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Oxidative stress pathways

Oxidative stress pathways

New insights into strdss tissue dysfunction in insulin resistance. Stress management techniques for healthy blood pressure Medica Iranica 44 3 — Oxidative Stress Psthways Pathway. Download PNG Download SVG Download JSON ;athways GPML Learn more about Downloads. The body Ketosis and Bone Health Oxidative stress pathways GSH to help convert more hydrogen peroxide so it needs to convert the GSSG back to GSH. Targeted drug delivery systems: nanotechnology allows for the creation of nanoparticles like liposomes and polymeric micelles that can be functionalized with ligands such as antibodies or peptides [ 95 ]. who reported an increase in the postprandial expression of both pro- and anti-oxidant genes in the MNC of individuals with metabolic syndrome in response to a week HF diet

Oxidative stress pathways -

Eating beef, chicken and fish should supply adequate sulphur containing amino acids. For vegetarians and vegans the following may provide some sulphur but in smaller amounts: garlic, onion, broccoli, Brussels sprouts, cauliflower, kale, watercress and mustard greens.

Some foods naturally contain glutathione however, it is poorly absorbed. Examples are spinach, avocados, and asparagus. Oxidative Stress PowerPoint Presentation Download Oxidative Stress Articles Nutrigenetics and Modulation of Oxidative Stress Da Costa et al , This website uses cookies so that we can provide you with the best user experience possible.

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This means that every time you visit this website you will need to enable or disable cookies again. Oxidative Stress by support dnalysis. DNA Health Oxidative Stress. Overview Pathway How It Works Articles Genes. Oxidative Stress Overview. Introduction Free radicals are highly reactive and dangerous molecules that damage DNA, proteins and cellular membranes.

Oxidative Stress Explained To understand oxidative stress better it is helpful to understand the chemistry of a free radical. Oxidative Stress The Pathway.

Reactive Species Effects. This leads to numerous effects such as: increased membrane rigidity decreased activity of membrane-bound enzymes e. sodium pumps altered activity of membrane receptors altered permeability In addition to effects on phospholipids, radicals can also directly attack membrane proteins.

Examples of reactive oxygen and nitrogen species. Oxidative Stress How It Works. Enzymatic Antioxidants. One way is that a SOD enzyme changes superoxide to hydrogen peroxide and oxygen which is less reactive but still potentially harmful.

Hydrogen peroxide is then neutralised by either GPx or CAT enzymes. Non-Enzymatic Antioxidants. Four prominent non-enzymatic antioxidants one should note are: Vitamin E is a fat-soluble antioxidant, and it reduces oxidative stress by protecting membranes from oxidative damage as it traps peroxy radicals in cellular membranes.

Vitamin C is a water-soluble antioxidant that can reduce radicals from a variety of sources and assists in recycling vitamin E radicals. Unfortunately, vitamin C can also be a pro-oxidant under certain circumstances. The carotenoids are fat- soluble antioxidants and may be important in the protection against lipid peroxidation.

Food sources of carotenoids are orange and red vegetables and fruits carrots, tomatoes, apricots, plums and green leafy vegetables spinach, kale. The glutathione molecule is often confused with two types of enzymes; glutathione peroxidase GPx and glutathione-s-transferase GST. GPx enzyme uses glutathione in the process where it converts harmful hydrogen peroxide to safe water and oxygen.

GST enzyme requires glutathione in the detoxification process where harmful intermediate compounds are converted to water soluble molecules that can be easily excreted. Exogenous Verses Endogenous Antioxidants.

Exogenous antioxidants: Vitamin C Vitamin E Carotenoids Polyphenols Zinc Selenium. Social media:. Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.

Disturbances in the normal redox state of tissues can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Some reactive oxidative species can even act as messengers through a phenomenon called redox signaling.

In humans, oxidative stress is involved in many diseases. For IRS-1 and -2, an increase in serine phosphorylation decreases the extent of tyrosine phosphorylation and is consistent with the attenuation of insulin action 52 , 53 Fig.

In L6 muscle cells, H 2 O 2 -mediated inhibition of insulin-stimulated glucose transport was accompanied by activation of p38 MAPK by H 2 O 2 40 , Insulin-stimulated glucose transport could be restored by LA and a specific inhibitor of p38 MAPK 40 , To determine whether the protective effects of LA could also be observed under more physiological conditions, we have used hyperglycemia to induce oxidative stress and blunt the effects of insulin.

and I. Activation of IKK-β, a serine kinase that regulates the NF-κB pathway, inhibits insulin action Salicylates lower blood glucose rev.

in 56 , augment glucose-induced insulin secretion in normal subjects, and restore insulin secretion in patients with type 2 diabetes 57 , In addition, salicylates inhibit IKK-β activity and restore insulin sensitivity, both in vitro and in vivo 56 , Treatment with aspirin or salicylates alters the phosphorylation patterns of IRS proteins, resulting in decreased serine phosphorylation, increased tyrosine phosphorylation, and improved insulin action 56 , Further support for the importance of IKK-β in insulin resistance is provided by results of recent gene knockout experiments in mice.

Although these latter data are preliminary and require confirmation in an expanded study, they are consistent with a role for activation of IKK-β in the pathogenesis of insulin resistance. Furthermore, they suggest that inhibition of IKK-β might be an attractive pharmacological approach to increasing insulin sensitivity.

Because insulin resistance is evident before the development of chronic fasting hyperglycemia 1 , 32 , it is unlikely that insulin resistance at the prediabetic stage results from oxidative stress triggered by hyperglycemia per se. However, the strong association of obesity and insulin resistance suggests that a mediator of oxidative stress-induced insulin resistance at the prediabetic stage might be an adipocyte-derived factor.

