed for advanced level of diabetes conditions, yet, herbal concoctions are potentially more effective due to single major factor that these concoctions include significantly diverse antidiabetic bioactive ingredients. In addition, plant phytochemicals are rarely recognized as xenobiotic by the individual’s body when compared to synthetic drugs, hence these phytochemicals can be consumed at all times, without worrying about drug rejections, adverse effects, and effective dosage regimen. Hence, for a multifactorial disease like diabetes, herbal concoctions are increasingly becoming a significant alternative to synthetic drugs. A detailed study on the subject has been discussed in Chaps. 3 and 4.

1.10 Role of Functional Food in Diabetes Management Natural herbs, barks of trees, fruits, vegetables, and spices are among various plant sources that have immense antidiabetic potential. Diverse phytochemicals in various plant parts trigger synergistic action against diabetes. Since they are natural in origin, they have fewer side effects. Wholegrain wheat is considered beneficial for diabetic patients because of its high fiber content, high bioavailability of phenolic acids, and low glycemic index (GI) (Belobrajdic et al. 2013). Similarly, oats exclusively contains avenanthramides, which contribute to anti-hyperglycemic responses through multiple molecular pathways (Meydani 2009). Citrus fruits, berries, and pomegranates reverse the diabetic complications because of the presence of abundant phenolic compounds that have high antioxidant potential. Green leafy vegetables including spinach and broccoli have high phenolic content, especially carotenoids. These phenolic compounds are involved in quenching free radicals of the body, thus eliminating possible factors that could trigger diabetes. However, none can compete with spices as the major source of phenolic compounds (Bi et al. 2017). Turmeric is considered as the most potent spice against diabetes due to the presence of curcumin, a phenolic compound. Similarly, clove and cinnamon are among the preferred spices that can reverse diabetic complications. Black pepper contributes to control and reversal of antidiabetic complications, in addition to reversal of hyperglycemia (Bi et al. 2017). This book identifies and highlights diverse plant sources and their various parts such as leaf, stem, bark, twig, roots, and fruits, in accordance to their antidiabetic potential. It also focuses on specific phenolic phytochemicals that are characteristic of diverse plants. Each of these phytochemicals tends to reverse, inhibit, or subdue

References

11

diabetic conditions and complications, through one or more molecular pathways. Medical-nutritional therapy (MNT) based diabetes management is fast catching up with the contemporary world because of the increasing awareness about ill effects of synthetic drugs on general health (American Diabetes Association 2003). This book caters to diverse audience, ranging from layman to academicians, scientists, dieticians, and clinicians.

References Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Diabet Med a J Br Diabet Assoc [Internet] 15(7):539–553. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9686693 American Diabetes Association (2003) Medical nutrition therapy: a key to diabetes management and prevention. J Nutr [Internet] 133(2):556S–562S. Available from: http://www.ncbi.nlm.nih. gov/pubmed/12566502 American Diabetes Association (2013) Physical activity, exercise and diabetes. Can J  diabetes [Internet] 37:359–360. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24353273 Belobrajdic DP, Bird AR, Shaw J, Sicree R, Zimmet P, Whiting D et  al (2013) The potential role of phytochemicals in wholegrain cereals for the prevention of type-2 diabetes. Nutr J  [Internet] 12(1):62. Available from: http://nutritionj.biomedcentral.com/ articles/10.1186/1475-2891-12-62 Bi X, Lim J, Henry CJ (2017) Spices in the management of diabetes mellitus. Food Chem 217:281–293 Bloom DE, Cafiero EE, Jané-Llopis E, Abrahams-Gessel S, Bloom L, Fathima S et  al (2011) The global economic burden of noncommunicable diseases [Internet]. World Economic Forum. Available from: http://ideas.repec.org/p/gdm/wpaper/8712.html%0A; https:// www.world-heart-federation.org/wp-content/uploads/2017/05/WEF_Harvard_HE_ GlobalEconomicBurdenNonCommunicableDiseases_2011.pdf Burn P (2010) Type 1 diabetes. Nat Rev Drug Discov 9:187–188 DeFronzo RA (1999) Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131(4):281–303 Drouin P, Blickle JF, Charbonnel B, Eschwege E, Guillausseau PJ, Plouin PF et  al (2009) Diagnosis and classification of diabetes mellitus. Diabetes Care [Internet] 32(SUPPL. 1):S62– S67. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2797383&to ol=pmcentrez&rendertype=abstract Education DS (2017) Lifestyle management. Diabetes Care 40(January):S33–S43 Fowler MJ (2011) Microvascular and macrovascular complications of diabetes. Clin Diabetes 29(3):116–122 IDF (2013) Global diabetes scorecard: tracking progress for action. Vol. 53, Global diabetes scorecard tracking progress for action McAdam Marx C (2013) Economic implications of type 2 diabetes management. Am J Manag Care Meydani M (2009) Potential health benefits of avenanthramides of oats. Nutr Rev 67:731–735 Nomiyama T, Yanase T (2015) Secondary diabetes. Nihon Rinsho 73(12):2008–2012 Perreault L, Færch K (2014) Approaching pre-diabetes. J Diabetes Complicat 28(2):226–233 Platel K, Srinivasan K (1997) Plant foods in the management of diabetes mellitus: vegetables as potential hypoglycaemic agents, Nahrung Food 41:68–74 Poretsky L (2010) Principles of diabetes mellitus. Principles of diabetes mellitus Savova R, Slavcheva O (2015) Monogenic forms of diabetes mellitus. Pediatriya 55(1):13–21 Simó R, Hernández C (2002) Treatment of diabetes mellitus: general goals, and clinical practice management. Revista Espanola de Cardiologia 55:845–860

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1  Diabetes: Its Implications, Diagnosis, Treatment, and Management

Thomas CC, Philipson LH (2015) Update on diabetes classification. Med Clin North Am 99:1–16 Wojciechowska J, Krajewski W, Bolanowski M, Kręcicki T, Zatoński T (2016) Diabetes and cancer: a review of current knowledge. Exp Clin Endocrinol Diabetes [Internet] 124(5):263–275. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27219686 Woodward M, Peters SA, Huxley RR (2015) Diabetes and the female disadvantage. Womens Health 11:833–839 World Health Organization (2016) Global report on diabetes. Isbn [Internet] 978:88. Available from: http://www.who.int/about/licensing/%5Cn; http://apps.who.int/iris/bitstr eam/10665/204871/1/9789241565257_eng.pdf Zhang Q, Dou J, Lu J (2014) Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses. Diabetes Res Clin Pract [Internet] 105(3):313–321. Available from: http://ovidsp.ovid.com/ ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25015317

2

Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

Abstract

Phenolic compounds are among the major group of phytochemicals that are extremely diverse in nature, ranging from flavonoids to polyphenolic amides. They are available in almost every plant part; however, their bioavailability differs from one plant to another. Their biosynthesis is a complex phenomena where one phenolic compound is an intermediate or precursor of another. In this chapter, classification of phenolic phytochemicals and their biosynthesis has been discussed. Various extraction and isolation techniques have been briefly discussed. Finally, a brief discussion on identification, quantification, and structural characterization of various phenolic compounds has been highlighted. Keywords

Phenolic phytochemicals · Shikimic acid pathway · Phenolic extraction · Medicinal chemistry

2.1

Introduction

Phytochemicals are mostly secondary metabolites that are synthesized as by-­ products of primary metabolism in plants, algae, and fungi. They play significantly diverse roles in a number of physiological, metabolic, and physicochemical functions in both endogenous and exogenous organisms (Sanchez and Demain 2011). Essentially, they are small molecules which are primarily organic in nature; however, a number of them are used as monomers for the synthesis of polymeric phytochemicals that have high molecular weights. Some phytochemicals may be toxic, while many others have wide range of beneficial aspects. Toxic phytochemicals present in plants act as a defense against herbivores, insects, and various types of pathogens and pollutants (Iriti and Faoro 2009). Some of them are also known to provide immunity and healing against various diseases (Surh 2003). While nontoxic © Springer Nature Singapore Pte Ltd. 2019 M. Hoda et al., Role of Phenolic Phytochemicals in Diabetes Management, https://doi.org/10.1007/978-981-13-8997-9_2

