Oxidative Stress And Metabolic Syndrome Pdf

oxidative stress and metabolic syndrome pdf

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Metabolic syndrome MS represents a cluster of physiological and anthropometric abnormalities.

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The metabolic syndrome MS recognized as a major cause of type 2 diabetes and cardiovascular diseases, has become one of the major public health challenges worldwide. The pathogenesis of the metabolic syndrome is multiple and still poorly understood. No single factor has yet been identified as an underlying causal factor. There is a growing belief, however, that obesity, especially visceral obesity, may play an important role in the development of the syndrome. Visceral adiposity seems to be an independent predictor of insulin sensitivity, impaired glucose tolerance, dyslipidemia and elevated blood pressure.

Oxidative stress in metabolic syndrome

Metabolic syndrome MS represents worldwide public health issue characterized by a set of cardiovascular risk factors including obesity, diabetes, dyslipidemia, hypertension, and impaired glucose tolerance. The link between the MS and the associated diseases is represented by oxidative stress OS and by the intracellular redox imbalance, both caused by the persistence of chronic inflammatory conditions that characterize MS.

The increase in oxidizing species formation in MS has been accepted as a major underlying mechanism for mitochondrial dysfunction, accumulation of protein and lipid oxidation products, and impairment of the antioxidant systems.

The antioxidant therapies indeed could be able to i counteract systemic as well as mitochondrial-derived OS, ii enhance the endogenous antioxidant defenses, iii alleviate MS symptoms, and iv prevent the complications linked to MS-derived cardiovascular diseases. The focus of this review is to summarize the current knowledge about the role of OS in the development of metabolic alterations characterizing MS, with particular regard to the occurrence of OS-correlated biomarkers, as well as to the use of therapeutic strategies based on natural antioxidants.

Metabolic syndrome MS represents worldwide public health issue. It is characterized by a group of metabolic risk factors in the same person.

The key factors are obesity, measured by waist circumference and body mass index BMI , dyslipidemia, increased blood pressure, hyperglycemia, and insulin resistance [ 1 ]. The pathogenesis of MS is very complex and not yet clear. Increased biomarkers of oxidative stress OS and decreased antioxidant defenses have been measured in blood of patients with MS suggesting an in vivo overproduction of oxidizing species [ 1 — 6 ].

Many studies are focused on preventing OS in MS. Recent literature data suggest that diets that are rich in whole grain cereals, fruits, and vegetables, with low animal fat consumption, can ameliorate OS status [ 7 , 8 ]. This review is aimed at presenting an overview on the role of OS in the pathogenesis of MS and the related diseases. In particular, it is focused on i mitochondrial redox state and dysfunction, ii most reported and validated biomarkers of stress in metabolic disease manifestations, and iii benefit of various nutritional antioxidants.

When available in appropriate low amounts, ROS and RNS act as signal transduction molecules driving cell activities and providing cell protection [ 9 ]. On the other hand, when produced in excess, as in the case of inflamed tissues, they can generate further highly reactive species able to oxidize irreversibly proteins, lipids, and nucleic acids. Very important is the oxidative modification of critical enzymes or regulatory sites, whose redox modification triggers cell signaling alteration and programmed cell death [ 9 ].

A suitable equilibrium between ROS and RNS generation and antioxidant levels allows, without any sort of damage, either the cross talk between cells or the control of fundamental intracellular functions, such as cell-cell interactions, proliferation, differentiation, migration, and contraction.

These activities are carried out through the direct or indirect reversible-redox modification of critical targets located within catalytic enzymes or regulatory sites [ 9 ].

These targets include iron-sulfur clusters, metals, flavin and nicotinamide cofactors, and quinones. These oxidative modifications represent the finest regulation of redox-based signaling affecting protein activity, protein—protein interactions, and protein location, inducing conformational and functional changes of fundamental target macromolecules involved in redox signaling. A slight imbalance by oxidant formation can be counteracted by a performance activity of the antioxidant system, which allows cells to return to their physiological status.

These amounts, in association with the impaired activity of the antioxidant systems, lead to the irreversible oxidation of proteins, lipids, and nucleic acids [ 9 , 10 ]. This unbalanced redox equilibrium, called OS, triggers cell signaling alteration leading to loss of essential cellular functions, senescence, and programmed cell death [ 9 , 10 ].

They are continuously produced within the cells particularly as i the result of the electron transfer processes in the mitochondria and ii the activity of several inflammation-linked enzymes, such as NADPH oxidase, nitric oxide synthase NOS , xanthine oxidase, myeloperoxidase MPO , lipoxygenase LOX , and cyclooxygenase COX [ 9 ]. These characteristics are expressed by the standard one-electron reduction potential, a parameter suitable to predicting the hierarchy of radical reactivity in terms of ability to transfer the unpaired electron to any oxidized species [ 11 ].