In this regard, several possible candidate molecules have been suggested including tumor necrosis factor-α 61 , leptin 62 , FFAs 5 , 6 , 63 , and, most recently, resistin However, the evidence is strongest that FFAs are the most likely link between obesity and insulin resistance 5 , 6 , Several mechanisms of how elevated FFA levels decrease insulin sensitivity have been proposed, including the Randle hypothesis 63 along with a more recent alternative concerning inhibition of insulin-stimulated glucose transport It also should be noted that FFAs and many of their metabolites interact directly with transcription factors to regulate gene expression, especially those involved in lipid and carbohydrate metabolism Malondialdehyde, a highly toxic by-product generated in part by lipid oxidation and ROS, is increased in diabetes In both normal individuals and in type 2 diabetic patients, restoration of redox balance by infusion of glutathione improves insulin sensitivity along with β-cell function Evidence in vitro indicates that elevated FFA levels have numerous adverse effects on mitochondrial function, including the uncoupling of oxidative phosphorylation 69 and the generation of ROS, including superoxide This latter situation is exacerbated because FFAs are not only capable of inducing oxidative stress, but also impair endogenous antioxidant defenses by reducing intracellular glutathione 36 , 71 , Numerous in vitro studies have reported FFA-mediated activation of NF-κB, a likely consequence of the ability of FFAs to increase ROS formation and reduce glutathione 72 — This effect might be also linked to FFA-mediated activation of PKC-θ 76 , which has the unique ability among PKC isoforms to activate NF-κB FFA-induced activation of NF-κB can be prevented by vitamin E 72 , suggesting that the alteration in cellular redox status is a contributory component of the proinflammatory effects of FFAs.

The association of obesity, fatty acids, and oxidative stress with insulin action clearly merits further attention, with a particular focus on identifying the molecular mechanisms. An additional target of oxidative stress is the β-cell. β-Cells are responsible for sensing and secreting the appropriate amount of insulin in response to a glucose stimulus Although this process is complex and dependent on many factors rev.

in 34 , the critical importance of mitochondrial glucose metabolism in linking stimulus to secretion is well established 78 — Therefore, the ability of oxidative stress H 2 O 2 to damage mitochondria and markedly blunt insulin secretion is not surprising Many studies have suggested that β-cell dysfunction is the result of prolonged exposure to high glucose, elevated FFA levels, or a combination of the two.

There is considerable evidence that chronic hyperglycemia in patients with type 2 diabetes contributes to impaired β-cell function 34 , However, in vitro evidence for a direct toxic effect of glucose has been conflicted because, in large part, of variations in the definition of toxicity along with subtle differences in experimental design For example, evidence of impaired secretion may simply reflect a normal decrease in β-cell insulin content caused by prior exposure to elevated glucose levels 34 , Moreover, recent data have suggested that the combined effects of elevations in glucose and FFA levels, acting by the generation of ROS, may be particularly toxic.

As discussed above, chronic exposure to these molecules can result in increased production of ROS and RNS, and activation of stress-sensitive pathways. β-Cells are sensitive to ROS and RNS because they are low in free-radical quenching antioxidant enzymes such as catalase, glutathione peroxidase, and superoxide dismutase Overexpression of the antioxidant enzymes in islets or transgenic mice prevents many of the deleterious effects noted above 84 , Oxygen stress generated by short exposure of β-cell preparations to H 2 O 2 increases production of p21 an inhibitor of cyclin-dependent kinase , decreases insulin mRNA, cytosolic ATP, and calcium flux in cytosol and mitochondria, and causes apoptosis rev.

in These results indicate that the mitochondrial processes involved in glucose-mediated insulin secretion are particularly affected by oxidative stress. Inhibition of insulin secretion and glucose oxidation also occurs when islets are exposed to lipid peroxidation products Conversely, antioxidants such as N -acetyl- l -cysteine NAC , aminoguanidine, zinc, and the spin-trapping agent α-phenyl-tert-butylnitrone, can protect against β-cell toxicity and the generation of glycation end products and inhibit the activation of NF-κB 87 — Recently, β-cell function was evaluated in islets after overexpression of glutamine:fructosephosphate amidotransferase, the rate-limiting enzyme of hexosamine biosynthesis Activation of the hexosamine pathway resulted in significant deterioration of glucose-stimulated insulin secretion along with other indexes of β-cell function, coincident with an increase in H 2 O 2 These effects were counteracted by treatment with the antioxidant NAC.

In patients with type 2 diabetes, reducing hyperglycemia with diet, insulin, or sulfonylureas results in improved insulin release rev. in 34 ; Conversely, in healthy individuals, high glucose infused as a clamp reduces insulin release In vitro, long-term culture of either HIT-T15 or βTC-6 cells with elevated glucose decreases insulin release, insulin mRNA, and binding of insulin mRNA transcription factors 94 , The antioxidants NAC and aminoguanidine markedly prevent glucotoxic effects on insulin gene activity These antioxidants have been shown to partially prevent glucose-induced decreases in insulin mRNA, DNA-binding of pancreatic duodenal homeobox-1, insulin content, and glucose-stimulated insulin secretion Increased sensitivity to low glucose after prolonged high FFA levels 96 — 98 and coculture of normal islets with high FFA levels and moderate glucose causes increased secretory response during a test stimulus 96 — Impaired insulin secretion has been associated with an FFA-induced increase in ROS Prolonged culture of β-cell preparations from animals with a predilection for type 2 diabetes, particularly those with impaired leptin production or leptin receptors, results in consistently demonstrable impaired secretion as well as other deleterious effects on β-cell function rev.

Therefore, genetic defects may amplify the toxic effects of FFAs that are not evident with normal insulin secreting cells. Because both glucose and FFA levels are elevated in type 2 diabetes, it is possible that their combination is required to maximize β-cell toxicity.

