Free Radical Biology of & Endocrine, Metabolic Immune Disorders E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
This reference explores the science of signaling mechanisms associated with diseases like endocrine, metabolic and immune disorders which are linked to oxidative stress mediated disease mechanisms. The common diseases in these categories include diabetes mellitus and arthritis and conditions defined by inflammation and autoimmunity. These diseases involve metabolic pathways mediated by reactive oxygen species or free radicals. The pathways are targets in the mechanism of drugs which aim to treat related disorders. The book covers key topics in free radical biology that help to understand the nature of the pathways and the pharmacology of the drugs that are designed to target them.5 chapters elucidate the free radical biology of the diseases.1. Role of free radical biology in diabetes mellitus2. Role of GSK3 in regulation of insulin release and glucose metabolism3. Regulatory role of NRF2 in rheumatoid arthritis4. Role of free radical biology in Alzheimer’s disease5. Regulatory role of immune cells mediated antibody on rheumatoid arthritis Key features:- Elucidates the key biochemical and pharmacological mechanisms that are mediated by free radicals in common endocrine, metabolic and immune diseases- Explains the activation of immunological factors (like RF and ACPA) that trigger inflammation and arthritis- Covers the role of free radicals in Alzheimer’s disease and new interventions that target mitochondrial mechanisms- Systematically explains the molecular biology of free radicals with the help of schematic diagrams - Includes references for further reading The accessible and structured text in this reference make it a suitable resource for all biomedical scientists, faculty and postgraduate students in academia and industry.
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Seitenzahl: 283
Veröffentlichungsjahr: 2001
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FOREWORD
It gives me great pleasure to introduce the book "Free Radical Biology of Endocrine, Metabolic and Immune Disorders". This book encompasses the knowledge of free radical biology in the therapy of endocrine metabolic and immune disorders, including rheumatoid arthritis, diabetes mellitus, and Alzheimer’s Disease. I hope this book successfully accomplished the aim to enumerate the scientific exploration of the signalling mechanism associated with the targeted disease. With a number of schematic representations or smart art, the proposed drug mechanism focuses on the management of endocrine, metabolic and immune disorders, which will help biomedical scientists.
I look forward to a successful publication.
PREFACE
Asis Bala, Ph.D.Free radicals and other mediated oxidants, especially superoxide (O2-) and hydrogen peroxide (H2O2), have attained great importance in the field of biology due to the pivotal role in a wide range of physiological conditions as well as their implication in endocrine, metabolic and immune diseases [1-3]. The regulatory role of different cellular signalling mechanisms, specially GSK-3, Nrf2, NF-κB mediated oxidative response for different disease progression and aetiology is still not well understood [4-7]. The book entitled “Free Radical Biology of Endocrine, Metabolic & Immune disorders” aims to enumerate the scientific exploration of the signalling mechanism associated with the targeted disease and the proposed mechanism of drug target for the management with a number of schematic representations to facilitate biomedical scientists.
As the goal of basic biomedical research is to provide a comprehensive and in-depth understanding of the disease mechanisms underlying the development and normal function of living organisms, the proposed book will hopefully reach all biomedical scientists worldwide, especially those who are looking for better ways to discover drugs in the field of endocrine, metabolic and immune disorders targeting the oxidative stress-mediated disease mechanism.