The values range from positive one-electron reduction potential highly oxidizing species to negative one-electron reduction potential highly reducing species [ 11 ]. At low concentrations, H 2 O 2 diffuses in intracellular compartments and reacts with specific protein residues, such as cysteine, methionine, and selenocysteine, assuming a key role in the regulation of the intracellular redox signaling [ 9 ].

These species are key contributors to the physiological microbicidal activity of phagocytes. However, excessive generation of MPO-derived oxidants has been linked to tissue damage in many diseases, especially in those characterized by acute or chronic inflammation [ 17 ].

Mitochondria are crucial, multifunctional organelles, which actively regulate cellular homeostasis. Their main function is to produce energy as adenosine triphosphate ATP via citric cycle tricarboxylic acid cycle, Krebs cycle. Other cell functions include ionic homeostasis, production and regulation of ROS, lipid and carbohydrate utilization, pH regulation, steroid hormone synthesis, calcium homeostasis, thermogenesis, and cell death [ 18 — 20 ].

As mentioned before, mitochondria are the primary intracellular site of oxygen consumption and the major source of ROS, most of them originating from the mitochondrial respiratory chain. Dysfunction of the respiratory chain may lower the ATP production, increase ROS production, reduce antioxidative capacity, and induce apoptosis.

ROS, highly reactive molecules radicals, and nonradicals have the ability to capture electrons from molecules proteins and nucleic acids with whom they get in contact, leading to cell damage.

In healthy cells, an intricate homeostatic system regulates and maintains optimal mitochondrial function. A failure of this system is observed in obesity, asthma, and metabolic syndrome progression [ 21 ].

Growing evidence suggests that these dysfunctions have a strong relationship with various MS components, resulting in clinical complications [ 22 , 23 ]. Cheng and Almeida declare that mitochondrial dysfunction is an early pathophysiological event in insulin resistance and obesity development [ 24 ]. Mitochondrial dysfunction leads to the activation of stress pathways, which reduce cellular sensitivity to insulin, limiting nutrient influxes and preventing further damages. Chronically, in organs such as liver and skeletal muscle, it appears as reduced mitochondrial metabolism and insulin resistance, following consequent hyperinsulinemia and different nutrient storages in adipose tissue [ 25 — 27 ].

Several studies demonstrate that in different tissues, mitochondria adapt physically to nutrient availability and that obesity causes mitochondrial OS and dysfunction [ 28 , 29 ]. Conversely, calorie restriction alleviates sarcopenia [ 31 ]. In cardiomyocytes of young patients, an excess of body weight impairs mitochondrial function also in the absence of heart failure and diabetes [ 32 ].

Moreover, in humans and mouse models, obesity results in mitochondrial dysfunction, skeletal muscle, and adipose tissue [ 33 ]. Mitochondria are subject to dynamic processes in order to establish a control system related to survival or cell death and adaptation to changes in the metabolic environment of cells. The mitochondrial dynamic includes several processes such as fusion and fission, biogenesis, and mitophagy. Modifications of the mitochondrial dynamic in organs involved in energy metabolism such as the pancreas, liver, skeletal muscle, and white adipose tissue could be of relevance for the development of insulin resistance, obesity, and type 2 diabetes.

Metabolic status can condition the number, form, and function of mitochondria, influencing organ function. Conversely, changes in mitochondrial dynamic influence organ metabolism.

Mitochondrial biogenesis is critical for the normal function of cells, and it can be produced in response to an oxidative stimulus. Mitochondrial fusion is linked to increased ATP production, while the inhibition of this process is associated with ROS production [ 34 — 36 ]. These methods rely to the use of specific probes, such as dihydrorhodamine, dihydroethidium, dihydrodichlorofluorescein, Amplex Red, and boronates.

All of these are able to interact with the formed oxidants and to provide information about the different species produced in the studied system. Initially, these methods have been used to study the changes of the redox environment in cell systems.

These limitations deal with the chemical features of the probes as well as their reactivity, such as i secondary chemical interactions between probe end products, the probe-derived radicals, and the oxidants generated in the studied system; ii redox cycling and generation of ROS by probes and their oxidation products; iii probe interaction with metals and with the intracellular antioxidants; iv intracellular compartmentalization of probes and sites of oxidant formation; and v probe sensitivity to light and pH changes [ 37 — 39 ].

The spin trapping technique permits the species-specific and time-dependent detection of products, showing typical EPR spectral characteristics. Recent literature data on this topic illustrate that the simultaneous use of different techniques, i. Each of them provides useful information concurring to identify the formed species by detecting the specific adducts and end products [ 38 — 40 ].