13

14

2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

phytochemicals play a diverse role, ranging from imparting color to the plants, releasing of pheromones in order to attract pollinators, providing mechanical strength, and supplementary nutritional values (Richards et al. 2015). The two major concepts of alternative medicine, i.e., Ayurveda and Unani, are entirely based on combination of various phytochemicals in the form of extracts, used in varying proportions (Shrivastava et al. 2015). Till date, these are among the most reliable methods of disease treatment, especially because of their minimal side effects (Metri et al. 2013). In fact, a number of allopathic drugs have been inspired from various phytochemicals that have been identified and isolated from plant sources, which include aspirin, quinine, digoxin etc. (Hauptman and Kelly 1999; Mates et al. 2007). Apart from medicine, phytochemicals that are nontoxic and have characteristic color and odor are frequently used for human consumption as seasonings in food, imparting aroma and flavor (Williamson 2017). Phytochemicals are highly diverse in nature, comprising of various categories that include terpenoids, phenolic compounds, organic acids, chlorophylls, and various other amines and glucosinolates (Mandal et al. 2015). Among them, phenolic compound is one of the largest groups of phytochemicals. The scope of the current book is therefore restricted to only phenolic phytochemicals derived from plant sources. Phenolic phytochemicals, also termed as plant phenolics, constitute a major part of phytochemical pool. Till date, more than 10,000 odd plant phenolics have been identified and reported, and the number is consistently increasing. Plant phenolics are simple and complex organic compounds that have at least one phenolic group attached to a parent carbon skeleton, apart from various other functional groups including hydroxyl, sulfate, amide, carboxyl, ether, and ester (Campos-Vega and Dave Oomah 2013). They are synthesized in the plant body in response to various internal and external stimuli that include stages of plant development, release of plant hormone, bacterial and fungal infections, ultraviolet radiations, pollination, and distinct climatic conditions (Khoddami et al. 2013). They are among the most structurally diverse groups of phytochemicals, ranging from a simple monophenol such as carvacrol (1) to complex polyphenols such as thearubigins (2). A number of them have been reported to show significantly high therapeutic potential against major diseases including diabetes, cancer, metabolic disorders, and neuronal and nephronal disorders (Saibabu et al. 2015). They have significant antioxidative properties due to the presence of phenolic group (Van Hoyweghen et al. 2012). The use of phytochemicals as preventive medicine is mainly based on experience over several centuries, while their mechanism of actions, bioavailability, and pharmacokinetic and pharmacodynamics have not been scientifically determined. Numerous in vivo and clinical studies have established that plant phenolics have anti-inflammatory, antiulcer, cardioprotective, hepatoprotective, neuroprotective, antidiabetic, anticancer, and antimicrobial potential (Saibabu et  al. 2015). Diverse types of phenolic compounds are present in various locations of the plant body including leaves, stem, flowers, fruits, roots, bark, etc. Their bioavailability and concentration may vary as the plant passes through various developmental stages of growth and maturity (Rojas et al. 2015). They generally exist in its native

2.2  Classification of Phenolic Compounds from Plant Sources

15

conditions as derivatives such as glucosides, glycosides, methoxides, gallates, etc., due to hydroxylation, methoxylation, acetylation, glycosylation, galloylation, prenylation, benzylation, etc. (Koleckar et al. 2008). They are rarely present in nature as aglycone forms (without derivatives) (Tsao 2010).

2.2

 lassification of Phenolic Compounds from Plant C Sources

Plant phenolic compounds are extremely diverse in their molecular structures. They are categorized under various classes ranging from the simplest 6-carbon molecules to complex multi-aromatic rings of 20-carbons and above. They are present in both aglycone and derivative forms. Diverse carbon skeletal structures and their functional groups confer various physical and chemical properties. A brief summary of various categories of phenolic compounds, based on their carbon skeleton, is summarized in Table  2.1. Some of these classes of compounds are important from medicinal perspective. The following are some of the major and minor classes of phenolic compounds.

Table 2.1  Classification of phenolic compounds No. of carbon S. No. atoms 1. 6 2. 7

Parent carbon structure C6 C6-C1

3.

8

C6-C2

4.

9

C6-C3

5. 6. 7. 8. 9. 10.

10 13 14 15 19 14

C6-C4 C6-C1-C6 C6-C2-C6 C6-C3-C6 C6-C7-C6 C6-C1-C1-C6

11. 12. 13. 14. 15.

18 30 n n n

(C6-C3)2 (C6-C3-C6)2 (C6-C1)n (C6-C3)n (C6-C3-C6)n

Major categories Phenol, benzoquinone Hydroxybenzoic acid derivative Hydroxybenzoic acid derivative phenylethanoids Hydroxycinnamic acid derivative Naphthoquinones Xanthone Anthraquinone, stilbenoids Flavonoids Curcuminoids Hexahydroxydiphenic acids Lignans and neolignans Biflavonoids Hydrolyzable tannins Lignins Condensed tannins

Examples ---Gallic acid, salicylic acid Methylsalicylic acid, vanillic acid, acetophenone, tyrosol Phenylpropanoids, coumarins, chromenes, hydroxycinnamic acids 1,4-naphthoquinone Resveratrol Curcumin Ellagic acid

1,3,6-Trigalloyl glucose Proanthocyanidins

16

2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

2.2.1 Flavonoids Flavonoids are 15-carbon (C6-C3-C6) phenolic compounds consisting of an oxygenated heterocyclic three-carbon ring flanked by two aromatic rings (flavan structure) (3). Each of these two aromatic rings is termed as ring A and B, while the middle heterocyclic ring is termed as ring C. This group is considered as the largest group of phenolic compounds consisting of approximately 60% of all phenolic compounds present in plant kingdom (Naczk and Shahidi 2006). Majority of the flavonoids are bound to various sugar residues such as glucose, galactose, rutinose, rhamnose, xylose, arabinopyranose, and arabinofuranose, rarely available in aglycone forms (Lewandowska et al. 2016). They are classified into seven major subclasses, based on functional group variations on basic flavan structure (Fig. 2.1).

2.2.1.1 Flavones, Isoflavones, and Neoflavones Flavones are characterized by a double bond between C2 and C3 carbon atoms. Additionally, C4 carbon atom has a carbonyl oxygen that identifies it as a ketone, hence the name flav(-one) (4). Some of the common flavones include apigenin, luteolin, nobiletin, and tangeretin (Škerget et al. 2005). Flavones have two structural isomers, namely, isoflavone (5) and neoflavone (6). Isoflavones differ from flavones in the location of the aromatic ring B. Flavones have the aromatic ring B covalently bonded to C2 of central heterocyclic ring, while in isoflavones, it is covalently

Fig. 2.1  Classification of flavonoids based on presence of various functional groups on flavan skeleton

2.2  Classification of Phenolic Compounds from Plant Sources

17

bonded to C3 position. Among all the polyphenols, isoflavones have the maximum bioavailability rate in human (Hendrich 2002). This could be due to the gut microflora bioactivity that results in the conversion of isoflavones into molecules of high absorption rates (Kris-Etherton et  al. 2002). Similar to some lignans, isoflavones also have structures and properties similar to estrogen hormone; hence, they are also known as phytoestrogens (Dixon 2004). Some of the most commonly known isoflavones include daidzein, genistein, glycitein, formononetin, and biochanin A (Yu and Jez 2008). In neoflavones, ring B is covalently bonded to C4 of ring C instead of C3 (as in isoflavones) or the normal C2 (as in flavones). Dalbergin is one of the few known neoflavonoids that is ubiquitous in plant kingdom (Chan et al. 1997). Other known neoflavonoids include melanettin, stevenin, and cearoin (Chan et al. 1997).

