Diallyl trisulfide, a garlic polysulfide protects against As-induced renal oxidative nephrotoxicity, apoptosis and inflammation in rats by activating the Nrf2/ARE signaling pathway.

BACKGROUND: Arsenic (As) contamination is an extremely dangerous global environmental problem as it can enter into the food chain and become bio-accumulated, endangering human health. Chronic As intoxication leads to undesirable toxic effects in various organ systems of the body, especially the kidney. Diallyl trisulfide (DATS) is an organosulfur compound which has been widely known for its uses as antibacterial, antitumorogenic, antioxidant agent and has been also reported to have anti-apoptotic and anti-inflammatory properties. PURPOSE: In the present work, we intend to investigate the protective role of DATS, a garlic organosulfur compound in preventing the As-induced oxidative stress mediated renal injury in rats. Study design The activity of DATS to antagonize As-induced renal oxidative toxicity was analyzed using rats as an in vivo model. METHODS: We investigated the nephroprotective effect of DATS on As treated rats by performing various serological, biochemical, molecular and histological studies. The activation of Nrf2 was investigated using western blot. RESULTS: The data showed that As exposure significantly increased the serum and urine nephritic, oxidative stress, apoptosis and inflammatory markers in the renal tissue of rats. As intoxication also decreased the antioxidant status of the renal tissue along with the disturbances in the membrane bound ATPases. As nephrotoxicity was further confirmed with the altered morphological and ultrastructural changes in the renal tissue. Conversely, the DATS pre-administration effectively recuperate the altered renal variables by As, which has been further supported by the histological and ultrastructural observations. This counteraction was achieved partially via the activation of Nrf2-ARE pathway through the activation of Akt. CONCLUSION: These findings explicate the prospective use of DATS as a promising organosulfur compound against As-induced renal oxidative dysfunction in rats.

Oxidative stress induced by cadmium in the plasma, erythrocytes and lymphocytes of rats: Attenuation by grape seed proanthocyanidins.

The present study has been designed to investigate the ameliorative effect of grape seed proanthocyanidins (GSP) on cadmium (Cd)-induced oxidative damage in rat erythrocytes. Twenty four male Wistar rats were divided into four groups: control, GSP-treated group (100 mg kg(-1) body weight (BW)), Cd-treated group (cadmium chloride, 5 mg kg(-1) BW), and GSP + Cd-treated group in which GSP was orally pre-administered 90 min before Cd intoxication for 4 weeks. At the end of the experimental period, blood samples were collected by cardiac puncture and were processed for various biochemical estimations. The extent of oxidative damage in isolated rat erythrocyte membrane was assessed by measuring lipid peroxidation, enzymatic and non-enzymatic content, calcium ion (Ca(2+))/magnesium ion (Mg(2+))-ATPase and sodium ion (Na(+))/potassium ion (K(+))-ATPase activities, free iron, calcium, hydrogen peroxide (H2O2) concentration, and osmotic fragility. Our results unveiled that Cd intoxication significantly increased the erythrocyte lipid peroxidation markers and decreased the activity of enzymatic and non-enzymatic markers in erythrocytes. Conversely, GSP pretreatment significantly prevented the decrease in the activities of antioxidant enzymes and membrane-bound ATPases. GSP also restored the levels of iron, calcium, and H2O2 in Cd-treated rats. Conformational changes in erythrocytes of various groups were also determined using morphological and ultrastructural electron microscopic analysis. The findings of our study clearly revealed that GSP affords superior protection against Cd-induced reactive oxygen species generation, lipid peroxidation, and free radical generation in Cd-treated rats, which presumably reflects the ability of this flavonoid to protect erythrocytes and lymphocytes of rats from the toxic effects of Cd.

Ameliorative efficacy of tetrahydrocurcumin against arsenic induced oxidative damage, dyslipidemia and hepatic mitochondrial toxicity in rats.