The primary antioxidant enzymes in tissues that are able to detoxify directly oxidizing species include SOD, glutathione peroxidase Gpx , and catalase CAT , and bilirubin. The latter are the key components of enzymes such as Gpx and TrxR [ 1 , 9 , 41 ].

GPx is an enzyme dependent on the micronutrient selenium and plays a crucial role in the reduction of lipid oxidation and peroxide detoxification. Prxs are thiol-specific antioxidant enzymes that reduce various cellular peroxide substrates, including H 2 O 2 and ONOO-, using cysteine-containing active sites.

TrxR and Grx have catalytic-redox-active cysteines and catalyze the reduction of protein mixed disulfides. Trx in particular has function in DNA and protein repair by reducing ribonucleotide reductase as well as methionine sulfoxide reductases. Some of these antioxidants, proteins, and redox enzymes belong to a network connected through substrates and products.

The main source of intracellular NADPH is the oxidative branch of the pentose phosphate pathway, with the cofactor being produced by the rate-limiting glucosephosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Other sources of NADPH are the cytoplasmatic and mitochondrial isoforms of isocitrate dehydrogenases, formyltetrahydrofolate dehydrogenases, methylenetetrahydrofolate reductase, and the NADP-dependent malic enzymes [ 43 ].

Low-molecular-weight compounds are fundamental antioxidant molecules because they can directly detoxify ROS and RNS and repair oxidized biological targets [ 1 , 9 , 41 ]. GSH is the predominant non-protein low-molecular-weight compound 0. It has been shown that physiological concentrations of ascorbic acid inhibit oxidation of LDL, lipid, and protein.

An important feature of ascorbic acid is acting synergistically with vitamin E and protecting this vitamin from the oxidative modifications. Bilirubin has been proved to be a powerful antioxidant in human blood plasma both in its unconjugated form and complexed with serum albumin. Prooxidant and antioxidant systems are shown in Figure 1. In addition to the indirect measurement of ROS and RNS levels, oxidized molecules reflect the damage mediated by OS in cells and tissues, and their measurement can be indicative for the occurrence of OS in a specific disease, as well as the potential efficacy of clinical treatments.

As already mentioned, ROS and RNS generically can react with all the macromolecules of biological importance in cell and tissues, generating oxidative modification in lipids, DNA, and proteins that, in some cases, can be the footprint of the oxidant generated [ 44 , 45 ]. Polyunsaturated fatty acids PUFAs , in particular linoleic and arachidonic acid, are important targets of lipid peroxidation.

MDA is one of several low-molecular-weight end products formed via the decomposition of certain primary and secondary lipid peroxidation products. It is a specific marker of omega-3 and omega-6 fatty acid peroxidation [ 46 ]. ROS and RNS generate a large number of oxidative modifications in DNA including nucleotide oxidation, strand breakage, loss of bases, and adduct formation.

The main cellular targets of ROS and RNS in tissues are doubtless the highly concentrated proteins, which undergo posttranscriptional oxidative modifications oxidation, carbonylation, nitrosylation, and nitration of specific amino acid residues cysteine, aromatic amino acids, histidine, and methionine. Some of these modifications are reversible i. The reversible oxidative modifications are involved in the physiologic redox regulation of cellular signaling and are involved in particular cysteine in specific proteins or enzymes.

This thiol modification, and its reversibility, plays a pivotal role in cell physiology and signaling, so that S-nitrosylation has been regarded as functionally equivalent to protein phosphorylation and dephosphorylation [ 50 ]. The irreversible oxidative protein modification can allow to the definitive alteration of protein expression and activity, which inevitably reflects on cellular trafficking and redox signaling.

This is particular true for cysteine residues in specific proteins or enzymes in which the oxidation processes, going further sulfenic acid formation, proceeds with the formation of sulfinic -SOOH and sulfonic -SOOOH acids, leading to the irreversible inactivation of their activity [ 9 ]. Carbamylated proteins are interesting to use as biomarkers, because they may quantitatively reflect the burden of pathological conditions inflammation and uremia and are present in plasma or whole blood.

Protein nitration induces a loss and gain of protein function, compete with protein phosphorylation, stimulate the autoimmune response, and affect protein turnover.

Biomarkers of OS are shown in Table 1. Elevated OS in individual with T2D and MS has been shown to be one of the major risk factors for an increased risk of cardiovascular disease [ 1 , 2 , 5 , 53 ]. The precise mechanism by which OS may accelerate the development of complications in diabetes is partly known [ 1 ].

T2D is characterized by chronically elevated blood glucose levels, which may be caused by increased insulin resistance and glucose intolerance. Persistent hyperglycemia in T2D causes nonenzymatic protein glycation and oxidative degeneration.

