Role of L-Arginine in Ibuprofen-induced Oxidative Stress and Neutrophil Infiltration in Gastric Mucosa

It has been proposed that neutrophil and oxygen dependent microvascular injuries may be important prime events in gastrointestinal (GI) toxicity of nonsteroidal antiinflammatory drugs (NSAIDs). l-arginine (l-ARG) is an essential amino acid which participates in many important biochemical reactions associated to the normal physiology of the organism. In these experimentations, we studied the role of l-ARG, aminoacid precursor of NO synthesis, on ibuprofen (IB) induced gastric lesions, and also on the inflammatory and oxidative mechanisms related to mucosal damage. Oral administration of IB (100 mg kg^-1), produced severe damage on gastric mucosa, which was more important after 6 h test-period, and was accompanied by a significant increment in myeloperoxidase (MPO) activity, as index of neutrophil activation, as well as lipid peroxidation (LP) levels and xanthine oxidase (XO) activity. However, no changes were observed in total mucosal glutathione (tGSH), nor glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. Simultaneous treatment with equimolar doses of l-ARG (oral and i.p.), considerably reduced the number and intensity of lesions, and at the same time (6 h) the maximum protection was also observed. In addition, l-ARG inhibited the IB-induced LP and XO enhancement, but did not produce changes in leukocyte infiltration, tGSH, GSH-Px and SOD activity. These findings suggest that (1) l-ARG protective effect on gastric mucosa against IB-induced mucosal lesions could be explained by a local effect and also might be due to the systemic action of the aminoacid; (2) the active oxygen species, derived both from XO and activated neutrophils, could play a role in the pathogenesis of gastric injury induced by IB, (3) l-ARG exhibit a protective effect against IB-induced mucosal damage, probably through the inhibition of oxidative stress derived via xanthine-XO, but it does not block the oxygen free radical production through polymorphe nuclear leukocytes.     

Role of antioxidants in protecting cellular DNA from damage by oxidative stress

We have previously derived 2 V79 clones resistant to menadione (Md1 cells) and cadmium (Cd1 cells), respectively. They both were shown to be cross-resistant to hydrogen peroxide. There was a modification in the antioxidant repertoire in these cells as compared to the parental cells. Md1 presented an increase in catalase and glutathione peroxidase activities whereas Cd1 cells exhibited an increase in metallothionein and glutathione contents. The susceptibility of the DNA of these cells to the damaging effect of H₂O₂ was tested using the DNA precipitation assay. Both Md1 and Cd1 DNAs were more resistant to the peroxide action. In the case of Md1 cells it seems clear that the extra resistance is provided by the increase in the two H₂O₂ scavenger enzymes, catalase and glutathione peroxidase. In the case of Cd1 cells the activities of these enzymes as well as of superoxide dismutases (Cu/Zn and Mn) are unaltered as compared to the parental cells. The facts that parental cells exposed to 100 μM Zn²⁺ in the medium exhibit an increase in metallothionein but not in glutathione and that these cells become more resistant to the DNA-damaging effect of H₂O₂ suggest that this protein might play a protective role in vivo against the OH radical attack on DNA.     

Therapeutic potential of flurbiprofen against obesity in mice

Obesity is associated with several diseases including diabetes, nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease, and cancer. Therefore, anti-obesity drugs have the potential to prevent these diseases. In the present study, we demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited therapeutic potency against obesity. Mice were fed a high-fat diet (HFD) for 6 months, followed by a normal-chow diet (NCD). The flurbiprofen treatment simultaneously administered. Although body weight was significantly decreased in flurbiprofen-treated mice, growth was not affected. Flurbiprofen also reduced the HFD-induced accumulation of visceral fat. Leptin resistance, which is characterized by insensitivity to the anti-obesity hormone leptin, is known to be involved in the development of obesity. We found that one of the possible mechanisms underlying the anti-obesity effects of flurbiprofen may have been mediated through the attenuation of leptin resistance, because the high circulating levels of leptin in HFD-fed mice were decreased in flurbiprofen-treated mice. Therefore, flurbiprofen may exhibit therapeutic potential against obesity by reducing leptin resistance.     

