Ozer Sehirli

Resveratrol treatment protects against doxorubicin-induced cardiotoxicity by alleviating oxidative damage.

The possible protective effects of resveratrol (RVT) against cardiotoxicity were investigated in Wistar albino rats treated with saline, saline+doxorubicin (DOX; 20 mg/kg) or RVT (10 mg/kg)+DOX. Blood pressure and heart rate were recorded on the 1st week and on the 7th week, while cardiomyopathy was assessed using transthoracic echocardiography before the rats were decapitated. DOX-induced cardiotoxicity resulted in decreased blood pressure and heart rate, but lactate dehydrogenase, creatine phosphokinase, total cholesterol, triglyceride, aspartate aminotransferase and 8-OHdG levels were increased in plasma. Moreover, DOX caused a significant decrease in plasma total antioxidant capacity along with a reduction in cardiac superoxide dismutase, catalase and Na+,K+-ATPase activities and glutathione contents, while malondialdehyde, myelopreoxidase activity and the generation of reactive oxygen species were increased in the cardiac tissue. On the other hand, RVT markedly ameliorated the severity of cardiac dysfunction, while all oxidant responses were prevented; implicating that RVT may be of therapeutic use in preventing oxidative stress due to DOX toxicity.

α-LIPOIC ACID PROTECTS AGAINST RENAL ISCHAEMIA–REPERFUSION INJURY IN RATS

1 Oxygen free radicals are important components involved in the pathophysiological processes observed during ischaemia–reperfusion (I/R). The present study was designed to assess the possible protective effect of a‐lipoic acid (ALA) on renal I/R injury. 2 Wistar albino rats were unilaterally nephrectomized and subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Saline or ALA (100 mg/kg, i.p.) was administered 15 min prior to ischaemia and immediately before the reperfusion period. At the end of 24 h, rats were decapitated and trunk blood was collected. Creatinine, blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) activity were measured in serum samples, whereas tumour necrosis factor (TNF)‐a, interleukin (IL)‐1b, IL‐6, 8‐hydroxydeoxyguanosine (8‐OHdG) and total anti‐oxidant capacity (AOC) were assayed in plasma samples. 3 Kidney samples were taken for the determination of tissue malondialdehyde (MDA) and glutathione (GSH) levels, as well as Na+/K+‐ATPase and myeloperoxidase (MPO) activity. The formation of reactive oxygen species in renal tissue samples was monitored using a chemiluminescence (CL) technique with luminol and lucigenin probes. Oxidant‐induced tissue fibrosis was determined by tissue collagen content and the extent of tissue injury was analysed microscopically. 4 Ischaemia–reperfusion caused a significant increases in blood creatinine, BUN, LDH, IL‐1b, IL‐6, TNF‐a and 8‐OHdG, whereas AOC was decreased. In kidney samples from the I/R group, MDA, MPO, collagen and CL levels were found to be increased significantly; however, glutathione levels and Na+/K+‐ATPase activity were decreased. Conversely, ALA treatment reversed all these biochemical indices, as well as histopathological alterations induced by I/R. 5 In conclusion, these data suggest that ALA reverses I/R‐induced oxidant responses and improves microscopic damage and renal function. Thus, it seems likely that ALA protects kidney tissues by inhibiting neutrophil infiltration, balancing the oxidant–anti‐oxidant status and regulating the generation of inflammatory mediators.