AGEs and RAGE interaction elicit OS generation in various types of cells and subsequently evoke proliferative, inflammatory, and thrombogenic reactions, playing an important role in the development and progression of diabetes-associated disorders [ 57 ].

HbA1c is more negatively charged than hemoglobin and has a higher oxygen affinity therefore reducing gaseous exchange to tissues.

Biomarker of oxidative degeneration in T2D is an oxidized low-density lipoprotein ox-LDL that, in contrast to gl-LDL, is a proinflammatory and proatherogenic particle containing protein adducts and inflammatory lipids that promote atherosclerosis. Studies have shown that ox-LDL within the vascular endothelium leads to the expression of monocyte chemoattractant protein-1 MCP-1 , known to promote vascular endothelial dysfunction and to increase thrombogenicity [ 58 ].

Moreover, ONOO - has been reported to inactivate prostacyclin synthase leading to the accumulation of inflammatory and prothrombotic eicosanoids [ 60 , 61 ].

Biomarkers of Oxidative Stress in Metabolic Syndrome and Associated Diseases

Ferreira 6. Metabolic syndrome MetS has a high prevalence around the world. Considering the components used to classify MetS, it is clear that it is closely related to obesity. These two conditions begin with an increase in abdominal adipose tissue, which is metabolically more active, containing a greater amount of resident macrophages compared to other fat deposits. Abdominal adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving MetS components, namely insulin resistance, hypertension and hyperlipidemia.

There is increasing evidence of the prevalence manifestations of metabolic syndrome worldwide. Metabolic syndrome is a cluster of abnormalities characterized by hypertension, central obesity, insulin resistance, endothelial dysfunction, dyslipidemia and oxidative stress. All these alterations predispose individuals to type 2 diabetes and cardiovascular disease that are major contributing factors to earlier mortality among people. The investigation of food nutrients that could reverse the features of metabolic syndrome is an important aspect for dietary-based therapies that may ameliorate the burden of the disorder. Antioxidant micronutrients are of great interest due to the recent described association between obesity, cardiovascular alterations and oxidative stress. These antioxidant nutrients are also being considered in the management of metabolic syndrome due to their potential benefits on hypertension, insulin resistance and hypertriglyceridemia since growing evidence has emerged that point to a causal link between oxidative stress and metabolic syndrome.

Oxidative stress is associated with many of the components of the syndrome, leading to the concept that the amelioration of risk factors comprising metabolic syndrome, including insulin resistance, elevated blood pressure, elevated lipid levels, inflammation and endothelial dysfunction may ameliorate oxidative stress.

Does total antioxidant capacity affect the features of metabolic syndrome? A systematic review

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes.

As antioxidants play a protective role in the pathophysiology of diabetes and cardiovascular diseases, understanding the physiological status of antioxidant concentration among people at high risk for developing these conditions, such as Metabolic Syndrome, is of interest. In present study out of first degree non-diabetic relatives and non-diabetic spouses, Low levels of antioxidants and increased oxidative stress with insulin resistance in metabolic syndrome suggests that besides therapeutic life style changes TLC as suggested in ATP III guidelines inclusion of antioxidant vitamins, fruits and vegetable could be beneficial to ward off the consequences of metabolic syndrome. This is a preview of subscription content, access via your institution. Rent this article via DeepDyve.

Metabolic syndrome MS represents worldwide public health issue characterized by a set of cardiovascular risk factors including obesity, diabetes, dyslipidemia, hypertension, and impaired glucose tolerance. The link between the MS and the associated diseases is represented by oxidative stress OS and by the intracellular redox imbalance, both caused by the persistence of chronic inflammatory conditions that characterize MS. The increase in oxidizing species formation in MS has been accepted as a major underlying mechanism for mitochondrial dysfunction, accumulation of protein and lipid oxidation products, and impairment of the antioxidant systems. The antioxidant therapies indeed could be able to i counteract systemic as well as mitochondrial-derived OS, ii enhance the endogenous antioxidant defenses, iii alleviate MS symptoms, and iv prevent the complications linked to MS-derived cardiovascular diseases.

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Role of oxidative stress in pathogenesis of metabolic syndrome

Камера, подрагивая, словно наехала на него, и кадр не сразу оказался в фокусе. А Смит тем временем безучастно продолжал свои комментарии: - Как вы видите, у Танкадо случился мгновенный сердечный приступ. Сьюзан стало дурно оттого, что она увидела.

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Metabolic syndrome (MS) represents worldwide public health issue characterized by a set of cardiovascular risk factors including obesity, Oxidative stress and vascular implications in metabolic syndrome. PDF Download Citation Citation.

Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies.

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There is some evidence that suggest a higher dietary total antioxidant capacity DTAC is associated with a lower risk of metabolic syndrome MetS.