REFERENCES
[1]Bala A, Chetia P, Dolai N, Khandelwal B, Haldar PK. Cat's whiskers flavonoid attenuated oxidative DNA damage and acute inflammation: its importance in lymphocytes of patients with rheumatoid arthritis. Inflammopharmacology 2014; 22(1): 55-61.[http://dx.doi.org/10.1007/s10787-013-0193-5][2]Bala A, Haldar PK, Kar B, Naskar S, Mazumder UK. Carbon tetrachloride: a hepatotoxin causes oxidative stress in murine peritoneal macrophage and peripheral blood lymphocyte cells. Immunopharmacol Immunotoxicol 2012; 34(1): 157-62.[http://dx.doi.org/10.3109/08923973.2011.590498] [PMID: 21721906][3]Mooko T, Bala A, Tripathy S, et al. Cannabis sativa l. flower and bud extracts inhibited in vitro cholinesterases and b-secretase enzymes activities: possible mechanisms of cannabis use in alzheimer disease. Endocr Metab Immune Disord Drug Targets 2021.[http://dx.doi.org/10.2174/1871530321666210222124349] [PMID: 33618651][4]Bala A, Mondal C, Haldar PK, Khandelwal B. Oxidative stress in inflammatory cells of patient with rheumatoid arthritis: clinical efficacy of dietary antioxidants. Inflammopharmacology 2017; 25(6): 595-607.[http://dx.doi.org/10.1007/s10787-017-0397-1] [PMID: 28929423][5]Bala A, Panditharadyula SS. Role of Nuclear Factor Erythroid 2-Related Factor 2 (NRF-2) Mediated Antioxidant Response on the Synergistic Antitumor Effect of L-Arginine and 5-Fluro Uracil (5FU) in Breast Adenocarcinoma. Curr Pharm Des 2019; 25(14): 1643-52.[http://dx.doi.org/10.2174/1381612825666190705205155] [PMID: 31298161][6]Asis Bala, Susmita Roy, Debanjana Das. Role of Glycogen synthase kinase-3 in the etiology of Type 2 Diabetes Mellitus: A review. Current Diabetes Reviews 2021.[http://dx.doi.org/10.2174/1573399817666210730094225][7]Chetia P, Khandelwal B, Haldar PK, Bala A. Dietary antioxidants significantly reduced phorbol myristate acetate induced oxidative stress of peripheral blood mononuclear cells of patients with rheumatoid arthritis. Curr Rheumatol Rev 2021; 17(1): 81-7.[http://dx.doi.org/10.2174/1573397116999200729154954] [PMID: 32729420]ACKNOWLEDGEMENTS
It gives me great pleasure to acknowledge the many requests I have received from many researchers and academicians to write a book on free radical biology. I am thankful to them for their continuous inspiration, support, and moral encouragement.
I would like to express my gratitude to the contributors who have willingly undertaken all of the many demands that have been imposed upon them, especially in the pandemic situation. I have had the pleasure of working with Bentham Science Publishers. I am most grateful for their support. They have handled a great deal of work with both efficiency and perfection.
Special thanks to the Director and Principal of Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, India.
Also, a special thanks to my family for allowing me to devote the time necessary to complete such a book.
List of Contributors
Free Radical Biology of Diabetes Mellitus
Bidita Khandelwal1,*,Chamma Gupta2,Levin Thomas3,Sonal Sekhar Miraj3,Mahadev Rao3,Rubi Dey4,Karma Gurmey Dolma5,Rinchen Doma Bhutia2,Vijay Pratap Singh6Abstract
Free radicals play a pivotal role in the etiology of different diseases, including diabetes mellitus (DM). In the past three decades, the understanding of the fundamental role of free radicals in the etiology and disease progression of DM was studied broadly. This chapter aimed to enumerate the recent progress in the areas of free radical biology for the management of DM. Free radicals, as well as reactive oxygen species (ROS), having extra electrons in their outer orbitals, react with all biomolecules, including “protein, lipids, and DNA,” causing oxidative stress and damage. DM is also associated with oxidative stress induced by the elevated production of free radicals or reduced antioxidant activity. Recently, the importance of an antioxidant rich diet, yoga, and exercise has been well documented for the management of DM. Studies confirmed that exercise-induced ROS is an acute effect, while the chronic effect of exercise produces endogenous antioxidant defences and promotes a state of endogenous antioxidant defence mechanism. Therefore, regulating oxidative stress will lead to a significant future area of research for DM disease management.