This hypothesis is supported by recent studies showing that when either isolated islets or HIT cells were exposed to chronic elevated glucose and FFA levels, there was a clear decrease in both insulin mRNA and the activation of an insulin-gene reporter construct In other studies, coculture of islets with high levels of glucose and palmitate resulted in almost complete impairment of glucose-stimulated insulin secretion, despite partially sustained stored insulin Recent studies have suggested that β-cell lipotoxicity is an amplifying effect only if mediated by concurrent hyperglycemia 7 , 8.

As discussed above, there is considerable evidence from in vitro and in vivo studies that in a variety of tissues, hyperglycemia and possibly elevated FFA levels both alone and in combination result in the generation of ROS and RNS and consequently increased oxidative stress.

Activation of these pathways results in the increased expression of numerous gene products that also cause cellular damage and play a major role in the etiology of the late complications of diabetes.

In addition, recent data in vitro and in vivo suggest that activation of the same or similar stress pathways results in insulin resistance and impaired insulin secretion. Accordingly, we propose the existence of a link among the hyperglycemia- and FFA-induced increases in ROS and oxidative stress, activation of stress-sensitive pathways, and the eventual development of not only the late complications of diabetes, but also insulin resistance and β-cell dysfunction.

Although our understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years 7 , 10 , 13 , , effective therapeutic strategies to prevent or delay the development of this damage remain limited.

We believe that research needs to be carried out on several fronts. First, antioxidant therapy needs to be improved. Either older antioxidants such as vitamin E, LA, and NAC need to be reformulated, or newer antioxidants need to be identified.

At this juncture, the general use of antioxidant mixtures may not prove useful and could even interfere with other therapies and, therefore, is not advised Moreover, screening tests to monitor oxidative stress need to be standardized and used in patients with diabetes.

Second, strategies to interrupt the stress pathways need to be studied more thoroughly. There has been some progress in this area.

The specific inhibitor of PKC-β, LY, is active in cell and animal models, and is now being used in clinical trials in humans. In addition, the recent finding that salicylates, which inhibit IKK, improve insulin action in both cells and animal models is a major advance.

A major challenge, however, is to obtain a more detailed understanding of the nature of the stress pathways, and to develop effective modulators that can be used clinically. Analysis of the effects of hyperglycemia and hypertriglyceridemia in muscle, fat, and pancreatic islets on the development of oxidative stress and activation of stress pathways is urgently needed.

Although small clinical studies with antioxidants such as vitamin E, LA, and NAC provide support for a role for oxidative stress in these conditions, several prospective clinical studies evaluating the effectiveness of vitamin E on cardiovascular outcomes have yielded disappointing results rev.

Nonetheless, the totality of available data provide support for conducting more extensive clinical studies evaluating the effectiveness of antioxidant treatment. Proposed general theory of how elevated glucose and possibly FFA levels contribute to the pathophysiology of diabetes via the generation of ROS and consequent activation of numerous stress-sensitive pathways.

The causative link among hyperglycemia, mitochondrial ROS generation, oxidative stress, and the development of diabetic complications has been previously suggested 10 , 11 , ROS and RNS , by inflicting macromolecular damage, may play a key direct role in the pathogenesis of diabetes.

Oxidative stress basically defines a condition in pathwayz prooxidant—antioxidant balance in Stress management techniques for healthy blood pressure cell is disturbed; cellular biomolecules undergo severe pahhways damage, ultimately compromising cells Oxdative. In recent years, Energy Boost Tips strfss of studies Energy Boost Tips Oxidatibe that oxidative stress Skinfold measurement for weight loss cause cellular Oxidatife via both the mitochondria-dependent and mitochondria-independent pathways. Since these Oxidative stress pathways are directly related to the survival stresw death of various cell types in normal as well as pathophysiological situations, a clear picture of these pathways for various active molecules in their biological functions would help designing novel therapeutic strategy. This review highlights the basic mechanisms of ROS production and their sites of formation; detail mechanism of both mitochondria-dependent and mitochondria-independent pathways of apoptosis as well as their regulation by ROS. Emphasis has been given on the redox-sensitive ASK1 signalosome and its downstream JNK pathway. This review also describes the involvement of oxidative stress under various environmental toxin- and drug-induced organ pathophysiology and diabetes-mediated apoptosis. We believe that this review would provide useful information about the most recent progress in understanding the mechanism of oxidative stress—mediated regulation of apoptotic pathways.


Dr. Marcus Cooke explains oxidative stress

Oxidative stress pathways -

The levels of thiobarbituric acid reactive substances TBARS are higher in smokers than in non-smokers with gastric cancer, and smokers have lower levels of SOD, CAT, GPX, GST, GSR and decreased vitamins A, E, and C Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol all dramatically rise in non-smokers while falling in smokers, whereas these reduced in smokers Plasma levels of malondialdehyde MDA were substantially higher and melatonin levels were substantially lower in smokers than non-smokers, which appears that melatonin can lessen the respiratory system damage caused by free radicals brought on by cigarette smoke Under oxidative stress, increased ROS in cells may harm tissues and trigger carcinogenesis, especially in the gastrointestinal system Figure 3.

ROS are initiating factor in gastric carcinogenesis in both humans and mice. Serum and tissue samples from the human gastrointestinal have dysregulated ROS levels In mice gastric cancer models induced by H. Proviral insertion in murine lymphomas 2 PIM2 is reported to act as an oncogene in gastric cancer, controlling apoptosis via ROS-triggered ER stress, and promoting the development of gastric cancer Moreover, it has been shown that stomach cancer is more likely to develop as a result of the oxidative stress brought on by CagA-positive bacteria 74 , in which H pylori CagA produces cells with oxidative DNA damage by inducing spermine oxidase SMO , and a portion of these cells are apoptosis-resistant and therefore highly susceptible to developing cancer Oxidative stress can cause DNA damage caused by H pylori infection.