2.2.1.2 Flavonols An additional hydroxyl group at C3 of the flavones is classified as flavonols (7). It is the largest among all the subclasses of flavonoids, and ubiquitous in plant kingdom, except in algae and fungi (Aherne and O’Brien 2002). Some of the medicinally significant polyphenols in this group include kaempferol, quercetin, myricetin, isorhamnetin, and fisetin (Aherne and O’Brien 2002). 2.2.1.3 Anthocyanidins Anthocyanidins (8) are subgroup of flavonoid that does not have carbonyl oxygen at C4 of heterocyclic ring C, in addition to having a lone electron in oxygen of the ring C. It has multiple –OH groups covalently attached to C3, C5, C7, and C4’ of the basic flavanol (9) structure. They are one of the significant phytochemicals of plant kingdom since they impart color to major parts of plants including leaves, flowers, vegetables, and fruits (Ibrahim et al. 2011). The colors imparted by various anthocyanidins are based on pH of the medium in which it is present (Ibrahim et  al. 2011). They are frequently present in glycosidically linked forms that are called anthocyanins. Apart from imparting color, they are also of significant medicinal potential (Del Rio et al. 2013). Some of the most common anthocyanidins include pelargonidin, cyanidin, delphinidin, peonidin, petunidin, and malvidin (Tsao 2010). 2.2.1.4 Flavanone and Flavononol Flavanone (10) is a subcategory of flavonoid group that is similar to flavones except that the C2-C3 double bond is absent, in addition to the presence of C2-chiral carbon. They also have –OH groups covalently bonded to C5 and C7 position of the flavonoid structure. Flavonones are present in two major types of glycosidically linked forms, namely, neohesperidosides and rutinosides (Tripoli et al. 2007). Neohesperidosides are responsible for the bitter taste of citrus fruits (Tripoli et al. 2007). Some of the common aglycone forms of flavonones include hesperitin, naringenin, and eriodictyol that are abundantly present in oranges, grapefruit, and lemons, respectively (Tripoli et al. 2007). A number of other derivatives of flavanones are increasingly being identified. One such 3-hydroxy derivative of flavanone is known as flavononol (11) or dihydroflavonols (Magalhães et al. 1999). Most prominent among flavononols includes taxifolin which is found in citrus fruits (Kawaii et al. 1999).

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2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

2.2.1.5 Flavanols/Flavan-3-ol/Catechins Flavanols/flavan-3-ol/catechins (9) are one of the most diverse flavonoids that range from simple aglycones to oligomeric and polymeric forms (Hackman et al. 2008). Its basic structure is similar to flavanone in lacking C2-C3 double bond while it also lacks carbonyl oxygen at C4 of ring C. In addition, it has a –OH group covalently bonded to C3 position similar to flavonols, thus resulting in two chiral centers (C2 and C3) within a single molecule. This results in four possible diastereoisomers, namely, (+/−)-catechins (trans-isomer) and (+/−)-epicatechins (cis-isomer). Among these four isomers, (+)-catechins and (−)-epicatechins are predominantly found in food plants (Ottaviani et  al. 2011). Some of the common monomeric flavanols include catechin and epicatechins, and their derivatives include gallocatechins, catechin gallate, gallocatechin gallate, galloepicatechin, epicatechin gallate, and galloepicatechin gallate. 2.2.1.6 Condensed Tannins Condensed tannins are polymeric (C6-C3-C6)n phytophenols made of flavan (C6-­ C3-­C6) monomers. They are also known as flavolans and proanthocyanidins (12). They are basically non-hydrolyzable flavanols which are highly interlinked. They are linear (4′➔8′ bonded) as well as branched (4′➔6′) in nature (Ferreira and Slade 2002). However, they may be cleaved into smaller anthocyanidins of varying molecular weights by acid catalysis (Matthews et al. 1997). Some of the common proanthocyanidins include procyanidin which is commonly found in grapes (Gabetta et al. 2000). Hydrolyzable tannins (13) are broadly subclassified into gallotannins and ellagitannins (Mueller-Harvey 2001). Ellagitanins have gallic acid monomers attached to core glucose/polyol unit by -C-C- covalent bonds, whereas in gallotannins, gallic acid monomers are linked to core glucose unit via depside bonds (Mueller-Harvey 2001). Apart from gallic acids, ellagitannins are also formed from hexahydroxydiphenic acids. Dilactone of hexahydroxydiphenic acids are called ellagic acids (14), hence the name ellagitannins (Mueller-Harvey 2001). Common oligomeric flavanols includes a trimer, procyanidin C1, thearubigins, and theaflavin, a dimer which is the principal flavanol of fermented tea leaves (Tsao 2010). 2.2.1.7 Chalcones Chalcones (15) are typical flavonoids which lack ring C. The oxygen atom in the flavonoid ring C is replaced by –OH group, thus opening up the ring. They are metabolic precursors of a number of flavonoids and ioflavonoids (Zhuang et al. 2017). They are present in significantly high concentration in some citrus fruits, apples, and hops (Rozmer and Perjési 2016). Some of the commonly known chalcones include xanthohumol and phloretin (Rozmer and Perjési 2016).

2.2  Classification of Phenolic Compounds from Plant Sources

19

2.2.2 Phenolic Acids and Phenyl Alkanoids Phenolic acids are among the most prominent group of phenolic compounds after flavonoids. They are broadly subcategorized into hydroxybenzoic acid and hydroxycinnamic acid derivatives. Hydroxybenzoic acid derivatives are 7-carbon (C6- C1) compounds (16) frequently found in plants (Khadem and Marles 2010). Some of the significant benzoic acid derivatives include salicylic acid, gentisic acid, and gallic acid. However, some benzoic acid derivatives such as methylsalicylic acid, vanillic acid, and syringic acid also belong to 8-carbon compound (C6- C2) (17) (Khadem and Marles 2010), in addition to phenylacetic acid and acetophenone. Hydroxycinnamic acid derivatives are 9-carbon (C6- C3) compounds (18) that include a number of prominent antioxidant molecules such as ferulic acid, caffeic acid, sinapic acid, and p-coumaric acid (Khadem and Marles 2010). Phenylpropanoids are another group of 9-carbon (C6- C3) compounds (19) that are among the first phytochemicals to be synthesized in plant, from amino acids phenylalanine and tyrosine (Yu and Jez 2008). They are precursors of a number of phytochemicals/ polyphenols. Cinnamic acid is one of the intermediates of phenylpropanoid biosynthesis. Some of the common phenyl propanoid derivatives include coumarins, chromones, and penylpropenes (Vogt 2010). Phenylethanoids are among other C6-C2 compounds (20) that are most commonly found in olive oils (Bianco and Ramunno 2006). Tyrosol and hydroxytyrosol are among the most abundant phenylethanoids.

2.2.3 Quinones These are a major group of phytochemicals, of which a number of derivatives exist. They have diverse medicinal properties, depending on various derivatives. Three major derivatives prominently recognized include benzoquinone (21), naphthoquinone (22), and anthraquinone (23). Benzoquinone is 6-carbon (C6-C4) molecule that is found in certain plants (Chitra et  al. 1994). Major phenolic compound in this group are naphthoquinone; however, a number of anthraquinone derivatives (anthracendiones) have been reported, among which aloe emodin and rufigallol are highly significant from therapeutic perspective (Mohanlall et al. 2011).

2.2.4 Stilbenoids These are a group of phenolic compounds that have two-carbon moiety flanked by two 6-carbon aromatic rings on either side (C6-C2-C6) (24). The -C2- in stilbenoid forms a linear chain between two aromatic rings, whereas in anthraquinone it forms a ring structure in between two aromatic rings. This group includes some of the medicinally significant group of phenolic compounds among which resveratrol is the most prominent one that has diverse medicinal properties (Kasiotis et al. 2013).