Role of oxidative stress in epileptic seizures

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetic rat models, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.     

Human polynucleotide phosphorylase reduces oxidative RNA damage and protects HeLa cell against oxidative stress

We examined HeLa cell viability and RNA oxidative damage in response to hydrogen peroxide (H₂O₂) treatment. The level of damaged RNA, measured by the content of 8-hydroxyguanosine (7,8-dihydro-8-oxoguanosine, 8-oxoG), increases depending on H₂O₂ dosage and is inversely correlated with cell viability. The elevated level of 8-oxoG in RNA decreases after removal of oxidative challenge, suggesting the existence of surveillance mechanism(s) for cleaning up oxidized RNA. Human polynucleotide phosphorylase (hPNPase), an exoribonuclease primarily located in mitochondria, has been previously shown to bind 8-oxoG-RNA with high affinity. The role of hPNPase in HeLa cell under oxidative stress conditions is examined here. Overexpression of hPNPase reduces RNA oxidation and increases cell viability against H₂O₂ insult. Conversely, hPNPase knockdown decreases viability and increases 8-oxoG level in HeLa cell exposed to H₂O₂. Our results suggest that hPNPase plays an important role in protecting cells and limiting damaged RNA under oxidative stress.     

Role of NF-κB transcriptional factor activation during chronic fluoride intoxication in development of oxidative-nitrosative stress in rat’s gastric mucosa

Fluoride compounds are known as hazardous environmental pollutants that can enter the body with drinking water. Chronic exposure to fluoride leads to development of oxidative stress and can lead to activation of nuclear factor κB (NF-κB). The aim of this work is to clarify the role of NF-kB activation in production of reactive nitrogen and oxygen species, activity of antioxidant enzymes and intensity of lipid peroxidation (LPO) in gastric mucosa of rats during chronic fluoride intoxication.Materials and methodsWe carried out the study on 18 mature male rats of the Wistar line. The animals were divided into 3 groups: control animals (6), group of chronic fluoride intoxication (6), and animals (6), which received the NF-κB inhibitor, namely ammonium pyrrolidine dithiocarbamate (PDTC) in a dose of 76 mg / kg (iNF-κB group) during modeling of chronic fluoride intoxication. To assess the development of oxidative stress we studied superoxide production (O₂^-), activity of superoxide dismutase (SOD), catalase (CAT) and concentration of free malondialdehyde (MDA). We also assessed NO production and concentration of its metabolites (peroxynitrite, nitrosilated thiol groups, nitrites).ResultsChronic fluoride intoxication leads to NO hyperproduction with subsequent increase in concentration of its later metabolites (peroxynitrite, nitrosilated thiol groups, nitrites). Production of O₂^- increases, SOD activity decreases, CAT activity increases and MDA concentration also increases. Inhibition of NF-kB activation by PDTC normalizes the parameters studied.ConclusionsActivation of NF-κB during chronic fluoride intoxication leads to the development of hyperproduction of NO and development of oxidative-nitrosative stress.     

Role of oxidative stress in experimental sepsis and multisystem organ dysfunction

Massive increase in radical species can lead to oxidative stress, promoting cell injury and death. This review focuses on experimental evidence of oxidative stress in critical illnesses, sepsis and multisystem organ dysfunction. Oxidative stress could negatively affect organ injury and thus overall survival of experimental models. Based on this experimental evidence, we could improve the rationale of supplementation of antioxidants alone or in combination with standard therapies aimed to reduce oxidative stress as novel adjunct treatment in critical care.     

炎症和氧化应激对内皮祖细胞动员及其功能的影响

内皮祖细胞对于维持血管内皮完整性和血管稳态具有重要作用.增强EPC的数量和功能可使心血管疾病患者获益.炎症、氧化应激对内皮祖细胞动员及其功能发挥具有重要影响,本文着重综述炎症和氧化应激对内皮祖细胞动员的调控,并探讨增进内皮祖细胞数量和功能的相关治疗策略.     