Arsenic (As) is a well-known human carcinogen and a potent hepatotoxin. Environmental exposure to arsenic imposes a serious health hazard to humans and other animals worldwide. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, exhibits many of the same physiological and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than the curcumin. It has been reported that THC has antioxidant efficacy attributable to the presence of identical ß-diketone of 3rd and 5th substitution in heptane moiety. In the present study, rats were orally treated with arsenic alone (5 mg kg(-1) bw/day) with THC (80 mg kg(-1) bw/day) for 28 days. Hepatotoxicity was measured by the increased activities of serum hepatospecific enzymes, namely aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin along with increased elevation of lipid peroxidative markers, thiobarbituric acid reactive substances. And also elevated levels of serum cholesterol, triglycerides, free fatty acids and phospholipids were observed in arsenic intoxicated rats. These effects of arsenic were coupled with enhanced mitochondrial swelling, inhibition of cytochrome c oxidase, Ca(2+)ATPase and a decrease in mitochondrial calcium content. The toxic effect of arsenic was also indicated by significantly decreased activities of enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase along with non-enzymatic antioxidant such as reduced glutathione. Administration of THC exhibited significant reversal of arsenic induced toxicity in hepatic tissue. All these changes were supported by the reduction of arsenic concentration and histopathological observations of the liver. These results suggest that THC has a protective effect over arsenic induced toxicity in rat.

Epigallocatechin gallate potentially attenuates Fluoride induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats.

The present study was undertaken to evaluate the cardioprotective role of (-)-epigallocatechin-gallate (EGCG) against Fluoride (F) induced oxidative stress mediated cardiotoxicity in rats. The animals exposed to F as sodium Fluoride (NaF) (25mg/kg BW) for 4 weeks exhibited a significant increase in the levels of cardiac troponins T and I (cTnT & I), cardiac serum markers, lipid peroxidative markers and plasma total cholesterol (TC), triglycerides (TG), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol, very low density lipoprotein cholesterol as well as cardiac lipids profile (TC, TG and FFA) with the significant decrease of high density lipoprotein cholesterol and cardiac phospholipids. F intoxication also decreased the levels of mitochondrial enzymes such as ICDH, SDH, MDH, α-KGDH and NADH in the cardiac tissue of rats. The mitochondrial Ca(2+) ion level was also significantly reduced along with the significant decrease in the levels of enzymatic and non enzymatic antioxidants. Furthermore, F treatment significantly increased the DNA fragmentation, up regulate cardiac pro-apoptotic markers, inflammatory markers and down-regulate the anti-apoptotic markers in the cardiac tissue. Pre administration of EGCG (40mg/kg/bw) in F intoxicated rats remarkably recovered all these altered parameters to near normalcy through its antioxidant nature. Thus, results of the present study clearly demonstrated that treatment with EGCG prior to F intoxication has a significant role in protecting F-induced cardiotoxicity and dyslipidemia in rats.

Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

The present study investigates the possible ameliorative effects of diallyl trisulfide (DATS) against arsenic (As)-induced hepatotoxicity and oxidative stress in rats. The four experimental groups evaluated include: (1) vehicle control; (2) As (5 mg/kg/day); (3) DATS (80 mg/kg/day) + As; and (4) DATS. Induction of As in rats caused severe hepatotoxicity as evidenced by an elevation of serum aspartate aminotransferase and alanine aminotransferase activities and increased total bilirubin concentration, indicating hepatic function abnormalities. Histopathological examination revealed various structural changes in the liver, characterized by hepatocyte degeneration/necrosis, congestion, sinusoidal dilatation, vacuolation, and inflammatory cell infiltration. The significant decrease in reduced glutathione content, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and the significant increase in lipid peroxidation (thiobarbituric acid reactive substance) and protein oxidation (protein carbonyl) contents indicated that As-induced hepatotoxicity was mediated through oxidative stress. As intoxication also elevated the levels of Cas-3 and nitric oxide and increased the expression of nuclear factor-κB p65 in the liver. In contrast, DATS pretreatment significantly improved As-induced serum biochemical, immunohistochemical, and histopathological alterations reflecting hepatic dysfunction. These results may contribute to a better understanding of the hepatoprotective role of DATS, emphasizing the influence of this garlic trisulfide in the diet for human health, possibly preventing the hepatic injury associated with As intoxication, presumably due to its ability to inhibit lipid peroxidation, protein oxidation, and restoration of antioxidant status.