Pomegranate peel extract prevents liver fibrosis in biliary-obstructed rats

Punica granatum L. (pomegranate) is a widely used plant that has high nutritional value. The aim of this study was to assess the effect of chronic administration of pomegranate peel extract (PPE) on liver fibrosis induced by bile duct ligation (BDL) in rats. PPE (50 mg kg−1) or saline was administered orally for 28 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels were determined to assess liver function and tissue damage. Proinflammatory cytokines (tumor necrosis factor‐alpha and interleukin 1 beta) in the serum and anti‐oxidant capacity (AOC) were measured in plasma samples. Samples of liver tissue were taken for measurement of hepatic malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Production of reactive oxidants was monitored by chemilumi‐nescence assay. Serum AST, ALT, LDH and cytokines were elevated in the BDL group compared with the control group; this increase was significantly decreased by PPE treatment. Plasma AOC and hepatic GSH levels were significantly depressed by BDL but were increased back to control levels in the PPE‐treated BDL group. Increases in tissue MDA levels and MPO activity due to BDL were reduced back to control levels by PPE treatment. Similarly, increased hepatic collagen content in the BDL rats was reduced to the level of the control group with PPE treatment. Thus, chronic PPE administration alleviated the BDL‐induced oxidative injury of the liver and improved the hepatic structure and function. It therefore seems likely that PPE, with its antioxidant and antifibrotic properties, may be of potential therapeutic value in protecting the liver from fibrosis and oxidative injury due to biliary obstruction.

Melatonin attenuates ifosfamide‐induced Fanconi syndrome in rats

Abstract:  Regarding the mechanisms of ifosfamide (IFO)‐induced nephrotoxicity and hemorrhagic cystitis, several hypotheses have been put forward, among which oxidative stress and depletion of glutathione (GSH) are suggested. This investigation elucidates the role of free radicals in IFO‐induced toxicity and the protection by melatonin. Wistar albino rats were injected intraperitoneally with saline (0.9% NaCl; control‐C group), melatonin (Mel group; 10 mg/kg daily for 5 days) or ifosfamide (50 mg/kg daily for 5 days; IFO group) or IFO + Mel. On the 5th day (120 hr) after the first IFO dose, animals were killed by decapitation and trunk blood was collected. Kidney and bladder tissues were obtained for biochemical and histological analysis. Urine was collected 24 hr before the rats were killed. The results demonstrated that IFO induced a Fanconi syndrome (FS) characterized by wasting of sodium, phosphate, and glucose, along with increased serum creatinine and urea. Melatonin markedly ameliorated the severity of renal dysfunction induced by IFO with a significant decrease in urinary sodium, phosphate, and glucose and increased creatinine excretion. Moreover, melatonin significantly improved the IFO‐induced GSH depletion, malondialdehayde accumulation and neutrophil infiltration in both renal and bladder tissues. In the kidney, Na+,K+‐ATPase activity which was significantly reduced by IFO, was increased with melatonin treatment. Increased collagen contents of the kidney and bladder tissues by IFO treatment were reversed back to the control levels with melatonin. Our results suggest that IFO causes oxidative damage in renal and bladder tissues and melatonin, via its antioxidant effects, protects these tissues. These data suggest that melatonin may be of therapeutic use in preventing acquired FS due to IFO toxicity.

Resveratrol protects against methotrexate-induced hepatic injury in rats.

PURPOSE The aim of this study to investigate the possible protective effect of resveratrol on some liver and serum/plasma parameters in methotrexate induced toxicity in rats. Methotrexate is used widely to treat various neoplastic diseases such as acute lymphoblastic leukemia, lymphoma, solid cancers, and autoimmune diseases. We hypothesized that resveratrol has a potential to decrease the oxidant damage in MTX-induced hepatic injury. METHODS Following a single dose of methotrexate (20 mg/kg, i.p.), either saline or resveratrol (10 mg/kg, orally) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the liver was removed to measure malondialdehyde and glutathione levels, myeloperoxidase and thromboplastic activities and collagen content. Aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase activity were measured in the serum samples, while TNF-alpha and total antioxidant capacity were assayed in plasma samples. RESULTS Our results showed that MTX administration increased the hepatic malondialdehyde levels, myeloperoxidase and thromboplastic activities and collagen contents and decreased glutathione, while these alterations were reversed in resveratrol-treated group. Elevated aspartate aminotransferase and alanine aminotransferase activities and TNF-alpha level observed following MTX treatment was depressed with resveratrol. CONCLUSIONS The present study showed that resveratrol protects against methotrexate-induced hepatic injury and may be of therapeutic potential in alleviating the systemic side effects of chemotherapeutics.