In vitro investigations have demonstrated that cells infected with H pylori that have defective DNA repair systems experience increased oxidative stress and DNA damage In vivo studies using mice lacking a component of the base excision repair process revealed significant stomach lesions after H pylori infection NO can block 8-oxoguanine glycosylase from removing DNA mutations.

Research has revealed that H. pylori infection increases phosphohistone H2AX, a marker of repair for double-strand DNA breaks The loss of a base following damage would create an abasic site, which could result in a single-strand break in the DNA.

Inadequate repair or continuous damage may cause double-strand breaks in the DNA, though DNA strands can be produced in various ways If a cell does not heal enough fractures, it may die.

Figure 3 ROS and its pathophysiological effects in gastric carcinogenesis. At low to moderate concentrations, ROS function as signaling molecules that support cellular differentiation and proliferation and activate survival pathways in response to stress. Excessive ROS harms lipids, proteins, and DNA, causing mucosal injury and trigger carcinogenesis.

Reactive aldehydes include 4-hydroxynonenal and other aldehydes The mutator phenotype is shown by the self-directed arrow at mutation Tumor hypoxia is well recognized in oncology as a major cause of therapy resistance and poor prognosis. Hypoxia promotes the production of several gene products implicated in tumor development, invasion, and metastasis formation of gastric cancer.

Hypoxia causes the production of ROS, which inhibit the degradation of the hypoxia-inducible factor 1 HIF-1 Subsequently, HIF-1α influences the expression of numerous genes that are crucial for gastric carcinogenesis.

For instance, Angiogenesis is promoted by HIF-1 to stimulate the vascular endothelial growth factor VEGF pathway in gastric cancer Caveolin-1 Cav-1 is expressed less while induced by HIF-1, which regulates E-cadherin to cause the epithelial-mesenchymal transition EMT in gastric cancer On the other hand, as a signaling molecule, ROS activates vital signaling pathways that are crucial to promote the onset and progression of gastric cancer.

Additionally, ROS activates nuclear factor-B NF-κB , facilitating invasion of gastric cancer Furthermore, H. pylori -colonized mucosal cells with deficient DNA repair systems are more vulnerable to oxidative stress and DNA damage Spermine oxidase SMOX is activated in H.

pylori in gastric epithelial cells, leading to oxidative stress pylori colonization also negatively affects the expression of antioxidant proteins, along with epigenetic modifications and DNA methylation, such as GATA-4, GATA-5 and TWIST-1 88 , as well as miRNAs dysregulation, such as mir, mira, mira, mira, mir, mir and mir 73 , pylori , which ultimately reduces T-cell capacity for repair, increasing the likelihood of DNA carboxy-terminal genetic alterations.

The oxidative stress defensive factors such as FOXO1, are known to be inhibited by miRa, which is recognized as an oncogenic miRNA in gastric cancer miR is downregulated in H. pylori -infected gastritis 90 , and the low level of miR activates CD44 to promote the differentiation of gastric stem cell pylori increases the expression of miR by controlling its methylation, which in turn suppressed dimethyl adenosine transferase 1 DIMT1 and oncoprotein 18 or metablastic STMN1 , which promotes the proliferation of gastric epithelial cells Due to the methylation of the gene promoter region by ROS, H.

pylori infection may change the expression of miRNAs in oxidative stress, interfering with the methylation of miRNAs, which may contribute to the mechanism triggering the onset of gastric carcinogenesis. The process of developing gastric cancer involves several stages, beginning with the change from normal mucosa to chronic superficial gastritis non-atrophic gastritis.

Atrophic gastritis, intestinal metaplasia, dysplasia and adenocarcinoma, among other conditions can be caused by gastritis Gastritis caused by H. pylori is the only condition that always precedes diffuse gastric cancer. The especially high risk of cancer exists in people who have antibodies to the CagA protein, which is a marker for the more inflammatory and virulent strain of H.

pylori that carries a pathogenicity island of genes. According to a meta-analysis of research, CagA-positive strains are two times more likely than CagA-negative strains to cause noncardia gastric cancer pylori strains have a stronger connection to gastric carcinogenesis than strains without cag ROS or RNS production is substantially increased in vascular endothelium, gastric mucosa infected with H.

pylori, and neutrophils aggregated in inflammatory mucosa Following H. pylori infection, phagocytes that have gathered in the stomach mucosa produce O2·, HO·, and HOCl Rat gastric mucosal cells have been shown to undergo apoptosis when exposed to NH 2 Cl Epstein-Barr virus EBV is recognized as a pathogen that causes stomach cancer.

The production of NH 2 Cl by infiltrating neutrophils can convert latent EBV into lytic EBV in the H. pylori -infected gastric, which may further contribute to gastric carcinogenesis Although the function of the ROS generated by infected gastric epithelial cells is not fully known, it is thought that these ROS trigger signaling processes that control how H.

pylori pathogenesis develops. pylori infection directly causes oxidative stress in gastric epithelial cells by the production of ROS, and it also stimulates host responses that result in ROS and controls the production of proinflammatory cytokines, inflammation, and cell death Continuous ROS production results in oncogene and tumor suppressor gene changes, as well as chromosomal abnormalities by oxidative genome damage, which includes the oxidation of guanine to form 8-OhdG and 8-oxo,7,8-dihydroguanosine 8-OHG in RNA and DNA When compared to normal mucosa, gastric adenoma and H.

As a result of H. pylori infection, both the gastrointestinal lumen and gastric juice ascorbic acid content decrease. This antioxidant lessens the effects of carcinogens by lowering carcinogenic substances including nitrosamines and ROS.

Depleting cellular antioxidants makes ROS more effective at killing cancer cells because this is the traditional treatment strategy for doing so. Perhaps, the disease can be regulated by blocking different antioxidant systems during neoadjuvant treatments.