Arsenic-induced hepatic mitochondrial toxicity in rats and its amelioration by diallyl trisulfide.

The present investigation was aimed to investigate the possible protective role of diallyl trisulfide (DATS) against arsenic (As)-induced hepatic mitochondrial toxicity in rats. Mitochondria were isolated from the liver tissue of rats from all the groups. Lipid profile, lipid peroxidation, antioxidant enzyme activities, hepatic function enzymes, mitochondrial swelling, cytochrome c oxidase activity, mitochondrial Ca(+)-ATPase and Na(+)/K(+)-ATPase activity, mitochondrial calcium content and mitochondrial enzyme activities were measured. Short-term As exposure (5 mg/kg bw/d for 28 d) caused liver damage as evidenced by changes in activities of liver enzymes. The effects of As were coupled with enhanced reactive oxygen species generation, mitochondrial swelling, inhibition of cytochrome c oxidase, complex I-mediated electron transfer, decreased Ca(2+)-ATPase and Na(+)/K(+)-ATPase activity, a reduction in mitochondrial calcium content, changes in indices of hepatic mitochondrial oxidative stress, significant increase in mitochondrial lipid peroxidation products and alterations in mitochondrial lipid profile. Significant decreases in mitochondrial antioxidants and tricarboxylic acid cycle enzymes were also found in the liver mitochondria of As-induced hepatic mitochondrial toxicity in rats. As also increased hepatic caspase-3 activity and DNA fragmentation. All these apoptosis-related molecular changes caused by As could be alleviated by supplementation with DATS, which likely suggests a protective role against As-induced hepatotoxic changes and hepatic mitochondrial toxicity. The protective effect of DATS on the liver mitochondria was evidenced by altering all the changes induced by As. Free radical scavenging and metal chelating activities of DATS may be the mechanism, responsible for the protective action against As-induced mitochondrial damage in liver.

Epigallocatechin gallate supplementation protects against renal injury induced by fluoride intoxication in rats: Role of Nrf2/HO-1 signaling.

Fluoride intoxication generates free radicals, causing oxidative stress that plays a critical role in the progression of nephropathy. In the present study, we hypothesized that epigallocatechin gallate (EGCG), found in green tea, protects the kidneys of rats treated with fluoride by preventing oxidative stress, inflammation, and apoptosis. Pretreatment of fluoride-treated rats with EGCG resulted in a significant normalization of creatinine clearance and levels of urea, uric acid, and creatinine. Fluoride intoxication significantly increased renal oxidative stress markers and decreased the levels of renal enzymatic and non-enzymatic antioxidants. In addition, renal NO, TNF-α, IL-6 and NF-κB were also increased in the renal tissue of fluoride-treated rats. Further, EGCG pretreatment produced a significant improvement in renal antioxidant status and reduced lipid peroxidation, protein carbonylation and the levels of inflammatory markers in fluoride-treated kidney. Similarly, mRNA and protein analyses showed that EGCG pretreatment normalized the renal expression of Nrf2/Keap1 and its downstream regulatory proteins in fluoride-treated rat kidney. EGCG also effectively attenuated fluoride-induced renal apoptosis by the up-regulation of anti-apoptotic proteins such as Bcl-2 and down-regulation of Bax, caspase-3, caspase-9 and cytochrome c. Histology and immunohistochemical observations of Kim-1 provided further evidence that EGCG effectively protects the kidney from fluoride-mediated oxidative damage. These results suggest that EGCG ameliorates fluoride-induced oxidative renal injury by activation of the Nrf2/HO-1 pathway.