INTRODUCTION-FREE RADICALS
Free radicals have acquired a significant momentum in biology along with other oxidants because of their crucial functions in numerous physiological states and pathological implications in a wide range of disorders [1]. Chemical entities like atoms, molecules, and ions with one or more unpaired electrons in their outer orbitals, are referred to as free radicals, which generally display remarkable reactivities and also show independent existence ability [1, 2]. The odd number of electrons in free radical has been attributed to its instability, short-life, and higher reactivity [2]. These radicals have the ability to remove the electrons from another compound or biomolecules to become stable due to their greater reactivity. Thereby, the molecule undergoing an attack gives up an electron and is subsequently converted to a free radical. This process sets off a chain of reactions that causes injury or kills the cell which is alive [3].
Free radicals act as both harmful as well as valuable substances [4]. Therefore, they might be recognized as a necessary evil for signalling in the regular differentiation and migration process [5]. These species are generated during normal cellular metabolism or external sources such as radiation, pollution, smoking, etc. [4]. When cells utilize oxygen to produce energy, these species are released by the mitochondrial adenosine triphosphate (ATP) synthesis pathway. As a by-product of the cellular redox process, reactive nitrogen species (RNS), as well as reactive oxygen species (ROS), are released. The vital aspect of life is maintaining a subtle equilibrium between these two species’ antagonistic effects. An adequate quantity of RNS and ROS exerts favourable actions on different cellular responses, signalling pathways, mitogenic responses, redox regulation, and immune function [6, 7]. However, at high concentrations, both the species exert oxidative stress as well as nitrosative stress, producing potential deleterious effects on the biomolecules like lipids, proteins, nucleic acids, and others [8-13]. Overload of ROS/RNS, as well as a deficit of antioxidants (enzymatic as well as non-enzymatic), can produce oxidative and nitrosative stress. These stresses play a significant role in aging as well as developing chronic and degenerative disorders (Fig. 1). On the other hand, both endogenous and exogenous antioxidants serve as “free radical scavengers” and subsequently inhibit or repair injuries produced by free radicals [14-16].
Fig. (1)) Physiological and pathological role of free radicals in the biological system.HISTORY ON THE CONCEPT OF FREE RADICALS IN BIOLOGICAL SYSTEM
The word ‘radical’ was first introduced in 1786 by French chemist Louis-Bernard Guyton de Morveau. Later, Gay-Lussac, Justus von Liebig, and Jöns Jakob Berzelius used the term to denote clusters of atoms that remained unaltered in several compounds. Early works involving free radicals were oxidative degradation of organic substances by hydrogen peroxide (H2O2) in the presence of ferrous (Fe2+) under acidic media, primarily discovered by British chemist Henry John Horstman Fenton in 1894. Subsequently, the reaction was applied to tartaric acid oxidation, with the Fenton reagent as the catalyst, and the process became known as Fenton reactions [17]. At that time, free radicals were unknown, and almost 30 years later, the hydroxyl radicals’ (OH•) role was suggested by Fritz Haber and Richard Willstätter [18]. Moses Gomberg, a chemistry professor at the University of Michigan, first prepared an organic radical, triphenylmethyl radical [(C6H5)3C•], and speculated the existence of the radical in the biological system in 1900 [19]. In 1922, Robert Williams Wood isolated and characterized atomic hydrogen for the first time in an electrical discharge tube [20]. Thereafter, atomic hydrogen’s chemical nature was experimented thoroughly by Karl Friedrich Bonhoeffer, a German physical chemist, in 1924 [21]. Methyl free radical (CH3•) was synthesized in 1929 by Friedrich Paneth, along with Wilhelm Hofeditz. To synthesize the CH3•, they followed pyrolysis of tetramethyl lead by adopting a system that Bonhoeffer used to investigate atomic hydrogen [22]. Elucidation of a free-radical mechanism and subsequent discovery of “the peroxide effect” has been credited to Morris Selig Kharasch and his fellow student, Frank Mayo, in 1933. Successively, they applied this mechanism to various other chemical systems too. They employed a free radical mechanism to add hydrogen bromide to olefins. Leonor Michaelis’s, a German biochemist, curiosity peaked when he found that free radicals were naturally occurring metabolic intermediates in a biological system and went on to observe the oxidation-reduction potential curves generated after enhancing the concentrations of oxidants added to hydroquinone in 1930. An electron loss at the onset was followed by the escape of an additional electron [23]. Michaelis believed that the initial electron loss led to the development of semiquinone radical while the subsequent loss of the later formed quinone, a wholly oxidized form.
