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OXIDATIVE STRESS, ANTIOXIDANT SCAVENGING SYSTEMS AND DIABETES MELLITUS: A CONCISE REVIEW. | Superoxide Dismutase | Antioxidant

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The enormous majority of complex life on earth requires oxygen for its survival. Oxygen is an extremely reactive molecule that damages living organisms by producing reactive oxygen species leading to oxidative stress. Oxidative stress arrived from increasing amount of ROS or as a consequence of increased levels of lipid peroxides and free-radical intermediates, as well as the reduced total antioxidant capacity that may cause the reduction of molecular oxygen or oxidation of water to leads to the formation of free radicals that could damage cellular lipids, membranes, proteins and DNA (Rains et al, 2011). Living organisms have a complex network of antioxidant metabolites and enzymes that work mutually to prevent oxidative damage to cellular components Ido et al, 1997). Advanced oxidative stress and alterations in antioxidant potential, observed in both clinical and investigational diabetes mellitus. Alteration in oxidative stress biomarkers, including Catalase, superoxide dismutase, glutathione, glutathione reductase, glutathione peroxidase, antioxidant vitamins, lipid peroxidation, non enzymatic glycosylated proteins, are helpful in identifying the risk of developing vascular complications in diabetics.
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  ISSN: 2320-5407 Int. J. Adv. Res. 5(7), 2205-2216 2205    Journal Homepage: -  www.journalijar.com Article DOI: 10.21474/IJAR01/4961 DOI URL:  http://dx.doi.org/10.21474/IJAR01/4961 RESEARCH ARTICLE    OXIDATIVE STRESS, ANTIOXIDANT SCAVENGING SYSTEMS AND DIABETES MELLITUS: A CONCISE REVIEW. Farah Jabeen, Farha Aziz and Husan Afroz Rizvi. Department of Biochemistry, Jinnah University for Women, Karachi  –   Pakistan. ……………………………………………………………………………………………………....   Manuscript Info Abstract …………………….   ………………………………………………………………   Manuscript History Received: 26 May 2017 Final Accepted: 28 June 2017 Published: July 2017 Key words:- Oxidative stress; ROS, antioxidants, lipid peroxides, free-radical, diabetes mellitus The enormous majority of complex life on earth requires oxygen for its survival. Oxygen is an extremely reactive molecule that damages living organisms by producing reactive oxygen species leading to oxidative stress. Oxidative stress arrived from increasing amount of ROS or as a consequence of increased levels of lipid peroxides and free-radical intermediates, as well as the reduced total antioxidant capacity that may cause the reduction of molecular oxygen or oxidation of water to leads to the formation of free radicals that could damage cellular lipids, membranes, proteins and DNA (Rains et al, 2011). Living organisms have a complex network of antioxidant metabolites and enzymes that work mutually to prevent oxidative damage to cellular components Ido et al, 1997). Advanced oxidative stress and alterations in antioxidant potential, observed in both clinical and investigational diabetes mellitus.   Alteration in oxidative stress  biomarkers, including Catalase, superoxide dismutase, glutathione, glutathione reductase, glutathione peroxidase, antioxidant vitamins, lipid peroxidation, non enzymatic glycosylated proteins, are helpful in identifying the risk of developing vascular complications in diabetics. For the period of the preceding few years, more attention has been gained on the involvement of oxidative stress in diabetes and it has  been established that oxidative stress in association with non-enzymatic glycosylation of protein and glucose auto-oxidation might contribute in the pathogenesis of secondary complications of diabetes (Mullarkey et al, 1990; Ceriello et al, 2000). In this review article, we summarize the effect of oxidative stress in the development and  pathogenesis of diabetes and its obstacle and the role of antioxidants in reducing oxidative stress and lessening of diabetic complications. Copy Right, IJAR, 2017,. All rights reserved. ……………………………………………………………………………………………………....   Introduction:- The oxygen which is utilized during normal cellular metabolism for generating energy produces ROS. In  physiological state, the superoxide anion is formed in various steps of the electron transport chain as a by-product, through the course of normal oxidative phosphorylation, which is essential for producing ATP. Moreover Peroxide is formed from the oxidation of reduced flavoproteins (Lenaz et al, 2001). These free radicals are counteracted by the body’s self defense system. The ROS formed inside the cells are hydrogen peroxide (H 2 O 2 ), hypochlorous acid (HOCl), and free radicals for example the hydroxyl radical (·OH) and the superoxide anion (O2−). These oxidants Corresponding Author:-Farah Jabeen. Address :- Department of Biochemistry, Jinnah University for Women, Karachi  –   Pakistan.    