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2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

2.2.5 Lignans and Neolignans These are basically dimers of two 9-carbon (C6-C3)2 phenylpropanoids, derived from phenylalanine. Depending on the linkage between the two phenylpropanoid monomers, they may be subclassified into lignan (25) and neolignan (26) (Miyazawa 2001). Their basic structure is similar to estrogens found in animal; hence, they are also known as phytoestrogens (Dixon 2004), similar to isoflavones. Some of the most commonly known plant lignans are secoisolariciresinol, matairesinol, and sesamin (Milder et al. 2005). Plant lignans are metabolized into mammalian lignans (enterodiol and enterolactone) by the gut microflora (Heinonen et al. 2001). Apart from lignans and neolignans, there are dimers of other non-lignan phenylpropanoid (C6-C3) compounds such as rosemarinic acid (27) which is essentially a dimer of two caffeic acids.

2.2.6 Polyphenolic Amides These are amide-containing phenolic compounds that are present in a number of vegetables and fruits (Tsao 2010). Two of the most common polyphenolic amides are capsaicinoids (28) and avenanthramides (29). Capsaicinoids such as capsaicin and dihydrocapsaicin are commonly found in chilli, especially capsaicin which is responsible for the “spicy heat” taste of the chilli (Lu et al. 2017). Avenanthramides are classified into A, B, and C, based on the functional groups attached to the parent structure. Avenanthramides have wide range of medicinal properties and are exclusively found in oats (Meydani 2009). Chlorogenic acids (30) are another such phenolic compounds which are esters of caffeic acid and quinic acid which are cyclohexanecarboxylic acid (Stalmach et al. 2011).

2.2.7 Xanthones and Curcuminoids Xanthones (31) are phenolic compounds that have two 6-carbon rings held in between a single carbon (C6-C1-C6). They are precursor of a number of therapeutic drugs (Na 2009). Curcuminoids (32) are 19-carbon (C6-C7-C6) compound that are among the most potent phytochemicals that have wide range of medicinal properties. The most prominent among them is curcumin and its many derivatives (Amalraj et al. 2017).

2.2.8 Dimeric and Polymeric Polyphenols Apart from monomeric polyphenols, there are also a number of dimeric and polymeric polyphenols. The most prominent among them are ellagic acid, a 14-carbon (C6-C1)2 dimer of gallic acid (Sepúlveda et  al. 2011). It is structurally similar to anthraquinone which is also a 14-carbon compound, having a cyclic ring

2.3  Biosynthesis of Phenolic Compounds

21

interspersed between two aromatic rings; however, ellagic acid has two heterocyclic rings interspersed between two aromatic rings. It has a number of derivatives present mostly in pericarps of various fruits and nuts (Daniel et al. 1989).

2.3

Biosynthesis of Phenolic Compounds

Phenolic compounds are diverse in structure; hence, their biosynthesis is also complex and overlapping. They are generally considered to be secondary metabolites produced by modulation of primary metabolites. Primary metabolites are intermediates and products of primary metabolism such as glycolysis, Kreb’s cycle, Calvin’s cycle, and nitrogen assimilations. These primary metabolites are precursor of diverse secondary metabolites (Sanchez and Demain 2011). A number of glycolysis and Kreb’s cycle metabolic intermediates act as precursor of phenolic compounds. Biosynthesis of phenolic compounds may be divided into two major phases; first phase includes aglycone biosynthesis of various secondary metabolites (Fig. 2.2), while the second phase mainly deals with addition and modification of acyl groups and sugar moieties via CoA thioesters, O-β-glucose esters, and UDPs, respectively.

2.3.1 Biosynthesis of Aglycone Phenolic Compounds Phosphoenol pyruvate (PEP), a glycolysis product, and erythrose-4-phosphate (E-4-P), which is one of the intermediates in pentose phosphate pathway (PPP) and Calvin cycle, are combined to form a 7-carbon compound, 3-deoxy-D-­ arabinoheptulosonate-7-phosphate (DAHP) (Tohge et al. 2013). This is catalyzed by DAHP synthase (DS). Essentially, E-4-P is a precursor of the biosynthesis of three aromatic amino acids, namely, phenylalanine, tyrosine, and tryptophan (Tohge et al. 2013). Among them, phenylalanine and tyrosine are the primary metabolites that act as precursor of majority of the phenolic compounds, and all of flavonoid compounds (Cheynier et al. 2013). Phenylalanine is synthesized by one of the primary metabolic pathways of amino acid biosynthesis, shikimic acid pathway, of which DAHP is an intermediate. DAHP undergoes cyclization by aldol condensation, thus producing 3-dehhydroshikimate which is a precursor of shikimic acid (Knop et al. 2001). It is this intermediate state from which diversion for biosynthesis of one of the first phenolic compounds takes place. 3-Dehydroshikimate undergoes oxidation reaction resulting in the aromatization of the ring, thus leading to the biosynthesis of gallic acid (Guzik et al. 2010). Gallic acid acts as precursor of hydrolyzable tannins such as gallocatechins, galloepicatechin, catechin gallate, and galloepicatechin gallate (Koleckar et al. 2008). Substitution of carbonyl oxygen with hydroxyl group at C3 position results in the formation of shikimic acid. Shikimate undergoes a number of subsequent reactions resulting in the formation of intermediates that are precursors of tryptophan and tyrosine, finally converting into phenylalanine (Tzin and Galili 2010). Shikimate is

22

2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

Fig. 2.2  General schematic representation of biosynthesis of various phenolic compounds in plants. Abbreviation: PEP- Phosphoenol pyruvate; E-4-P- Erythrose-4-phosphate; DAHP3-deoxy-D-arabinoheptulosonate-7-phosphate; DS- DAHP synthase; CoA- Coenzyme A; PALPhenylalanine ammonia lyase; C4H- Cinnamate-4-hydroxylase; 4-CL- 4-Coumaroyl:CoA ligase; CHS- Chalcone synthase; CHI- Chalcone isomerase; FS- Flavone synthase; IFS- Isoflavone synthase; DFR- Dihydroflavonol-4-reductase/flavonone-4-reductase; FLS- Flavonol synthase; F3HFlavanone-3-hydroxylase/flavanone-3-dioxygenase; ANS- Anthocyanidin synthase

also an independent precursor of an important 7-carbon (C6-C1) phenolic compound, salicylic acid, via an intermediate molecule, isochorismate (Vogt 2010). Phenylalanine undergoes deamination process resulting in the formation of phenolic carboxylic acid, cinnamic acid. The enzyme that catalyzes this significant step is phenylalanine ammonia lyase (PAL) (Hyun et al. 2011). Cinnamic acid acts as a precursor of majority of the phenolic compounds (Vogt 2010). The first among them is benzoic acid which is formed by side chain degradation. Benzoic acids are in turn precursors of xanthones (C6-C1-C6) biosynthesis (Abd El-Mawla and Beerhues 2002). Cinnamic acid undergoes hydroxylation at the C4 position, catalyzed by cinnamate-4-hydroxylase (C4H), thus resulting in the formation of p-coumaric acid. Addition of coenzyme A to the carboxylic carbon of p-coumaric acid results in the formation of p-coumaroyl CoA, catalyzed by 4-coumaroyl:CoA ligase (4-CL)

2.3  Biosynthesis of Phenolic Compounds

23

(Abd El-Mawla and Beerhues 2002). p-Coumaroyl CoA is the parent compound of all the flavonoids, lignins, coumarins, and stilbenes (Vogt 2010). Among the flavonoids, the first stable molecule formed is a chalcone. Three malonyl-­CoA molecules are added stepwise to p-coumaroyl-CoA, resulting in the formation of naringenin-chalcone, catalyzed by chalcone synthase (CHS) (Dao et  al. 2011). Chalcone undergoes isomerization reactions catalyzed by chalcone isomerase (CHI), resulting in the formation of flavanones (Gensheimer 2004). Flavanones further catalyze into flavones and isoflavones by flavone synthase (FS) and isoflavone synthase (IFS), respectively (Sankawa and Hakamatsuka 1997; Martens and Mithöfer 2005). Flavanones are also converted into flavanonols (dihydroflavonols) and flavan-3-ols (Winkel 2006). Flavan-3-ols on polymerization results in the formation of proanthocyanidins. Acid catalysis of proanthocyanidins results in smaller anthocyanidins. A number of other enzymes such as hydroxylase, synthase, and isomerase play a central role in the development of specific secondary metabolites (Winkel 2006).