Later in 1954, Rebeca Gershman and Daniel Gilbert proposed the “free radical theory of oxygen toxicity,” claiming that oxygen's toxicity is attributable to its capacity to produce free radicals [24]. At the same time, Barry Commoner, Jonathan Townsend, and George E. Pake conducted electronic spin resonance (ESR) studies and confirmed the presence of free radicals in enzyme-substrate systems [25]. In 1956, Denham Harman suggested the “free radical theory of aging”, which proposed free radicals’ biological implication in the aging process [26]. A new free radical research era was started by two American biochemists, Joe Milton McCord and Irwin Fridovich, in 1969. They were the first to describe superoxide dismutase’s (SOD) enzymatic activity. This is a primary enzymatic defense system for superoxide anion [27]. In 1971, G Loschen demonstrated that ROS are released in cellular metabolic respiration by indicating the production of H2O2 in mitochondria of the pigeon’s heart [28]. In 1977, F Mittal and C K Murad reported that guanylate cyclase enzyme activation by hydroxyl radicals induces second messenger cyclic guanosine monophosphate (cGMP) production [29]. In 1989, Barry Halliwell and John M.C. Gutteridge stated that ROS comprises free radical as well as non-radical oxygen derivatives [30]. In 1993, Reid et al. found the association of free radicals with muscle fatigue [31]. In 2000, V.J. Thannickal and B.L. Fanburg elucidated cellular signalling mechanisms initiated by ROS [32]. In the last few decades, there has been tremendous research on free radicals to understand their involvement in several disease pathogenesis and the protective effects of antioxidants.
CHARACTERISTICS OF FREE RADICALS AND OXIDANTS
Pro-oxidants and oxidants, in general, are referred to as ROS/NOS. Moreover, non-radical derivatives are included in oxidants. Although their reactivity is often more robust, the stability of radicals is relatively lower compared to non-radical entities. In the outer shell, free radicals have one or more unpaired electrons [4, 8-10]. The oxygen molecule is a radical (O2••) referred to as a biradical because of the presence of two unpaired electrons. Generally, free radicals are created when a chemical bond is broken, and each fragment retains an electron, when one radical is cleaved to yield a new radical, or when a redox reaction occurs [8, 9]. Free radicals include ROS such as OH•, superoxide (O2•-), alkoxy radical (RO•), peroxyl (ROO•), and lipid peroxyl (LOO•). Similarly, RNS includes nitric oxide (NO•) and nitrogen dioxide (NO2•). Whereas ROS such as singlet oxygen (1O2), ozone (O3), H2O2, hypochlorous acid (HOCl), hypobromous acid (HOBr), lipid peroxide (LOOH), and RNS such as nitrous acid (HNO2), dinitrogen trioxide (N2O3), and peroxynitrite (ONOOH) are non- radicals. These are also referred to as oxidants and can readily involve free radical reactions in biological systems [33]. These free radicals are extremely unstable as they possess electrons to carry out reactions with many organic molecules like lipids, proteins, and nucleic acids.
Types of Free Radicals
Free radicals are categorized into the following three types [1, 5, 34]:
Reactive oxygen species (ROS).Reactive nitrogen species (RNS).Reactive chlorine species (RCS).As discussed earlier, ROS and RNS are classified as ‘radicals’ as well as ‘non-radicals’ (Table 1).