Gastric MALT lymphomas are a slow-growing type of non-Hodgkins lymphoma, developed from the extranodal marginal zone of lymphoid follicles Gastric MALT lymphoma is an illustration of the intimate pathogenetic relationship between chronic inflammation and tumor development.

pylori infection which makes H. pylori easier to develop and diffuse The H. pylori strains linked to gastric MALT lymphoma are less virulent than those linked to gastric adenocarcinoma. The latter strains may have the VacA m2 gene without the CagPAI, which could make H.

pylori carriers easier to develop diffuse large B-cell lymphoma pylori infection increased the incidence of low-grade gastric MALT lymphoma by an odds ratio of 2. pylori -negative individuals Within gastric MALT lymphomas, T lymphocytes activated by H. pylori are responsible for B-cell proliferation Most individuals with early-stage H.

pylori disease have been in durable remission for more than ten years after completing a single brief course of combination antibiotic therapy. Therefore, preventive removal of H. pylori is particularly helpful in reversing MALT lymphoma either in the early MALT stage or in the late bone marrow-involved stage.

However, the recurring possibility of MALT lymphoma should not be ignored because it frequently returns several years following surgery, which may due to risk factors for gastric cancer have not been totally blocked.

Gastric MALT lymphoma is regarded as one of the greatest models for understanding how genetic events contribute to oncogenesis, influence tumor biology, govern clinical behavior, and represent feasible treatment targets.

Genetic aberrations arise through the release of ROS, H. pylori -induced endonucleases, and other effects. Stronger oxidative stress is caused by H.

Surprisingly, the nucleotide-binding oligomerization domain protein 2 NOD2 functions as a receptor for pattern recognition. pylori activates NF-κB signaling via NOD2.

However, the NF-κB signaling is uncontrolled when the RW gene is mutated, protecting the organism against the harm caused by oxidative stress induced by H.

Thus, it is essential to consider how the gastric MALT lymphoma is influenced by the NOD2 gene Table 2. Table 2 A partial list of signaling pathways linked to oxidative stress in gastric cancer.

Enhancing antioxidant defense capability decreases ROS as a result of one strategy Table 3. However, utilizing antioxidants has been shown to change the effectiveness of treatment and, in some cases, even speed up the development of tumors.

According to a recent study, the garlic compound S-allyl cysteine has anti-inflammatory and antioxidant properties, which greatly raises the GSH levels in the liver, gastric tissue, and serum of rat models of gastric cancer, and lowers the risk of developing gastric cancer In experimental settings using AGS cells infected with H.

pylori strains, GSH levels are lower in individuals with gastric cancer than in those with duodenal ulcers, indicating a more severe oxidative stress response to gastric cancer with H. pylori infection pylori infection, and glutamine levels are also low. Additionally, the production of hydrogen peroxide is encouraged, aggravating the effects of oxidative stress.

However, GSH therapy is proved successful in alleviating the high ROS buildup In conclusion, intestinalization in the gastric host cells is caused by low GSH levels. Therefore, the risk of H. pylori -induced carcinogenesis of gastric mucosal may be ameliorated in rats by raising their GSH levels, which may also prevent oxidative stress damage Antioxidants, such as vitamin E and selenium, have been the subject of numerous research in this context.

In , the first large, randomized, double-blind, primary prevention trial to investigate the potential cancer prevention benefits of supplementing with vitamin E, selenium and β-carotene was conducted, and the cocktail has been found to dramatically lower mortality from gastric cancer Interestingly, the protective effects of these antioxidants can still be noticeable ten years after the end of supplementation It has been proposed that intake of diet rich in vitamin C, carotenoids, and alpha-lipoic acid α-LA may lessen the morbidity of gastric disease linked to H.

It is reported that omega-3 fatty acids inhibit the oxidation of polyunsaturated long-chain fatty acids and boost the antioxidant and anti-inflammatory effects of other nutrients However, omega-3 may result in oxidative stress, and the process is associated with the suppression of the production of antioxidant enzymes.

Therefore, antibiotics such clarithromycin, metronidazole, quinolones, amoxicillin, and tetracycline to counteract the oxidative effects of omega-3 is recommended In specifically, the Mn-SOD ratio levels in normal and malignant tissue is demonstrated as an independent predictive indicator in patients of gastric cancer, and it appears to be therapeutically relevant for the survival of patients, the higher the ratio, the poorer overall survival MnSOD is elevated in primary tumors with lymph node metastases while comparing gastric cancer patients with and without metastasis, indicating that MnSOD and ROS are involved in metastasis More importantly, it is necessary to block oxidative stress completely sometimes.

For instance, HsrA, the in vivo exclusive regulator for epsilon proteobacteria, is involved in altering redox homeostasis and protein expression. Consequently, it may serve as a potential therapeutic target to eradicate H.

pylori , The increased expression of apoptosis-regulated gene in the gastric host cells of patients with H. pylori infection, such as BID, ZMAT3, PMAIP1 and FAS, can also be successfully controlled by the combination of curcumin and Res, which causes apoptosis to decline , Gastric cancer is the third leading cause of cancer-related death worldwide.

Free radicals and oxidative stress are continuously imposed upon cells in tissues and organs on a regular basis. More and more evidences show that ROS functions an essential role in the gastric cancer. Despite a number of mechanisms have been discussed in this review, most of the ROS-induced signaling targets are yet unknown.

The elevated ROS production in gastric cancer can initiate genotoxic consequences, contributing to genetic instability, DNA damage, metabolic adaptation, drug resistance and occasional cell death.

However, certain amounts of ROS can be advantageous because they trigger the antioxidant defense system and shield cells. There is an urgent need to find selective and readily available therapeutic therapies for gastric cancer and gastric cancer-predisposed patients. In order to treat and prevent ROS in gastric cancer, it may be crucial to focus on the enhancement of ROS by neutralizing antioxidants to induce cancer cell death, and the inhibition of ROS activity or increase of antioxidant capacity to regulate pro-tumorigenic signaling pathways.