Investigation of inflammation,oxidative stress,and DNA damage in COVID-19 patients

COVID-19 disease, which spreads worldwide, is a disease characterized by widespread inflammation and affects many organs, especially the lungs. The resulting inflammation can lead to reactive oxygen radicals, leading to oxidative DNA damage. The pneumonia severity of 95 hospitalized patients with positive RT-PCR test was determined and divided into three groups: mild, moderate, and severe/critical. Inflammation markers (neutrophil–lymphocyte ratio, serum reactive protein, procalcitonin, etc.) were determined, and IL-10 and IFN-γ measurements were analyzed using the enzyme-linked immunosorbent assay method. In evaluating oxidative damage, total thiol, native thiol, disulfide, and ischemia-modified albumin (IMA) levels were determined by measuring spectrophotometrically. The comet assay method’s percentage of tail DNA obtained was used to determine oxidative DNA damage. As a result, when the mild and severe/critical groups were compared, we found that total thiol, native thiol, and disulfide levels decreased significantly in the severe/critical group due to the increase in inflammation markers and cytokine levels (p < 0.05). We could not detect any significance in IMA levels between the groups (p > 0.05). At the same time, we determined an increase in the tail DNA percent level, that is, DNA damage, due to the increased oxidative effect. As a result, we determined that inflammation and oxidative stress increased in patients with severe pneumonia, and there was DNA damage in these patients.     

Gut regulatory peptides bombesin and neurotensin reduce hepatic oxidative stress and histological alterations in bile duct ligated rats

Gut regulatory peptides bombesin (BBS) and neurotensin (NT) exert a wide spectrum of biological actions on gastrointestinal tissues and we have previously shown that they improve intestinal barrier function and oxidative stress in experimentally jaundiced rats. In the present study, we explored their potential action on liver histology and oxidative status in bile duct ligated rats. Seventy male Wistar rats were randomly divided into five groups: controls, sham operated, bile duct ligated (BDL), BDL+BBS (10 μg/kg, s.c. ×3), BDL+NT (300 μg/kg, i.p.). At the end of the experiment, on day 10, serum total bilirubin and alanine aminotransferase (ALT) levels were determined and endotoxin was measured in portal and aortic blood. Liver tissue samples were examined histologically for evaluation of the ratio of portal tracts presenting changes of obstructive cholangiopathy and neutrophils' number in portal tracts. In addition, hepatic oxidative status was estimated on liver homogenates by measurements of lipid peroxidation (malondialdehyde), protein oxidation (protein carbonyl groups) and thiol redox state [reduced glutathione (GSH), oxidized glutathione (GSSG), total non-protein mixed disulfides (NPSSR) and protein thiols (PSH)]. Administration of BBS or NT significantly reduced portal and aortic endotoxaemia observed in obstructive jaundice. Both agents significantly ameliorated liver injury, as demonstrated by improvement of obstructive cholangiopathy and reduction of ALT. This effect was accompanied by prevention of lipid peroxidation, protein oxidation and decrease of the oxidized forms GSSG and NPSSR. Moreover, neutrophil accumulation in portal tracts was significantly decreased. In conclusion, this study shows that gut regulatory peptides BBS and NT reduce cholestatic liver injury, exerting protective effects on portal tract architecture, neutrophil infiltration and hepatic oxidative stress in bile duct ligated rats.     

Mechanisms involved in the development of diabetic retinopathy induced by oxidative stress

Background: Diabetic retinopathy (DR) is one of the main complications in patients with diabetes and has been the leading cause of visual loss since 1990. Oxidative stress is a biological process resulting from excessive production of reactive oxygen species (ROS). This process contributes to the development of many diseases and disease complications. ROS interact with various cellular components to induce cell injury. Fortunately, there is an antioxidan t system that protects organisms against ROS. Indeed, when ROS exceed antioxidant capacity, the resulting cell injury can cause diverse physiological and pathological changes that could lead to a disease like DR.