GENERATION/SOURCE OF FREE RADICALS AND OXIDANTS
These radicals can be formed from endogenous as well as exogenous sources. ROS’s endogenous sources comprise various cellular organelles like mitochondria, endoplasmic reticulum, and peroxisomes, where oxygen consumption is high. These free radicals are released from the activation of immune cells, phagocytic cells, prostaglandin synthesis, inflammation, auto-oxidation of adrenalin, mental distress, intensive exercise, ischemia, infection, neoplasia, and aging [35]. Whereas exogenous sources include water and air pollution, alcohol, tobacco smoke, high temperature, cooking (used oil, fat, smoked meat), pesticides, industrial effluents, heavy metals (Fe, Cu, Cr), transition metals (Pb, As, Hg), radiation (UV) and iatrogenic (acetaminophen, halothane, bleomycin, gentamycin, tacrolimus, etc.) [4, 36-38].
Intracellular production of the free radicals can happen in two types of reactions, either enzymatic or non-enzymatic ways. The former process of producing free radicals involves prostaglandin synthesis, phagocytosis, respiratory chain, and the cytochrome P450 system [3, 19, 24, 27-30]. Superoxide radicals are generated by various cellular oxidase systems, including xanthine oxidase, peroxidases, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, etc. Complex I, as well as complex III, are the major sites of superoxide formation in the electron transport chain (ETC) [39]. Once generated, the radical participates in multiple reactions yielding several ROS and RNS (Table 1). On the other hand, the non-enzymatic process of organic substances with oxygen and the ionizing radiations also produces free radicals in the mitochondria during oxidative phosphorylation [4, 33, 36].
BIOLOGICAL ROLE OF FREE RADICALS AND OXIDANTS
As previously mentioned, free radicals are considered a necessary evil since they have a vital role in the origin as well as the evolution of life. In adequate quantity, free radicals are essential for the physiological process, including cellular structures’ maturation, and serve as a biological weapon for the body’s defence system. Invading pathogenic organisms will be targeted by the free radicals released from phagocytes, thereby working as the host defence towards infections [36, 40]. The body’s immune system merely influences the ROS generation that is exemplified in individuals suffering from granulomatous disease [36]. Since these patients possess an impaired membrane-bound NADPH oxidase system, resulting in failure superoxide radical generation, consequently produce recurrent infections.
Another significant physiological role of the free radicals is that it is essential for modulating various intracellular signalling pathways. These contain mitogen-activated protein kinase (MAPK) (induces mitogenic responses) as well as extra-cellular-signal-regulated kinase (ERK) pathways, which regulates the expression of the gene and, together with SOD, initiates cellular necrosis [41]. For example, neurons generated RNS acts as neurotransmitters, and macrophages produce one act as immunity mediators. Besides, these species are involved in angiogenesis, leukocyte adhesion, and thrombosis and have implications in vascular tone. Likewise, ROS mediates gene transcription and single transduction activities and modulates several cellular processes [42]. The free radical formation by non-phagocytic NADPH oxidase isomers plays a pivotal role in modulating intracellular signalling cascade in different non-phagocytic cells such as thyroid tissue, fibroblasts, cardiac myocytes, endothelial cells, and smooth muscle cells of vasculatures. Indeed, NO is an intracellular messenger, which is involved in the regulation of blood circulation, thrombosis, and various neuronal activities [43]. Additionally, as a nonspecific defense of the host, NO is involved in terminating intracellular pathogenic microbes as well as tumor cells [33, 43].