Nevertheless, considering that multiple studies have connected some dietary antioxidants with a rise in cancer incidence, it will be crucial to thoroughly investigate all biochemical reactions within cancer cells, including their precise targets and downstream effects while boosting antioxidant capacity.

More researches are needed to put on the agenda to explore the function of elevated ROS and identify the exact ROS target pathways that will be most beneficial in treating gastric cancer.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. Young Talent Project of Jiangsu Provincial Traditional Chinese Medicine Science and Technology Development Plan QN The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer YP declared a shared parent affiliation with the author YS to the handling editor at the time of the review. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Rawla P, Barsouk A. Epidemiology of gastric cancer: Global trends, risk factors and prevention.

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Conclusions: These findings may represent an adaptive oxidative response to mitigate increased stress induced by acute nutritional excess. Further, the results suggest an increased predisposition of obese subjects to oxidative stress.

Chronic nutritional excess resulting in increases in body weight and adiposity might lead to decompensation leading to worsening insulin resistance and its sequel. Insights from this study could impact on nutritional recommendations for obese subjects at high-risk of cardiovascular diseases.

Oxidative stress occurs early in the development of nutritional excess-induced insulin resistance in healthy men 5 , 6. Oxidation of excess nutrients increases mitochondrial formation of reactive oxygen species ROS and reactive nitrogen species RNS 7.

The resultant oxidative stress might induce deleterious changes in macromolecules such as DNA, proteins, and lipids. In addition, a number of stress-sensitive pathways including p38 mitogen-activated protein kinase p38 MAPK , c-Jun N-terminal kinase JNK , or inhibitor of NF-κB kinase IκKβ are activated 8.

These pathways, in turn, impede insulin signaling and glucose transport activity, leading to insulin resistance which is associated with metabolic syndrome, obesity, type 2 diabetes T2D and diabetic vascular complications 9.

Cumulative perturbations in the regulation of oxidative responses to meal intake, may contribute to the higher risk for atherogenesis and cardiovascular diseases among obese individuals It is well-known that acute or chronic consumption of a diet rich in i. A meal high in carbohydrate, not fat or protein, best elicited these differential responses.

Here, we investigated whether the same group of obese insulin resistant individuals demonstrates distinct oxidative stress responses to mixed meals enriched in either of three macronutrients, using both direct urinary F 2 -isoprostanes and indirect [expression of genes of oxidative stress pathways in circulating mononuclear cells MNC ] approaches.

Furthermore, we explored if such responses associated with obesity differ with that in lean healthy individuals. Changes in oxidative gene expression profiles in circulating MNC has been previously shown to correspond with that in the adipose tissue in patients with metabolic syndrome 12 , Written consent was obtained from each subject before participation in this study.

The methods have been published before 16 — The modified-WHO definition for obesity in Asians was used to define lean The experimental design has been described previously 16 — Briefly, the screening visit included measurements of height, weight and waist circumference, as well as determination of plasma glucose, serum insulin, electrolytes, non-esterified fatty acid NEFA concentrations, and lipid profile in fasting blood.

Isocaloric liquid mixed meals [high-carbohydrate HC , high-fat HF , or high-protein HP ] were administered to eligible participants in random order with 7 days interval in-between. HC, HF, and HP meals were composed of Ensure Plus ® manufactured by Abbott Nutrition and Beneprotein ® manufactured by Nestlé Nutrition were used for preparation of test meals.

Baseline and postmeal venous blood samples were collected at 30 min intervals up to min for the measurement of glucose, insulin, triglyceride and NEFA concentrations. Fasting and postprandial min midstream urine samples were also collected for the measurement of urinary F 2 -isoprostanes, a biomarker of oxidative stress -induced lipid peroxidation 22 , 23 to assess systemic oxidative stress.

Measurements of plasma glucose and triglyceride concentrations AU, Beckman Coulter Inc. Measurement of plasma NEFA Cobas ® , Roche Diagnostics, Indianapolis, USA was performed at Mayo Medical Laboratories Rochester, MN, USA.

Urinary free F 2 -isoprostanes were measured using a method described previously 23 , Briefly, urine samples were processed by anionic solid-phase extraction. Creatinine levels were measured to standardize the dilution of urine Cobas c Photometric Analyzer Roche Diagnostic GmbH, Mannheim, Germany.

Quantitation was achieved by comparing the peak area of free F 2 -isoprostanes with that of the relevant deuterated internal standard. Blood samples collected at 0, , and min, were layered over Ficoll-paque Plus GE Healthcare, Buckinghamshire, UK and centrifuged.

Following red blood cell lysis Sigma-Aldrich, St. Louis, MO, USA , total RNA from MNC was isolated using RNeasy Mini Kit QIAGEN, Netherlands. For reverse transcription of total RNA, high capacity cDNA Reverse-Transcription Kit Applied Biosystems, Waltham, MA, USA was used.

ViiA 7 Real-Time PCR System Applied Biosystems was used to perform gene expression assay. The PCR mix included 2 μL 10 ng cDNA, 5 μL QuantiFast SYBR Green PCR Master mix QIAGEN, Netherlands , and 0.

Primers were designed using Primer Express software v3. All values were normalized to the expression of a housekeeping gene GAPDH , which did not differ among the different phenotypes, time points and types of test meal. The panel of genes studied included, Nuclear factor, erythroid 2-like 2 NRF2 , Glutathione peroxidase GPX3 , Thioredoxin TXN , Thioredoxin reductase 1 TXNRD1 , Superoxide dismutase SOD- 1 and -2 , Human neutrophil cytochrome —A light chain and —B light chain CYBA and CYBB , Neutrophil cytosolic factor NCF-1,-2, and -4 , and Spi-1 PU.