2.3.2 Functional Group Derivation of Primary Aglycones Each of the major categories of phenolic compounds has hundreds of molecular variants due to the secondary modification of aglycones. Addition of diverse side groups to aglycones imparts characteristic properties such as color, polarity, volatility, stability, bioavailability, and biological activity. A number of reactions such as hydroxylation, methoxylation, acetylation, glycosylation, galloylation, prenylation, benzylation, etc., are involved in imparting these secondary functional groups. Each of these secondary modifications are catalyzed by specific enzymes. Two of the largest groups of aglycone-modifying enzymes include the acyltransferases (ATs) and glycosyltransferases (GTs) (Vogt 2010). Acyltransferases are involved in O- and N-acylation of various phenolic moieties by attacking nucleophiles (-OH and -NH) of acceptor molecules, resulting in the covalent bonding between aglycone moiety and subsidiary functional groups (D’Auria 2006). Acyltransferases are classified into two major groups: BAHD-ATs and SCPL-ATs (Bontpart et al. 2015). BAHD-ATs are a group of enzymes that catalyze the transfer of acyl-CoA thioesters from donor groups to acceptor groups by forming O- and N-glycosidic bonds. They have been named after the discovery of the first four enzymes, namely, Benzylalcohol-O-ATs (BEAT), Anthocyanin O-Hydroxycinnamoyltransferase (AHCT), Anthranilate N-Hydroxycinnamoyl/ benzoyltransferase (HCBT), and Deacetylvindoline 4-O- ATs (DAT) (Bontpart et al. 2015). SCPL-ATs, on the other hand, utilize 1-O-β-glucose esters as the donor molecule. SCPL-ATs are comparatively smaller groups that have been recently identified. They are homologous to serine-carboxypeptidase (SCP), hence the name SCP-like-ATs (SCPL-ATs) (Bontpart et  al. 2015). GTs are extremely diverse in nature and are involved in the addition of sugar moieties to phenolic aglycones by O- and N-glycosidic bonds (Lairson et al. 2008). They are grouped into 92 distinct families of which family 1 is the largest of all, which is UDP-glycosyltransferases

24

2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

(UGTs). They utilize uridine diphosphate (UDP)-activated sugar moieties including glucose, galactose, and arabinose, to bind to almost every phenolic aglycones, thus distinguishing them based on altered physicochemical and biological properties (Palcic 2011).

2.4

 xtraction and Isolation Processes of Phenolic E Compounds

A number of phytochemicals are considered to be more stable when present in its natural state, while they tend to degrade into more stable forms when isolated. Depending on the type of phytochemicals to be isolated, a workflow needs to be predetermined based on their physicochemical properties under various manipulating conditions. A common property among all phenolic compounds is the presence of one or more phenolic groups based on which extraction processes may be implemented. Extraction and isolation of phenolic compounds may be done in various stages, namely (1) sample preparation; (2) crude phytochemicals extraction; (3) crude phenolic compounds separation; and (4) specific phenolic compound isolation.

2.4.1 Sample Preparation Sample preparation is a critical step because a number of labile phenolic compounds may get degraded. Samples could be any part of the plant such as leaves, stems, buds, roots, fruits, flowers, or the bark. The first stage in sample preparation is removal of dust, microorganisms, insects, weeds, and various other unwanted parts of the plant that may contribute to phytochemical decompositions. It may be done manually or washing in mild detergents and drying. Drying may be done in one of the three major ways, namely, air-drying, freeze-drying, and oven-drying. Drying continues until there is complete removal of water, resulting in dehydrated sample. Dehydration enhances sample storage time and minimizes metabolic changes in the phytochemical content. Depending on the type of sample to be dried, any of the above mentioned techniques may be used; however, in the case of phenolic compounds’ extraction, it has been observed that freeze-drying retains more total phenolic content (TPC) when compared to air-drying (Abascal et al. 2005), whereas air-drying is more effective in retaining TPC as compared to oven-drying (Sejali and Anuar 2011). Then the samples are subjected to grinding, milling, and sorting in order to reduce them into fine particles, thus enhancing their surface area. Higher surface area exposure results in greater phytochemicals yield (Gião et  al. 2009). Mechanically degraded samples may be further enzymatically treated with cell-­ degrading enzymes such as cellulase, hemicellulase, pectinase, xylanase, arabanase, and β-glucanase (Huynh et al. 2014).

2.4  Extraction and Isolation Processes of Phenolic Compounds

25

For phenolic extraction from plant sources that are rich in oil and lipid content, de-fatting may be an essential step in sample preparation since the yield of phenolics may be drastically lowered due to the presence of oils and lipids. De-fatting may be done after grinding, using a hydrophobic solvent such as hexane (Weidner et al. 2012).

2.4.2 Phytochemical Extraction and Isolation Post sample preparation, crude phytochemicals extraction is the first major step. Different plant sources respond differently to various techniques. To ensure maximum phytophenols’ yield from a particular plant source, trial and error approach has to be followed. Extraction process is broadly divided into conventional and modern techniques, which are summarized in Table 2.2.

2.4.2.1 Conventional Extraction Techniques Conventional techniques involve extraction in organic solvents such as methanol, ethanol, acetone, ethyl ether, ethyl acetate, and their various aqueous proportions. Two of the frequently performed conventional techniques include soxhlet extraction and maceration. The former involves high temperature and sufficient solvent-to-­ feed ratio. Advantages of this include shorter extraction time (4–12  h) and high solubility of phytochemicals in organic solvents due to elevated temperature. The limitations of soxhlet extraction include potential degradation of phenolic compounds and altered phytochemical profiles from the native state. Maceration, on the other hand, involves usage of organic solvents and their various aqueous proportions but in controlled temperature (4–25 °C). It is a slow process where the sample is submerged in organic solvents and incubated for long periods of time (4–7 days) with occasional stirrings. It potentially minimizes the degradation of the phenolic compounds. Here temperature, incubation time, solvent combinations, pH of the solvents, and solvent-to-feed ratio need to be optimized (Chan et  al. 2014). Contamination of the phytochemical extract with toxic organic solvents is a major limitation in both these techniques. 2.4.2.2 Modern Extraction Techniques Modern techniques of phytochemical extractions supersede the conventional techniques due to two major factors, namely, extremely short extraction time and minimal or no organic solvent involvement. Short extraction times minimize extracellular oxidations and degradation of phenolic compounds, while toxicity issues are significantly lowered due to minimal organic solvents exposure. Some of the frequently practiced modern techniques include ultrasound-assisted extraction (UAE), microwave-­assisted extraction (MAE), ultrasound-microwave-assisted extraction (UMAE), supercritical fluid extraction (SFE), pressurized fluid extraction (PLE)/ subcritical water extraction (SWE), and high hydrostatic pressure extraction (HHPE).

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2  Phenolic Phytochemicals: Sources, Biosynthesis, Extraction, and Their Isolation

Table 2.2  Various extraction and isolation techniques for phenolic compounds from plant sources Extraction type Principle feature Soxhlet Reflux of organic method solvents against plant sample at boiling points

Advantages Basic instrumentation, cost-effective process

Maceration

Basic instrumentation, cost-effective process, extraction of thermolabile phytochemicals Minimal solvent toxicity, cell debris, and incubation time

Supercritical fluid extraction

Subcritical water extraction

High hydrostatic pressure extraction

Ultrasound-­ assisted extraction

Microwave-­ assisted extraction

Long incubation of plant samples in organic solvents under controlled temperatures (4–25 °C) High penetration power of gas and high density of liquid allow SCF to extract phytochemicals from within the cells with high payload Dielectric constant (polarity) of water similar to organic solvents at subcritical conditions allows extraction of polar phytochemicals at subcritical conditions Nonthermal high hydraulic pressure enhances cell membrane permeability, enhancing solvent extraction Ultrasonic frequencies create cavitations, causing the cells to implode and allowing solvent to penetrate and trigger mass-transfer of phytochemicals Microwaves induce a molecular vibration that generates heat, resulting in water evaporation and explosion of cell wall