ISSN: 2320-5407 Int. J. Adv. Res. 5(7), 2205-2216 2206 can spoil the cells by initiating chemical chain reactions through lipid peroxidation, or by oxidizing DNA or proteins (Sakurai et al, 1988). Hyperglycemic induced Oxidative Stress in Diabetes:-  Homeostasis of Glucose is retained by the well synchronized communication of three physiologic routes: insulin secretion, up taking of glucose by tissue and hepatic glucose production. The body strives to maintain a continuous delivery of glucose for providing energy to cells by keeping constant glucose concentration in blood. Usually glucose homeostasis corresponds to the equilibrium between intake (glucose assimilation from gut), tissue consumption (Glycolytic pathway, HMP shunt, TCA cycle and glycogen production) and endogenous production (gluconeogenesis and glycogenolysis) (Meyer et al, 2002). Failure to maintain this homeostasis results various disturbances in carbohydrate, protein and fat metabolism. Inadequate or inactive release of insulin or less utilization of glucose by cell leads to hyperglycemia, which if not treated, produce serious long term micro and macro vascular complications. Uncontrolled blood glucose level over a longer period results severe micro-vascular impediments including nephropathy, neuropathy and retinopathy (Yamagishi et al, 2005; Van Dam et al, 2002) as well as macro-vascular complications such as cerebrovascular disease, cardiovascular and peripheral vascular disease (Grobbee et al, 2003; Thompson et al, 2008). It is reported that micro-vascular complications start developing at least 7 years  prior to the confirmed diagnosis of type-2 diabetes (Harris et al, 1995). As no early symptoms of diabetes appear, most of the people remain unaware of the disease for many years. People usually consult physician when symptoms of hyperglycemia like polyurea, polydipsia, polyphagia, fatigue, blurred vision, unexplained weight loss, slow healing of wound, deadness (numbness) or itchy (tingling) in hands or feet and cardiovascular disease appear. The vascular complications are believed to be the major cause of morbidity and mortality in diabetic patients (Klein et al, 1995; Haffner et al, 1998; Patel et al, 2008 ) and hyperglycemia is supposed to be a major factor responsible for these complications. The mechanism, how these vascular diseases are produced, is still not clear. However, the evidences suggested, that hyperglycemia produce major disturbances in number of metabolic pathways leading to damages in vascular tissues. The most prominent pathways which indicate, that hyperglycemia promotes cellular dysfunctions include: the aldose reductase or Polyol pathway (Setter et al, 2003).AGE pathway (Brownlee et al 1998; Gillery et al, 2001), activation of protein kinase C (Xia et al, 1994; Inoguchi et al, 2003) and oxidative stress  produced by enhanced production of ROS and defective defense system (Baynes et al, 1999; Vincent et al, 2004). The studies conducted by Diabetic Control and Complication Trial (DCCT) and the United kingdom prospective diabetes study (UKPDS) have undoubtedly demonstrated that improve glycemic control reduces the risk of development and progression of several micro and macro-vascular complications in diabetes (DCCT Research Group; 1993). Hyperglycemia is unusually high blood glucose levels that take place when the body does not make adequate insulin or whenever the body can’t utilize the produced insulin appropriately. It induces oxidative stress in diabetes (both in type 1 and type 2), either by the direct production of ROS or by changing the redox equilibrium in the cells. The redox balance can be altered in several ways such as, by raising the Polyol pathway flux, increasing the intracellular  production of AGEs, activation of PKC or by the over-making of superoxide by mitochondrial electron transport chain (Rains et al, 2011). In polyol pathway, reductions of glucose to sorbitol take place by means of aldose reductase with the help of  NADPH. Resultant Sorbitol is oxidized to fructose and NADH is oxidized to NAD+ by sorbitol dehydrogenase. In the reaction, the aldose reductase reduces the toxic aldehydes produced by ROS or other substrates to inactivate alcohols. In hyperglycemia there is an improved production of sorbitol and an increased activity of aldose reductase, which decreased NADPH, an important cofactor in the production of GSH. GSH is an intracellular antioxidant that  prevents the damages of cellular components by ROS. Hyperglycemia does not generate ROS directly, but promotes the redox inequity