Objective: This paper reviews the possible mechanisms of common and novel biomarkers involved in the development of DR and explores how these biomarkers could be used to monitor the damage induced by oxidative stress in DR, which is a significant complication in people with diabetes.

Conclusion: The poor control of glucemy in pacients with DB has been shown contribute to the development of complications in eyes as DR.     

Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response

Nonsteroidal anti-inflammatory drugs (NSAID) are well known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and animals too. These effects are related with the inhibition of the enzyme cyclooxygenase, which is the main established mechanism of action for these drugs. Fasted rats were given piroxicam, preferential COX-1 inhibitor (10-20 mg/kg) or meloxicam, preferential COX-2 inhibitor (7.5-15 mg/kg) orally. Six or nine hours (h) later, respectively, the stomach was excised, the severity of the damage assessed and myeloperoxidase (MPO) activity measured, as well as prostaglandin PGE(2) content. Furthermore, in order to assess the effects of these oxicams over previously damaged gastric mucosa, 1 ml of 0.6 N HCl was administered p.o. followed, 1 h after, of the correspondent dose of each NSAID, and the same parameters were determined. Oral administration of both drugs dose-dependently caused acute gastric haemorrhage erosions. Myeloperoxidase activity was significantly increased by piroxicam administration. In addition, PGE(2) content was significantly reduced. The association between the administration of the acid and NSAID caused a worsening of the damage and, while myeloperoxidase activity did not modify by both piroxicam and meloxicam, PGE(2) levels were reduced. These results suggest that the PG derived from both COX-1 and COX-2 pathway plays a beneficial role in the gastroprotection, and thus caution should be exercise in the clinical use of preferential COX-2 inhibitors.     

Role of fructose in the adaptation of plants to cold-induced oxidative stress

This work presents findings, which indicate important role of fructose, fructose 6-phosphate (F6P), and fructose 1,6-bisphosphate (FBP) in preservation of homeostasis in plants under low temperature. Cold combined with light is known to incite increased generation of superoxide in chloroplasts leading to photoinhibition, but also an increased level of soluble sugars. In the present study, oxidative stress in pea leaves provoked by cold/light regime was asserted by the observed decrease of the level of oxidized form of PSI pigment P700 (P700(+)). Alongside, the increased antioxidative status and the accumulation of fructose were observed. The antioxidative properties of fructose and its phosphorylated forms were evaluated to appraise their potential protective role in plants exposed to chilling stress. Fructose, and particularly F6P and FBP exhibited high capacities for scavenging superoxide and showed to be involved in antioxidative protection in pea leaves. These results combined with previously established links implicate that the increase in level of fructose sugars through various pathways intercalated into physiological mechanisms of homeostasis represents important non-enzymatic antioxidative defense in plants under cold-related stress.     

The effects of dietary restriction on oxidative stress in rodents

Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends life span in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules. The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. Here we present a comprehensive review of the existing literature on the effect of DR on mitochondrial ROS generation, antioxidant enzymes, and oxidative damage. In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.     

Effects of microcystins over short- and long-term memory and oxidative stress generation in hippocampus of rats

Microcystins produced by cyanobacteria are potent inhibitors of some protein phosphatases, but recent evidence also indicates its potential to generate oxidative stress. In the present study, the effects of microcystin raw extracts (Mic; 0.01 and 20microg/L) and purified okadaic acid (OA; 0.01 and 10microg/L) on short- and long-term memory alteration and antioxidant and oxidative damage were investigated in hippocampus of rats. The results showed an amnesic effect with 0.01 and 20microg/L Mic on retrieval and only with 0.01microg/L Mic on spatial learning. Parallel to these effects oxidative damage was observed as evidenced by augmented levels of lipid peroxides and DNA damage and the absence of antioxidant responses in terms of total oxyradical scavenging capacity. Phase II reactions catalyzed by glutathione-S-transferase were not modified after microcystins exposure. Overall this study showed physiological events (retrieval and spatial learning) that can be related to the classical toxic effects of microcystins (i.e., phosphatase inhibition). In addition, evidence of alternative toxicity mechanisms via oxidative stress generation was also obtained. The fact that organic anion transporter polypeptides (OATP) involved in microcystins uptake are expressed not only in liver but also in brain points to the environmental relevance of the observed effects.     