Alpha-lipoic acid protects against hepatic ischemia-reperfusion injury in rats.

Background and Aim: To evaluate the protective effect of alpha-lipoic acid in reducing oxidative damage after severe hepatic ischemia/reperfusion (IR) injury. Methods: Wistar albino rats were subjected to 45 min of hepatic ischemia, followed by 60 min reperfusion period. Lipoic acid (100 mg/kg i.p.) was administered 15 min prior to ischemia and immediately before reperfusion period. At the end of the reperfusion period aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) activity, and cytokine, TNF-α and IL-1β levels were determined in serum samples. Malondialdehyde (MDA), and glutathione (GSH) levels and myeloperoxidase (MPO) activity were determined in the liver tissue samples while formation of reactive oxygen species was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Tissues were also analyzed histologically. Results: Serum ALT, AST, and LDH activities and TNF-α and IL-1β levels were elevated in the I/R group, while this increase was significantly lower in the group of animals treated concomitantly with lipoic acid. Hepatic GSH levels, significantly depressed by I/R, were elevated back to control levels in lipoic acid-treated I/R group. Furthermore, increases in tissue luminol and lucigenin CL, MDA levels and MPO activity due to I/R injury were reduced back to control levels with lipoic acid treatment. Conclusion: Since lipoic acid administration alleviated the I/R-induced liver injury and improved the hepatic structure and function, it seems likely that lipoic acid with its antioxidant and oxidant-scavenging properties may be of potential therapeutic value in protecting the liver against oxidative injury due to ischemia-reperfusion.

Protective effect of MESNA (2-mercaptoethane sulfonate) against hepatic ischemia/reperfusion injury in rats.

PurposeReoxygenation of ischemic tissue generates various reactive oxygen metabolites (ROMs), which have a deleterious effect on various cellular functions. We evaluated the possible protective effect of 2-mercaptoethane sulfonate (MESNA) on hepatic ischemia/reperfusion (I/R) injury.MethodsWistar albino rats were subjected to 45-min hepatic ischemia, followed by 60-min reperfusion. 2-Mercaptoethane sulfonate, 150 mg/kg, or saline was given intraperitoneally (i.p.) twice, 15 min before ischemia and immediately before reperfusioin. We measured serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to assess liver function. Liver tissue samples were taken to measure the levels of malondialdehyde (MDA), an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant; and myeloperoxidase (MPO) activity, as an indirect index of neutrophil infiltration. We also measured hepatic collagen content, as a fibrosis marker.ResultsPlasma ALT and AST levels were higher in the I/R group than in the control group, but this increase was significantly decreased by MESNA treatment. Hepatic GSH levels, which were significantly depressed by I/R, increased back to the control levels in the MESNA-treated I/R group. Increases in tissue MDA levels and MPO activity caused by I/R injury decreased back to the control levels after MESNA treatment. Similarly, the increased hepatic collagen content in the I/R group decreased to the level of the control group after MESNA treatment.ConclusionThe fact that MESNA alleviated I/R-induced injury of the liver and improved hepatic structure and function suggests that its antioxidant and oxidant scavenging properties may be of therapeutic value in protecting the liver against oxidative injury caused by I/R.