in the cell, leading to oxidative stress 24 . Hyperglycemia increases the synthesis of AGEs (advanced glycation end products); a variety of protein adducts whose accumulation has been concerned with tissue damage (Suzuki et al, 1999). The AGEs are created through covalent attachment of aldehyde or ketone moiety of reducing sugars to free amino groups of proteins, form a Schiff´s base. The base will reorganize into an Amadori  product, a very established ketoamine, which can directly be changed into AGEs. The AGEs are supposed to be concerned in the genesis of the irreparable complications of diabetes (Maritim et al, 2002). Hyperglycemia contributes to the direct and indirect formation of ROS by stimulating DAG-PKC pathway. Protein kinase C (PKC) consists of isoforms of the protein and is activated by DAG, a lipid courier. PKC can be activated through attachment of AGE receptors, which in turn causes fluctuations in cell signaling. The over production of  ISSN: 2320-5407 Int. J. Adv. Res. 5(7), 2205-2216 2207 superoxide by mitochondrial ETC is a major factor in the production of ROS. Normally the glucose oxidation initiate in the cytoplasm, where glucose undergoes glycolytic pathway. During glycolysis NADH and pyruvate are formed, both of them provide electrons to the ETC for ATP production through chemical reactions. The electrons are then provided to molecular oxygen, which consecutively amplifies the mitochondrial superoxide production (Rains et al, 2011). Oxidative stress can stimulate the multiple genes expression including signaling molecules for example protein kinase C, nuclear factor-B, and extracellular signal-regulating kinase in vascular cells, which may  boost up atherogenesis (Mironova et al, 2000). Sources of Oxidative Stress in Diabetes:-  There are several sources of oxidative stress in diabetes including non-enzymatic and enzymatic ways. Non-Enzymatic Sources:-   Non-enzymatic basis of oxidative stress initiate from the oxidative biochemistry of glucose. In addition to the routine mitochondrial source other metabolic pathways also contributing towards the generation of ROS. The following are the major processes where excess glucose might be shunted into when it accumulates beyond the capacity of glycolytic enzymes, ultimately producing ROS (Sies et al, 1993). Glucose Autoxidation:- Hyperglycemia could directly caused amplification of ROS creation. Glucose can go through autoxidation and  produce ãOH radicals through metal catalyzed redox reaction of hydrogen peroxide. Auto -oxidation of glucose is well-recognized to make oxygen-cored free radicals ( Niedowicz et al, 2005). Protein Glycation:-  Glucose reacts non-enzymatically with proteins causing the Amadori products development following the formation of heterogeneous class of compounds, together called as advanced glycation end products (AGEs). ROS is produced at various steps throughout this process. Excess glycemia accelerates this process of making (AGEs) in diabetes (Wolff et al, 1991). Sorbitol Pathway:-  In hyperglycemia the glucose metabolism via polyol (sorbitol) pathway is greatly augmented, which in turn results in greater ãO2 formation ( Johansen et al, 2005). Mitochondrial Source:-  An additional source of non-enzymatic generation of reactive species is the mitochondrial respiratory chain. Oxidative phosphorylation during aerobic glycolysis produces ROS, a normal process that might become extreme in hyperglycemic states. It has been established that hyperglycemia-  provoked production of ãO2 - at the mitochondrial stage, is the prime event in eliciting a violent cycle of oxidative stress in diabetes (Nishikawa et al, 2000). The major function of mitochondria is to supply energy for almost all cellular processes. Another important function of mitochondria is the regulation of insulin linked to the glucose level (Rains et al, 2011). ROS may damage some mitochondrial components including lipids, proteins and mitochondrial DNA which disturb mitochondrial normal functions and ultimately lead to insulin resistance. There are two possible ways of oxidative stress that gives insulin resistance. One of them is the increase of uncoupling protein 2 (UCP2), which is a protein on the internal membrane of mitochondria. When it is activated it causes protons to escape across the membrane and instead of the ATP  production, heat is produced. This is a mitochondrial dysfunction which is going to reduce mitochondrial fatty acid oxidation, resulting increased fatty acyl-CoA and DAG. Serine- and threonine kinase are activated and hold back the glucose transport. The other way is, when oxidative stress directly reduces ATP that will decrease glucose transport and consequently cause insulin resistance (Rains et al, 2011). Enzymatic