Three sets of samples 2 lean subjects, 1 obese subject were excluded from analysis due to poor quality of RNA. The primary outcome of the original study which was designed to assess postprandial inflammatory responses, was fold changes in expression of inflammatory genes regulated by NF-κB in MNC, from baseline as an indicator of NF-κB activity.

Statistical analyses were performed using SPSS version A linear mixed model was employed to analyse MNC gene expression between groups and meals.

Fold-change from baseline in gene expression MNC was entered as the dependent variable, while time and meal were entered as repeated factors. Change in the trajectories of gene expression was further tested for interaction. Linear model with fixed effects for meal and individual was used to test whether postprandial changes in urinary F 2 -IsoP was significant in obese and lean group.

An independent sample t -test was used to test the differences in fold-changes in MNC gene expression at a single time point between groups. Postprandial changes in plasma glucose and insulin concentrations over 6 h were calculated as the incremental area under the curve iAUC. Fold changes in expression of genes were tested for a significant correlation with glucose and insulin iAUC.

Obese subjects had higher age obese: lean: lean: 0. lean: 4. lean: 1. Fasting blood glucose, total and LDL cholesterol and NEFA were not statistically different between groups 16 — Overall, the postprandial insulin and triglycerides levels increased to a higher level in the obese than lean subjects while postprandial glucose responses were similar between the two groups.

These data have been reported previously in detail 16 — NADPH-oxidases constitute an enzyme complex at cell membrane that produces superoxide, a substrate for subsequent reactions to generate ROS.

Mean postprandial fold changes for gene expression of NADPH-oxidase subunits CYBA and CYBB; NCF-1,-2, and -4 were not significant between groups, meals or single time points Table 1 , Supplementary Data Sheet 2. Table 1.

Fold changes in MNC gene expression in lean and obese subjects 2 and 6 h after consuming 3 isocaloric liquid mixed meals. Figure 1. Values are mean ± SEM. TXN is a small redox protein and TXNRD1 is the enzyme that reduces TXN from the oxidized to the reduced, active form for neutralization of ROS.

Mean postprandial fold changes for expression of the aforementioned genes were not significant between groups, meals or single time points Table 1 , Figures 1D,E , Supplementary Data Sheet 2. This may represent an adaptive response to counter the upregulation of NADPH-oxidases in the obese individuals, and thus achieve redox homeostasis.

Mean postprandial fold changes for expression of the aforementioned genes were not significant between groups, meals or single time points. Mean postprnadial fold changes for expression in NRF2 was not significant between groups, meals or single time points Table 1 , Supplementary Data Sheet 2.

The NRF2 transcription factor is an antioxidant response regulatory transcription factor, and an increase in its expression in nucleus indicates oxidative damage at the cellular level.

In the cytosol, it is bound to Keap1 and remains in an inactivated state. Upon cellular encounter with stress, the Keap1-NRF2 complex undergoes disruption and NRF2 is transferred to the nucleus.

Urinary creatinine Cr levels, measured to standardize the dilution of urine, did not differ between the different dietary interventions.

F 2 -IsoPs are prostaglandin PG F 2 -like compounds. These are produced as a result of free radical catalyzed peroxidation of arachidonic acid and are currently considered the gold standard among markers of systemic oxidative damage.

Figure 2. Values are mean ± SEM and analyzed by using two-tailed t -tests between lean vs. We analyzed the relationship between postprandial fold changes in MNC gene expression at and min vs. iAUC of serum insulin and plasma glucose Table S2. Insulin iAUC correlated with increased fold changes in expression of CYBB r : 0.

Glucose iAUC correlated with increased fold changes in expression of NCF1 r : 0. In this study, we compared expression of genes of oxidative stress pathways in MNC following intake of HC, HF, and HP meals in a metabolically distinct cohort of lean insulin-sensitive and obese insulin-resistant individuals with hypertriglyceridemia.

We found that the individual's underlying metabolic phenotype has a differential impact on oxidative gene expression in circulating MNCs. This was evident based on differences in the direction and magnitude of changes seen in the postprandial oxidative gene expression profiles in MNC as well as systemic oxidative stress marker F 2 -IsoP in urine, over the postprandial period between the two groups.

The overall trend toward higher expression of the pro-oxidant genes involved in the oxidative pathway in both obese and lean groups may indirectly reflect a physiological increase in ROS generation in the postprandial state. However, we found that the expression of anti-oxidant group of genes were also elevated suggesting an adaptive response to mitigate the higher postprandial oxidative stress among the study participants.

Our findings are in concordance with that by Camargo et al. who reported an increase in the postprandial expression of both pro- and anti-oxidant genes in the MNC of individuals with metabolic syndrome in response to a week HF diet Likewise, in another study, Patel et al.

showed that a single HF-HC meal challenge induced oxidative and inflammatory stress responses greater both in magnitude and duration, as evident by increases in the expression of NCF-1 a major ROS-generating enzyme , intracellular NF-κB binding activity and plasma concentrations of MMP-9, in the MNCs in obese compared to lean individuals Of note, in the current study, there were consistent trends toward greater duration and magnitude of oxidative responses in obese individuals with hypertriglyceridemia following HC and HP meals compared to HF meal, suggesting an increased predisposition of these subjects to oxidative stress.

In the current study, expressions of CYBB and CYBA catalytic parts of NADPH oxidase genes increased over 6-h following meal consumption in obese compared to lean patients, while changes in expression of NCF-4 cytosolic activator of NADPH oxidase gene were the contrary.

The opposite direction of postprandial changes in NCF-4 expression following intake of HC and HF vs. HP meal, led to a significant group x meal interaction.