Protective effects of Ginkgo biloba against acetaminophen-induced toxicity in mice

Background: The analgesic acetaminophen (AAP) causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. It was reported that these toxic effects of AAP are due to oxidative reactions that take place during its metabolism. Objective: In this study, we aimed to investigate the possible beneficial effect of Ginkgo biloba (EGb), an antioxidant agent, against AAP toxicity in mice. Methods: Balb/c mice were injected i.p. with: (1) vehicle, control (C) group; (2) a single dose of 50 mg/kg Ginkgo biloba extract, EGb group; (3) a single dose of 900 mg/kg i.p. acetaminophen, AAP group, and (4) EGb, in a dose of 50 mg/kg after AAP injection, AAP + EGb group. Serum ALT, AST, and tumor necrosis factor-alpha (TNF-α) levels in blood and glutathione (GSH), malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity, and collagen contents in liver tissues were measured. Formation of reactive oxygen species in hepatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lusigenin probe. Tissues were also examined microscopically. Results: ALT, AST levels, and TNF-α were increased significantly (p < 0.001) after AAP treatment, and reduced with EGb. Acetaminophen caused a significant (p < 0.05–0.001) decrease in GSH levels while MDA levels and MPO activity were increased (p < 0.001) in liver tissues. These changes were reversed by EGb treatment. Furthermore, luminol and lusigenin CL levels in the AAP group increased dramatically compared to control and reduced by EGb treatment (p < 0.01). Conclusion: Our results implicate that AAP causes oxidative damage in hepatic tissues and Ginkgo biloba extract, by its antioxidant effects protects the tissues. Therefore, its therapeutic role as a “tissue injury-limiting agent” must be further elucidated in drug-induced oxidative damage.

Aqueous garlic extract alleviates ischaemia‐reperfusion‐induced oxidative hepatic injury in rats

This study was designed to examine the effects of aqueous garlic extract (AGE) on hepatic ischaemia‐reperfusion (I/R) injury in rats. For this purpose, Wistar albino rats were subjected to 45 min of hepatic ischaemia, followed by a 60‐min reperfusion period. AGE (1 mL kg−1, i.p., corresponding to 500 mg kg−1) or saline was administered twice, 15 min before ischaemia and immediately before the reperfusion period. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined to assess liver functions. Liver tissues were taken for the determination of malondialdehyde (MDA) levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant; and myeloperoxidase (MPO) activity, as an indirect index of neutrophil infiltration. Hepatic collagen content, as a fibrosis marker, was also determined. Plasma ALT and AST activities were elevated in the I/R group as compared with the control group, while these increases were significantly decreased by AGE treatment. Hepatic GSH levels, significantly depressed by I/R, were elevated back to control levels in the AGE‐treated I/R group. Increases in tissue MDA levels and MPO activity due to I/R injury were reduced back to control levels by AGE treatment. Similarly, increased hepatic collagen content in the I/R group was reduced to the control level with AGE treatment. Since AGE administration alleviated the I/R‐induced injury of the liver and improved the hepatic structure and function, it seems likely that AGE, with its antioxidant and oxidant‐scavenging properties, may be of potential therapeutic value in protecting the liver against oxidative injury due to ischaemia‐reperfusion.

Resveratrol protects against irradiation-induced hepatic and ileal damage via its anti-oxidative activity

The present study was undertaken to determine whether resveratrol (RVT) could ameliorate ionizing radiation-induced oxidative injury. After a 10-days pre-treatment with RVT (10 mg/kg/day p.o.), rats were exposed to whole-body IR (800 cGy) and the RVT treatment was continued for 10 more days after the irradiation. Irradiation caused a significant decrease in glutathione level, while malondialdehyde levels, myeloperoxidase activity and collagen content were increased in the liver and ileum tissues. Similarly, plasma lactate dehydrogenase and pro-inflammatory cytokine levels, 8-hydroxy-2′-deoxyguanosine and leukocyte apoptosis were elevated, while antioxidant-capacity was reduced in the irradiated rats as compared with the control group. Furthermore, Na+, K+-ATPase activity was inhibited and DNA fragmentation was increased in the ileal tissues. Resveratrol treatment reversed all these biochemical indices, as well as histopathological alterations induced by irradiation. In conclusion, supplementing cancer patients with adjuvant therapy of resveratrol may have some benefit for a more successful radiotherapy.