Sources:- Enzymatic sources of amplified generation of reactive species in diabetes comprise of Nitric oxide synthase (NOS),  NADPH oxidase and Xanthine oxidase. Uncoupled Nitric Oxide Synthase (NOS):- Endothelial nitric oxide synthase (eNOS) is the enzyme which normally synthesizes ãNO from L -arginine, that serve as substrate for the enzyme. There are five cofactors/prosthetic groups mandatory for all isoforms of NOS. If NOS  ISSN: 2320-5407 Int. J. Adv. Res. 5(7), 2205-2216 2208  be deficient in its substrate or one of its cofactors, it possibly will produce ãO2 - as a substitute of ãNO. This is termed as the uncoupled condition of NOS (Guzik et al, 2002). NADPH Oxidase (Nox):-   NADPH Oxidase has a committed role of producing ROS. Several evidences suggest that in cellular stress responses  Nox has an imperative role in signal transduction. The system of Nox can be triggered by a collection of chemical,  physical, and biological cellular stresses. In various condition, activation of Nox happen in response to the cellular stress paradigm, in the sense that the response can initiate by verity of cellular stresses, stimulation of mitogen-activated protein kinases by Nox-derived ROS and involvement of Nox in stress cross-tolerance development. Nox may also convey signals in the direction of apoptosis in irreversibly injured cells. Following injury at later phase,  Nox is concerned with tissue repair by transforming cell proliferation and fibrosis and angiogenesis. It has been idealized that Nox might have a fundamental role in cell stress responses and the successive tissue repair (Jiang et al, 2011). Xanthine Oxidase (XOD):-  Xanthine oxidase is an oxidoreductase enzyme that creates ROS. It catalyzes hypoxanthine to xanthine oxidation and can additionally catalyze the xanthine to uric acid oxidation. XOD enzyme actively participates in the catabolism of purines in some species, together with humans (Hille et al, 2005; Harrison et al, 2002). Xanthine oxidase inhibition has been projected as a mechanism for improving cardiovascular health state (Dawson et al, 2006). Cyclooxygenase (COX):- Cyclooxygenase also known as prostaglandin-endoperoxide synthase (PTGS), is responsible for synthesis of important biological mediators collectively known as prostanoids (prostaglandins, prostacyclin and thromboxane). The formation of prostaglandins, levuloglandins and thromboxane, is catalyzed by the cyclooxygenase isoenzymes COX-1 and COX-2. The prostaglandins are important mediators that affect almost all known physiological and  pathological processes by means of their reversible interaction with G-protein coupled membrane receptors. The  pyretic, inflammatory, thrombotic, oncological and neuro-degenerative diseases can be relieved by inhibition of COX (Fitzpatrick et al, 2004). Metabolic Alterations Caused by Oxidative Stress and their Deleterious Effects:-  Metabolic derangements are related with diabetes mellitus including hyperglycemia, AGEs, amplified intensities of FFAs, and lipoprotein aberrations, such variation have been found in people with type 1 and type-2 diabetes (Bierhaus et al, 1998). Metabolic alterations caused by oxidative stress and their harmful effects are as follows: Lipid Peroxidation:-  In oxidative stress, ROS may enhance the oxidation of LDL. The oxidized LDL thus produced, is not recognized by LDL receptor and can be use by scavenger receptors in macrophages directs to foam cell formation and atherosclerotic plaques (Boullier et al, 2001). ROS-provoke membrane peroxidation of lipids transforms the  biological membranes structure and the fluidity, which ultimately affects its roles. All these modifications involve in the pathogenesis of vascular dysfunction (Davi et al, 2005). Advanced Glycation End Products (AGEs):-  Reactive glycation precursors, both endogenous or exogenous, assault proteins and lipids to form multifaceted and irreversible substances, which are extremely harmful to the vessel wall integrity and function (Baynes et al, 1991). This can happen in a number of ways:-    AGE cross-bridges (formed between the macromolecules) mediated Mechanical dysfunction    The enhance accumulation of AGE into the vessel wall by means of catching blood components, e.g., lipoproteins, immunoglobulins and cells (including platelets and nitrous oxide derivatives).    Wide range of modification in cell function, that appears to engage in receptor and non-receptor pathways (Bierhaus et al, 1998). Oxidation in DNA:-  Like oxidation of proteins and lipids, DNA can also be oxidized. If there is an elevated rate of ROS, there is a  possibility of abnormally high DNA oxidation, which is exhibited in many diabetic patients. It is essential to
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