The trend toward lower NCF-4 expression in obese group may be explained as a protective negative feedback phenomenon exerted by existing exaggerated oxidative stress associated with obesity.

It is known that enhanced production of reactive oxygen or nitrogen species due to augmented NADPH oxidase activity and ER stress in adipose tissue characterizes obesity 26 , Further, antioxidant defenses are lower in obese compared to that in lean individuals 28 , NRF2 is a nuclear transcription factor and its activation can be characterized by protein expression assay, i.

Since fresh MNC were not available at the time of this oxidative stress response study for protein isolation, the protein expression levels of NRF2 could not be assessed.

An upregulation in its expression at gene level could not be observed alongside the increases in expression of several anti-oxidant genes in the current study, as would have been expected.

However, the transcription level data can only suggest whether the protein is present and approximately its expected level and needs to be validated by western blot assay. F 2 -isoprostanes, are accurate indicators of systemic oxidative stress in vivo 23 , and showed trends similar to those observed for MNC gene expression.

These results may suggest an increased predisposition of obese subjects with hypertriglyceridemia to oxidative stress. Camargo et al. found positive correlations between plasma levels of oxidative stress markers such as protein carbonyl, H 2 O 2 , etc.

and expression of genes of oxidative pathway in obese-derived MNC, 2-h after meal intake Although the marker of systemic oxidative stress assessed in the current study is different from those in the aforementioned study, the postprandial changes we observed in the obese, are similar to theirs.

Interestingly, significant postprandial increases in urinary F 2 -IsoP level could be observed in lean individuals following HF meal and the changes were near-significantly higher than that following HC meal.

It is well known that MUFA rich diet exerts an anti-inflammatory, antioxidant effect 30 — The total caloric content as well as SFA proportion was much higher in previous studies as compared to that in our study 11 , 32 , We observed positive correlations between the postprandial serum insulin response with expression of pro- and antioxidant genes in the obese insulin resistant individuals with hypertriglyceridemia.

The obese subjects had significant postprandial hyperinsulinemia compared to the lean group despite similar glycemic response, indicative that they require more insulin to maintain the same glucose tolerance owing to peripheral tissue insulin resistance.

Our findings are in agreement with that of Patel et al who demonstrated significantly higher insulin levels, alongside higher expression of oxidative stress markers in the MNCs of obese individuals in the postprandial state These results support the emerging notion that oxidative stress is among the key events leading to insulin resistance, which is pivotal in the pathogenesis and progression of T2D 9 , 35 , An increase in the mitochondrial ROS generation from a nutrient-rich environment induces cellular stress pathways resulting in insulin resistance by interrupting insulin receptor signal transduction.

We propose that it represents a check-and-balance response in the obese individuals such that the expression of anti-oxidant genes increased in tandem to the pro-oxidant genes regardless of the macronutrient content.

Strengths of our study include the fact that we compared two distinct metabolic phenotypes, i. In addition, we compared three test meals of different macronutrient composition in the same group of subjects. The caloric contents of these test meals were well representative of normal dietary intake.

By contrast, previous studies examined only a single phenotype in isolation either metabolic syndrome or non-obese individuals , following intake of one type of meal mostly HF, not representative of normal dietary intake 5 , 6 , 12 — To our understanding, postprandial changes in expression of oxidative stress pathway genes have not been assessed previously, following intake of different types of isocaloric mixed- meals enriched in either of all three major macronutrients carbohydrate, fat, or protein , in a cohort both obese insulin-resistant and lean insulin-sensitive individuals.

However, these findings, researched using a gene expression approach, could be further validated with protein expression studies. We acknowledge postprandial changes in gene expression in MNC are indeed among indirect measures of oxidative stress, while that in urinary isoprostane level are among direct measures.

Perhaps this may be why we have seen significant changes in expression of some, but not all genes. The direction and magnitude of changes in the measured parameters trended to be different between the two groups, despite being otherwise healthy and normoglycemic.

To conclude, acute nutritional intake may lead to oxidative stress followed by an adaptive, compensatory response in order to mitigate postprandial stress. However, chronic nutritional excess resulting in weight gain and increased adiposity may lead to decompensation and in turn, worsen insulin resistance and its sequelae.

Our findings support an increased predisposition of obese subjects with hypertriglyceridemia to oxidative stress, particularly in response to a meal rich in carbohydrate or protein. All subjects gave written informed consent in accordance with the Declaration of Helsinki.

The protocol was approved by Singapore's National Healthcare Group Domain Specific Review Board. SB contributed to planning and execution of wet laboratory experiments, acquisition, analyses and interpretation of data from these experiments, prepared the first draft of the manuscript and secured funding.

EP contributed to planning and execution of physiology experiments, acquisition, analyses and interpretation of data from these experiments, edited the manuscript and secured funding. CC, MS, and NA performed MNC isolation, the gene expression assay and edited the manuscript. TL, AV-P, FM, and RS contributed to study design, grant proposal and critically revised the manuscript.

CK and S-AT contributed to study conception and design, data interpretation and critical revision of the manuscript. AV-P is funded by British Heart Foundation.

Oxidative stress occurs as Lean protein sources result of Stress management techniques for healthy blood pressure imbalance in reactive oxygen species ROS and antioxidant defences within the cells. Therefore, it Oxdiative vital to understand the sterss biology Oxidative stress pathways oxidative stress pthways order to effectively pwthways the many Lathways that it is related to. In this chapter, computational approaches applied for understanding oxidative stress in bacteria and eukaryotes will be detailed together with the relevant biological advances. These approaches include construction of protein—protein interaction networks, logical and flux balance modelling techniques, machine learning applications and, lastly, high-throughput genomic methods such as next-generation sequencing, which generates data to be used in the aforementioned techniques. Finally, several case studies will be presented and discussed in the context of oxidative stress. This is a preview of subscription content, log in via an institution.

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