OXIDATIVE DAMAGE TO DNA, LIPIDS, AND PROTEINS
The loss of homeostatic balance in free radical and ROS production and/ or consumption, in due course of time, damage the macromolecules (Lipids, Proteins and, Carbohydrates), including the nucleic acid [38, 44]. This course of the reaction is referred to as Oxidative stress (OS). Increased OS can either show the way towards disease development or can also be a consequence in the pathophysiology of various diseases such as metabolic syndrome [45], neurodegenerative diseases [46-48], cancers [49], and many more. For example, oxidative stress as an early event can be attributed to an individual’s lifestyle that influences health. Consumption of high calorie diet beyond the body’s energy requirement decrease physical activity, and environmental factors all put in towards an early event in developing OS [50]. Glucose tends to increase the concentration of ROS in the form of superoxide by increasing the activity of the enzyme NADPH oxidase in polymorphonuclear leucocytes and mononuclear cells in the blood. Increased enzyme activity is a function of increased p47 phox protein, an important component of NADPH oxidase [51, 52]. Likewise, excess protein and fat consumption also contribute towards an increase in ROS generation via the same pathway as glucose. They increase ROS generation in its own distinctive pattern [53], which, if continues to prevail, then causes damage to DNA, lipid, and protein. A brief mechanism of the reaction between the different types of ROS with these functional units is hereby underlined.
OXIDATIVE DAMAGE TO LIPID
Oxidative damage to lipid has been clearly explained. PUFA are highly susceptible to reaction with free radicals because of the chemical structure consisting of several double bonds [54], this damages the lipid molecule, and the process of deterioration of lipids by the free radicals is called lipid peroxidation (LPO). LPO proceeds in three stages: initiation, propagation, and termination. Initiation begins with the reaction of PUFA with a free radical, for example, a hydroxyl radical (OH•). The reaction results in the removal of the hydrogen atom from the methylene group adjacent to the C-C cis -double bond of the PUFA molecule. Due to the presence of the double bond, the adjacent C-H bond conformation of the methylene group weakens, predisposing them to easy removal of its H atom. This reaction generates a carbon centered radical (R.) which, upon reaction with molecular oxygen, creates a lipid peroxyl radical (ROO./ PUFA·) that subsequently attacks other PUFAs [55]. In the propagation stage, the aforementioned reaction repeats, thus initiating a chain reaction, which results in the extension of the initial oxidative event. Potentially, all PUFAs within the membrane could be oxidized, destructing the integrity of membranes. This entire reaction terminates when a lipid peroxyl radical reacts with another lipid peroxyl radical to ultimately produce an inactive product. Additionally, termination occurs when the radicals interact with a chain breaking antioxidant like vitamin E [56] to produce a non-radical product. During this time, LPO generates a wide variety of relatively stable metabolic end products like Malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), 2-propenal (acrolein) [57, 58], and isoprostanes [59, 60], which can then be measured in plasma and urine as an indirect marker of oxidative stress.
OXIDATIVE DAMAGE TO PROTEIN
Oxidative damage to protein can be induced either by direct reaction of protein molecules with ROS or reaction with secondary by products of oxidatively damaged lipid and carbohydrate molecules [61, 62]. Buildup of such modified proteins disrupts the cellular function either by loss of catalytic activity due to a change in the structural integrity or by disruption of regulatory pathways [12]. These modified proteins are usually removed by proteolytic degradation, but if the extent of damage exceeds the cells' capability to remove them, then the cellular content of these oxidatively modified proteins accumulates and thus can be quantified. The most common protein oxidative modifications that can be estimated as an index of oxidative stress include the formation of protein carbonyls, nitrotyrsoine, dityrosine, and chlorinated tyrosine [63, 64]. Protein carbonyl is by far the most sought-after oxidative protein modification because of the extent to which they are generated [61]. The tissues injured by oxidative stress also generally contain increased concentrations of carbonylated proteins, making it the most widely used marker of protein oxidation [65]. Additionally, the assessment of protein carbonyls as an indicator of protein oxidation has been found to be in concordance with other oxidative stress markers [66]. Carbonylated proteins are generated as a result of:
The direct oxidation of ROS on amino acid residues like arginine, histidine, lysine, proline, and threonine [67, 68].By reactions of products of lipid peroxidation such as MDA, 4-hydroxy-2-nonenal, and 2-propenal with side chains of amino acids like Lysine, Histidine, and Cysteine [69-71].