Disadvantages Solvent toxicity, degradation of thermolabile polyphenols Solvent toxicity, long incubation time, low phytochemical yield

High instrument maintenance, no extraction of polar phytochemicals

No solvent toxicity, low incubation time, specialized in polar phytochemicals extraction

No extraction of nonpolar phytochemicals

Minimal solvent toxicity, polarity of extracting solvent is variable, low incubation time

High instrument maintenance, low phytochemical yield

Minimal solvent toxicity, low incubation time, minimal equipment maintenance

Lacks reproducibility and homogeneity in extraction process

Selective extraction of phytochemicals based on polarity, extraction of photolabile compounds such as resveratrol, low incubation time, and solvent/feed ratio

Degradation of thermolabile phytochemicals

(continued)

2.4  Extraction and Isolation Processes of Phenolic Compounds

27

Table 2.2 (continued) Extraction type Ultrasound-­ microwave-­ assisted extraction

Principle feature Combination of ultrasonic waves and microwave radiations

Advantages Enhanced phytochemical yield, low incubation time, minimal solvent/feed ratio

HPLC/FPLC/ UPLC

Based on differential coefficient of various molecules in a mixture

Real-time isolation of individual molecules, high resolution, detectable, quantifiable, low separation time period

Disadvantages Careful optimization and synchrony of both techniques needed, low yield of thermolabile phytochemicals, lacks homogeneity in the extraction process Low quantity of isolated compounds, low sample loading

Supercritical Fluid Extraction SFE employs supercritical fluid (SCF) as a solvent front due to its high penetration abilities like that of a gas while maintaining the density of a liquid that enables it to extract maximum payload of phytochemicals. Some of the common SCFs include carbon dioxide (CO2), ethanol, propane, hexane, benzene, and water. As the pressure is gradually increased at a constant temperature, the phytochemical yield also increases due to increase in solvent density. Similarly as the temperature is gradually elevated at a constant pressure, the density of the solvent decreases so would be the yield of the phytochemicals (Junior et al. 2014). Generally, CO2-SCF is most frequently used in phytochemical extraction due to its moderate supercritical conditions (31.2 °C/ 73.87 bar/ 0.47 g/ml), non-combustibility, non-toxicity, chemically stable, and zero surface tension properties. However, SFE is restricted to extraction of low to moderately polar phytochemical extraction; hence, large quantities of phenolic compounds are generally left out because supercritical CO2 is nonpolar in nature. Nevertheless, enhanced phenolic extraction can be achieved by introduction of co-solvents such as argon, propane, and ethanol, in experimentally optimized proportions. In general, phenolic compounds may be extracted from various sources, subject to optimal supercritical conditions ranging between 50 and 600 bars, 35–20 °C, and 5–180 min of critical pressure (PC), critical temperature (TC), and incubation time, respectively (Junior et al. 2014). Water, as a SCF, is also effective in phytochemical extraction; however, the major drawback of water as SCF is its high TC (373.4 °C) and PC (221.19 bars) which imparts extreme corrosive properties to water, hence limiting its application (Dai and Mumper 2010). Subcritical Water Extraction (SWE) Subcritical water is referred to the state of water when the temperature is elevated above its boiling point but below TC, i.e., 101–373.4 °C, simultaneously increasing the pressure until it reaches subcritical levels ( 1is antagonism

The efficacy of herb-drug combinations in antidiabetic studies is largely determined from in vitro glucose uptake by cells, usually 2-NBDG or 2-DG are used instead of glucose because glucose is metabolised by the cells. In addition comparison of diabetic gene expression under individual and combined treatments are also estimated. Animal studies are used to study the pharmacokinetic behavior of drug and glycemic control in the presence or absence of phytochemical (Prabhakar and Doble 2009a, b; Prabhakar et al. 2013; Nankar and Doble 2015, 2017). Since diabetes is a highly complex metabolic disease, different parameters and end points are employed to analyze the type of interaction between the herb and drug.

5.3

Herb-Drug Interactions

Herbal products have been increasingly used in combination with synthetic/chemical drugs to maintain the glycemic level in diabetic patients. This is largely due to recent surge in the herbal industry with up to 72.8% of people with diabetes use dietary supplements, herbal medicine and other complementary and alternative (CAM) therapies (Chang et al. 2007), self-administration of herbal products or food ingredients of plant origin by diabetic patients to effectively control glycemic level, and/or concomitant use of herbal products with oral diabetic drugs to achieve faster glycemic control. This can lead to either herb-drug-related adverse reactions or beneficial interactions. Over 50% of diabetic patients in Nigeria use herbal medicines alongside their conventional drugs for their disease management, where patients are exposed to positive and negative herb–drug interactions (Ezuruike and Prieto 2016). So it becomes necessary to study herb–drug interactions

5.3.1 Herb–Biguanide Interaction Metformin, a biguanide is the first-line therapy for patients with type 2 diabetes. It is an efficient glucose lowering drug, but is associated with adverse effects such as dose-dependent gastrointestinal disorders and rare cases of life-threatening lactic acidosis. Metformin rarely causes hypoglycemia and has no effect on body weight. It sometimes causes vitamin B12 deficiency leading to macrocytic anemia or peripheral neuropathy. Kidney failure reduces metformin elimination and an increased risk of lactic acidosis (Prescrire International 2014). When metformin is combined with a phytochemical or herbal extract, the glycemic level can be effectively controlled as well as the dose of metformin can be reduced thus minimizing its side effects. Different polyphenols or herbal extracts in combination with metformin is listed in Table 5.1.

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Table 5.1  Combination of phytochemical/herbal extract with metformin affecting glucose uptake in vitro in cells or in vivo Phytochemical/plant formulation or extract Honey

Arecoline Berberine Caffeic acid Chlorogenic acid p-coumaric acid Eugenol Ferulic acid

Nisha Amalaki (NA), formulation with Curcuma longa L. and Phyllanthus emblica L. Curcuminoids Cassia auriculata L. (CA) leaf extract Oleanolic acid

Ginseng (Ginsenoside CK)

Karela – bitter melon (Momordica charantia)

Ginger (Zingiber officinale)

Gymnema tea

Indications Decreased blood glucose Decreased level of bilirubin, triglycerides, total cholesterol, LDL, VLDL, increased HDL compared to metformin alone Increase glucose uptake in vitro by cells

Increase glucose uptake in vitro by cells, decrease blood glucose, improve lipid profile, and increase β-cell regeneration and its mass in β-cells. Significantly reduced blood glucose, triglycerides, and total cholesterol levels. PK interactions were drastically different in diabetic and normal rats A reduction in metformin dose with combination of CA with a better blood glucose lowering effect. Improved liver pathology, the combination therapy additively or synergistically decreased the mRNA expression levels of GP, PGC-1α, PEPCK1, and G-6-Pase and increased the synthesis of glycogen Combined treatment with CK-ginsenoside and metformin significantly improved plasma glucose and insulin levels when compared to individual compounds. Extract plus half doses of metformin or glibenclamide caused hypoglycemia greater than that caused by full doses Combination showed significant hypoglycemic effect in combination in normal, STZ-, and alloxan-diabetic rats Ginger and metformin combination reduces hyperglycemia, hyperlipidemia and improved renal dysfunction

Beneficial pharmacodynamic effects on blood glucose reduction by combination

References Erejuwa et al. (2011) Nasrolahi et al. (2012)

Prabhakar and Doble (2009a, b), (2011a, b) and Prabhakar et al. (2013)

Shengule et al. (2018)

Elango et al. (2015)

Wang et al. (2015)

Yoon et al. (2007)

Tongia et al. (2004)

Poonam et al. (2013)

Baradaran and Rafieian-Kopaei (2013) and Rafieian-­ Kopaei and Baradaran (2013) Srujan et al. (2014) (continued)

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Table 5.1 (continued) Phytochemical/plant formulation or extract St. John’s wort

Scutellaria baicalensis

Aqueous extract of turnip leaf (AETL)