Sex differences in oxidative stress after eccentric and concentric exercise

Objectives: Comparison of redox balance changes in the blood of women and men as a result of submaximal eccentric (ECC) and concentric (CONC) efforts.

Methods: 10 women and 10 men performed three 45-minute submaximal treadmill runs at constant velocities (downhill run – ECC, uphill run – CONC and level run). Prior to the 45-minute exercises, after their completion and following 24 hours of recovery, the concentration of lactate, oxidized low-density lipoprotein (ox-LDL), 3-nitrotyrosine, uric acid (UA) and the white blood cell count (WBC), neutrophil (NEUT), lymphocyte (LYMPH) and monocyte content in the blood were determined.

Results: In women, the ox-LDL increased significantly 10 minutes and 24 hours following ECC (P?P?P?P?Discussion: ECC cause impaired redox balance only in women. Due to the increase in antioxidant capacity of the blood without accompanying oxidative damage to macromolecules, for both sexes, it is recommended to perform concentric running efforts at the highest possible subliminal intensity.     

Cellular and biochemical parameters of exercise-induced oxidative stress: relationship with training levels

To better clarify the relationship between physical activity and oxidative stress, we determined the effects of a maximal test in 18 young subjects with different training levels (six professional Athletes and 12 non-agonists (NA)). Redox homeostasis (total antioxidant activity (TAS), vitamin C and glutathione (GSH)), oxidative damage (diene conjugation and hemolysis), lymphocyte cell death and repair systems (apoptosis, micronuclei and Hsp70 expression) were evaluated. We found that agonistic training led to a chronic oxidative insult (high baseline values of oxidized glutathione (GSSG), micronuclei and hemolysis). On the contrary, NA with the lowest level of training frequency showed a well balanced profile at rest, but they were more susceptible to exercise-induced variations (GSSG/GSH and diene increased values), respect to the NA with an higher level of training. As almost all the parameters employed in this study showed inter-individual variations, the GSSG/GSH ratio remains the most sensitive and reliable marker of oxidative stress, accordingly with other data just reported in the literature.     

Roots and leaves display contrasting oxidative response during salt stress and recovery in cowpea

In this study, we compare some antioxidative responses of leaves and roots associated to growth reduction in cowpea plants (Vigna unguiculata) during short-term salt stress and recovery. The salt treatment was imposed (200 mM NaCl) for six consecutive days and the salt withdrawal after 3 d. The salt treatment caused an almost complete cessation in the relative growth rate of both leaves and roots. Although NaCl withdrawal has induced an intense reduction in the Na(+) content from the leaves and roots, the growth recovery was slight, after 3 d. The leaf lipid peroxidation was increased in salt-stressed plants and slightly reduced in recovered plants after 3 d. Surprisingly, in the salt-stressed roots it decreased markedly after 3 d treatment and in the pre-stressed/recovered roots it was restored to levels near to the control. In leaves, catalase (CAT) activity showed a rapid and prominent decrease after 1 d of NaCl treatment and salt withdrawal had no effect on its recovery. In contrast, the root CAT activity was not changed by effects of both NaCl and salt withdrawal, over time interval. Leaf superoxide dismutase (SOD) activity did not change in all treatments, whereas in roots it significantly decreased after 3 d of salt treatment and recovered after NaCl withdrawal. Contrasting to the other enzymes, the guaiacol-peroxidase activity increased in leaves and roots, reaching almost 200% of control values and it significantly decreased in both organs from the pre-stressed/recovered plants. In conclusion, cowpea roots and leaves present distinct mechanisms of response to lipid peroxidation and CAT and SOD activities during salt stress and recovery. However, these responses and/or the oxidative damages caused by reactive oxygen species were not related with the growth reduction.