Scutellariae radix extract Houttuynia cordata ethanol extract

Ojamin (OJ), a polyherbal antidiabetic formulation

Indications Decreased renal clearance of metformin, improved glucose tolerance by enhancing insulin secretion independent of insulin sensitivity Combined treatment significantly elevated plasma and pancreatic insulin levels, reduced plasma, hepatic triglycerides, and cholesterol levels Co-administration of AETL and metformin in a dose-dependent manner significantly improved hypoglycemic activity of metformin Increased metformin hepatic distribution via rat MATE1 (multidrug and toxin extrusion protein 1) Reduced rat OCT2 (organic cation transporter 2) mediated renal excretion of metformin, increased its systemic exposure and improved glucose lowering effect Co-treatment of diabetic rats with OJ and metformin failed to control blood glucose levels

References Stage et al. (2015)

Waisundara et al. (2008)

Hassanzadeh-Taheri et al. (2018)

Yim et al. (2017)

You et al. (2018)

Choudhari et al. (2017)

Honey is a common household ingredient which is a supersaturated solution of fructose and glucose and contains a wide range of compounds such as minerals, proteins, vitamins, polyphenols, and flavonoids. Honey is known to act in combination with metformin by significantly reducing the levels of bilirubin, triglycerides, total cholesterol, LDL, VLDL, and increasing HLDL when compared to metformin alone (Nasrolahi et al. 2012). It also when combined with metformin significantly reduced the blood glucose when compared to drug alone (Erejuwa et  al. 2011). Similarly, cinnamic acid derivatives that are common minor ingredients of plants are known to synergistically combine with metformin to increase glucose uptake in 3 T3-adipocytes and L6 myotubes. The combinations resulted in an increase in the expression of genes belonging to insulin cascade and a decrease in fatty acid synthase and HMGCoA reductase genes that are involved in the secondary complications of diabetes (Prabhakar and Doble 2011a, b). A combination of ferulic acid and metformin decreased the lipid parameters and induced glycemic control in diabetic Wistar rats when compared to those treated with the drug alone through several pathways (Fig. 5.1). Improved kidney and liver functions and an enhanced regeneration of pancreatic β-cells were observed in the combinations (Prabhakar et al. 2013). The interaction of honey or cinnamic acid derivatives with metformin represents the synergistic pharmacodynamic type of interactions. Oleanolic acid, a pentacyclic triterpene, present in many medicinal herbs pharmacodynamically interacts with metformin and showed synergistic antidiabetic potentials in animal studies (Wang et al.

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2015). The combination reduced hepatic gluconeogenesis by reducing expressions of G-6-Pase (Glucose 6-phosphatase), PGC-1α (peroxisome proliferator-­activated receptor gamma coactivator 1-alpha) and PEPCK (phosphoenol pyruvate carboxykinase 1). In addition to the improved liver pathology, the combination therapy additively or synergistically decreased the mRNA expression levels of GP, PGC-1α, PEPCK1, and G-6-Pase and increased the synthesis of glycogen. The combination therapy partly activated the AMPK and AKT signaling pathway to a greater extent when compared with the activation by either of the individual components. The combination improved insulin resistance by stimulating PI3K pathway that phosphorylates Akt and downregulated mTOR. Alternatively pharmacokinetic type of interaction between herbs and metformin takes place due to the interference of the former with the transporters that deliver/ expel the drug and thereby its bioavailability. Certain transporters are involved in the delivery of metformin to liver (organic cation transporter 1, OCT 1) and in the excretion of metformin from kidney (Multidrug and toxin extrusion protein 1, MATE1). Yim et  al. (Yim et  al. 2017) accounted that Scutellariae Radix extract enhanced metformin-mediated glucose tolerance by activating its distribution among liver cells. Similarly, Houttuynia cordata ethanol extract is shown to reduce renal excretion of metformin through rat OCT2 and increased its systemic exposure which enhanced hypoglycemic effect when compared to only the drug treated rats (Chen et al. 2018).

5.3.2 Herb–Thiazolidinedione Interaction The thiazolidinediones (TZDs), pioglitazone and rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) agonists with hypoglycemic effect to treat type 2 diabetes mellitus. Pioglitazone improves insulin sensitivity (Miyazaki et al. 2002) but has a risk of bladder cancer and cardiovascular complications. It is hypothesized that a reduction in its dose when combined with herbal extracts or phytochemicals would minimize the risk associated with this drug. Table 5.2 lists the interaction between thiazolidinediones and polyphenols/herbal extracts. Ellagic acid, a polyphenolic phytochemical which is abundant in pomegranate enhanced pioglitazone-mediated insulin sensitivity in a synergistic manner. In vitro studies using L6 myotubes (Nankar and Doble 2015) reported that the dose of pioglitazone was reduced from 3 to 1 μM (by threefold) when combined with 1 μM of ellagic acid, to achieve the same fixed insulin stimulated 2-NBDG uptake. The combination of ellagic acid and pioglitazone improved hyperglycemia, dyslipidemia in diabetic rats by upregulating GLUT4, PPAR-γ, and adiponectin expression and restored pancreatic β-cell mass. Pioglitazone dosage was reduced by twofold (from 10 mg/kg BW to 5 mg/kg BW) when combined with ellagic acid (10 mg/kg BW) (Nankar and Doble 2017). Nephropathy and myocardial infarction are independent predictors for the development of bladder carcinoma within pioglitazone users. A combination of quercetin and pioglitazone at lower concentrations is reported to deliver synergistic vascular

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Table 5.2  Combination of phytochemical/ herbal extract with thiazolidinediones affecting glucose uptake in vitro in cells or in vivo Phytochemical/ extract Ellagic acid

Thiazolidinedione Pioglitazone

Momordica charantia

Rosiglitazone

Arecoline Berberine Caffeic acid Chlorogenic acid p-Coumaric acid Eugenol Ferulic acid

2,4-Thiazolodinedione

Quercetin

Pioglitazone

Dietetic supplement based on barley and beer yeast enriched with chromium (BBCr) Cinnamomum cassia

Rosiglitazone (R)

Pioglitazone

Effect Synergistic activity by improving insulin sensitizing activity of pioglitazone in L6 myotubes Dose of pioglitazone reduced by twofold in combination with ellagic acid and it significantly increased the expression of GLUT4, adiponectin and PPAR-γ in skeletal muscle An hypoglycemic effect was observed with the combination with an increase in the volume of islet cell in pancreas and ameliorated the liver functions Increased glucose uptake in vitro by cells

Decreased blood glucose, improve lipid profile and increase β-cell regeneration and its mass in β-cells damaged rats Provides maximal vascular protection Pretreatment with BBCr, R and BBCr+R prevented the onset of experimental diabetes caused by alloxan

Combination reduced the glucose levels and body weights significantly than pioglitazone. Cinnamon decreased metabolism of pioglitazone through CYP 3A4 inhibition

References Nankar and Doble (2015)

Nankar and Doble (2017)

Nivitabishekam et al. (2009)

Prabhakar and Doble (2009b), (2011a, b) and Prabhakar et al. (2013)

Kunasegaran et al. (2014, 2017) Cekic et al. (2011)

Mamindla et al. (2017)

(continued)

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Table 5.2 (continued) Phytochemical/ extract Bavachinin (BVC), a component of Malay tea scurfpea fruit Naringenin

Pioglitazone

Radix Astragali

Pioglitazone

Radix Rehmanniae

Pioglitazone

Thiazolidinedione Rosiglitazone Pioglitazone

Effect Combination induced PPAR transcriptional activity, as well as lower glucose and triacylglycerol levels in db/db mice Oral administration of naringenin attenuated the hypoglycemic action of pioglitazone in TSOD mice – antagonistic in nature Co-administration did not affect the pharmacokinetics of pioglitazone especially in diabetic groups Altered the pharmacokinetic profiles of pioglitazone to statistically significant levels

References Feng et al. (2016)

Yoshida et al. (2017)

Yuan et al. (2012)

Shi et al. (2014)

protection in type II diabetes and reduce oxidative stress (Kunasegaran et al. 2017). A synergistic combination of quercetin and pioglitazone decreased superoxide anion (O2•−) and increased the nitric oxide (NO) production in the aorta of diabetic rats when compared to the individual treatments. A synergistic effect was demonstrated, where the combination (10–7 M each drug) improved endothelial function isolated diabetic aorta with a significantly greater effect than 10–6 M of either agent. Also angiotensin II-induced contraction of diabetic but not normal aorta with minimally effective concentrations of pioglitazone and quercetin combination occurred through inhibition of O2− and increasing NO bioavailability (Kunasegaran et  al. 2014). Also a combination of Momordica charantia and rosiglitazone enhanced the hypoglycemia in streptozotocin-induced diabetic adult and neonatal rats (Nivitabishekam et al. 2009). Administration of both M. charantia and rosiglitazone increased the volume of pancreatic islet cells and prevented liver damage in rats when compared to the control.

5.3.3 Herb–Sulfonylurea Interaction Sulfonylurea (SU) has been categorized as insulin secretagogues which act by stimulating the pancreatic β-cells to secrete insulin. Glibenclamide, commonly used sulfonylurea in the management of Type II diabetes, is associated with numerous risks that limit its use in therapy. It is associated with hypoglycemia, hyperinsulinemia, pancreatic deterioration, weight gain, and an increased risk of cardiovascular-related deaths (in long-term treatments). Patients also have a higher risk of developing

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Table 5.3  Combination of phytochemical/herbal extract with sulfonylureas affecting glucose uptake in vitro in cells or in vivo Phytochemical/extract Aralia root bark extract

Sulfonylurea Glipizide

Gymnema sylvestre

Glimepiride

Aloe vera

Glibenclamide

Cassia

Glibenclamide

Aqueous extract of garlic (ASE)

Glibenclamide

Tinospora cordifolia

Glibenclamide

Boswellic acids (BA) and andrographolide (AD)

Glyburide

Curcumin

Gliclazide

18α-Glycyrrhizin (18α-GL) is one of the main active components of traditional Chinese medicine – licorice (Radix Glycyrrhizae) Piperine

Glibenclamide

Glimepiride

Effect Moderately lowered HbA1c and LDL-C levels when compared to glipizide alone Reduced glucose and HbA1c levels Additive effect on blood glucose lowering Similar to effect of glibenclamide Hypoglycemic effect observed with combinations was greater than either of the drug given alone At 400 mg/kg dose, a marked increase in the bioavailability of glibenclamide BA and AD led to the PK/ PD changes because of glyburide-increased bioavailability by inhibiting CYP3A4 enzyme Pharmacokinetics of gliclazide not altered but improved glycemic control 18α-GL enhanced hypoglycemic effect of glibenclamide by inhibiting CYP3A

The combination enhanced the bioavailability of glimepiride by inhibiting CYP2C9 enzyme

References Liu et al. (2015)

Kamble et al. (2016) Bunyapraphatsara et al. (1996)

Poonam et al. (2013)

Sahu et al. (2018)

Samala and Veeresham (2016)

Vatsavai and Kilari (2016)

Ao et al. (2008)

Veeresham et al. (2012)

complications such as neoplasias, nephropathies, and neuropathies (Vigneri et al. 2009). Numerous reports suggest synergistic pharmacokinetic or pharmacodynamic interaction between herbs and sulfonylureas (Table 5.3). Glibenclamide is known to work in combination with sesame oil and it resulted in 36% reduction in blood glucose and 43% reduction of HbA1c. Sesame oil combination therapies resulted in significant reduction in the plasma total cholesterol, LDL-C, and triglyceride levels.

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There was significant improvement in Plasma HDL-C and nonenzymatic and enzymatic antioxidants in sesame oil combination therapies. Curcumin at single doses did not alter peak reduction in blood glucose levels achieved by gliclazide in rats and in rabbits. Multiple-dose interaction studies with curcumin showed a reduction in blood glucose levels ranging from 23.4% to 42.4% in normal rats, 27.6% to 42.3% in diabetic rats, and 16.5% to 37.9% in rabbits. Gliclazide pharmacokinetics was not changed by single or multiple dosages of curcumin treatment and hence believed to be pharmacodynamics in nature. A combination of TCM extracts containing Astragalus membranaceus, Radix rehmanniae, and Radix trichosanthis together with sulfonylurea, glibenclamide, has been approved in China as Xiaoke pills. Clinical data support the synergistic activity of TCM and glibenclamide (Han and Liu 2009). Glinides, similar to sulfonylureas, bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells and may be linked with a higher risk of hospitalized heart failure in type 2 diabetic patients (Lee et al. 2017). Grapefruit juice increased the bioavailability of repaglinide without affecting the blood glucose concentration. Polyphenols such as caffeic, p-coumaric, and ferulic acids inhibited the intestinal uptake of nateglinide through nateglinide/H+ transport system (Itagaki et al. 2005; Saito et al. 2005).

5.3.4 Interaction Between Herb–Αlpha Glucosidase Inhibitors Alpha glucosidase enzymes in the brush border of small intestine are involved in digestion of complex carbohydrates. Competitive inhibition of α-glucosidase by the pseudo carbohydrates including acarbose, voglibose, or miglitol leads to a delay in the digestion of carbohydrates. Consequently, the absorption of glucose is delayed and postprandial hyperglycemia is averted. α-Glucosidase inhibitors cause more adverse gastrointestinal side effects such as flatulence, diarrhea with decreasing effect on fasting, and post load insulin levels. Additionally, acarbose is known to possess α-amylase inhibitory potential which results in gastrointestinal side effects due to undigested, readily fermentable starch reaching the colon (Van de Laar et al. 2005). Antidiabetics of phytochemicals including alkaloids, polyphenolics, curcuminoids, terpenoids, and anthocyanins are known to inhibit α-glucosidase (Ríos et al. 2015). Research on the combination of acarbose with phytoconstituents or plant extracts can help in glycemic control is listed in Table 5.4. In a study, Rowanberry extracts rich in chlorogenic acids (65% total) and black currant extracts rich in anthocyanins (70% total) were found to potentiate the α-glucosidase inhibition by acarbose (Boath et  al. 2012). Similarly, the extracts of Oroxylum indicum (tea; OISE) containing baicalein, baicaelin-7-O-glucoside, chrysin, baicalein-7-diglucoside, and oxoxylin A are reported to act in synergy with acarbose against α-glucosidase under in  vitro conditions. Individual phytochemicals of OISE, baicalein, and baicalein-­ 7-­ Oglucoside when combined with acarbose against rat intestinal α-glucosidase exhibited synergy (Zhang et  al. 2017a). A combination of aqueous extract of black tea

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Table 5.4  Combination of phytochemicals with acarbose against α-glucosidase activity affecting glucose uptake in vitro in cells or in vivo Plant component/ extract Baicalein, baicalein-7-O-­ glucoside Oroxylum indicum (tea) extract Oroxylum indicum (tea) extract

Rowanberry extracts black currant extracts Aqueous extracts of black tea (Camellia sinensis) Baicalein Quercetin Luteolin (+) – Catechin Baicalein

Apigenin

α-Glucosidase source Small intestinal mucosa

Prediabetic mice

Rat intestinal acetone powder Small intestinal α-glucosidase activity in GK rats Maltose-­ hydrolyzing activity of rat small intestinal α-glucosidase activity Sucrose-­ hydrolyzing activity of rat small intestinal α-glucosidase activity Saccharomyces cerevisiae

Morin Ceylon cinnamon, Thai cinnamon, Chinese cinnamon Green tea extracts (GTE), green tea polyphenols (GTP) or epigallocatechin gallate (EGCG)

Rat intestinal α-glucosidase Baker’s yeast α-glucosidase

Nature of interaction Synergy

References Zhang et al. (2017)

Reduce the dose of acarbose by 80%, reduce the risk of diabetes by 75% and one fold higher activity than acarbose alone. Combination improved glucose tolerance, lipid metabolism, reduced oxidative stress, and tissue damage Synergy

Zhang et al. (2017b)

Synergy

Synergy. CI