Feral Öztürk

Potent protective effect of apricot and β-carotene on methotrexate-induced intestinal oxidative damage in rats

Several studies have well confirmed the contribution of oxidative stress in the pathogenesis of methotrexate (MTX)-induced damage in the small intestine. Many agents have been tried experimentally to reduce or inhibit the oxidative stress. To our knowledge, there is no study about apricot consumption on the MTX-induced damage in the small intestine. The aim of this study was to determine the possible protective effects of apricot and beta-carotene on MTX-induced intestinal damage in rats. The rats were randomly divided into seven groups as follows; I-control group; II-apricot group; III-beta-carotene group; IV-MTX group; V-apricot+MTX group; VI-beta-carotene+MTX group and VII-apricot+beta-carotene+MTX group. In the MTX group; fusion and shortening in the villus, epithelial desquamation, crypt loss, inflammatory cell infiltration in the lamina propria, goblet cell depletion and microvillar damage were observed in the small intestine. Parallel to histological results, malondialdehyde (MDA) content and myeloperoxidase (MPO) activity were found to be increased, whereas superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GP-x) activities and glutathione (GSH) content were decreased in the MTX group. However, single or combined application of apricot and beta-carotene ameliorated all of these hazardous effects in antioxidant system in MTX-treated groups. In conclusion, our results demonstrate that apricot and/or beta-carotene treatment may protect the impairment of oxidative stress and ameliorate MTX-induced intestine damage at biochemical and histological levels.

Carbon tetrachloride-induced nephrotoxicity and protective effect of betaine in Sprague-Dawley rats.

OBJECTIVES To observe the changes in the antioxidative defense enzymes and to detect the alterations of renal microscopy after carbon tetrachloride (CCl4) administration in rats and to investigate the possible protective effects of betaine against CCl4-induced renal damage. METHODS Thirty-two adult Sprague-Dawley rats were divided into four groups as follows: control group, betaine group, CCl4 group, and CCl4 + betaine group. CCl4 was given subcutaneously at 1 mL/kg. In the CCl4 + betaine group, rats were pretreated with betaine, then exposed to CCl4 at the same dose. Betaine group rats received concentrated betaine solution. The rats were killed and the kidneys taken for enzyme analyses and histologic examination. Glutathione peroxidase, superoxide dismutase, and catalase activities were measured in right kidney homogenates. Left kidneys were processed for light microscopic evaluation. RESULTS In the CCl4-treated group, significant increases in kidney superoxide dismutase and catalase activities and significant decrease in glutathione peroxidase activity were observed (P <0.01). These changes were found to be normalized in the CCl4 + betaine group. Betaine did not change the enzyme activities. Exposure to CCl4 resulted in glomerular and tubular alterations in the renal cortex. These alterations were found to be prevented by betaine pretreatment. CONCLUSIONS These results indicate that exposure to CCl4 leads to renal damage in rats and betaine exerts an improvement on nephrotoxic effects of CCl4.

Melatonin protects against myocardial doxorubicin toxicity in rats: role of physiological concentrations

Abstract: Doxorubicin (Dox) is a widely used antineoplastic drug. Oxygen radical‐induced injury of membrane lipids is considered to be the most important factor responsible for the development of Dox‐induced cardiotoxicity. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce Dox‐induced cardiac damage. However, the physiological role of melatonin in the prevention of this damage is unknown. We investigated physiological and pharmacological effects of melatonin on Dox‐induced changes in the levels of malondialdehyde (MDA), a lipid peroxidation product, and morphological changes in heart. Rats were pinealectomized (Px) or sham‐operated (control) 2 months before the studies. Melatonin was administered [4 mg/kg, intraperitoneally (i.p.)] 1 hr before or 24 hr after the administration of a single dose of Dox (20 mg/kg, i.p.) and continued for 2 days. The levels of MDA Dox was found to be significantly higher in the Px rats (55.9 ± 0.6 nmol/g tissue) than intact control animals (42.6 ± 0.4). Dox administration to Px and non‐Px rats significantly increased the MDA levels. Pre‐ and post‐treatment with melatonin in both Px and intact rats significantly reduced MDA levels. Morphological changes parallelled the MDA alterations. These findings strongly suggest that both physiological and pharmacological concentrations of melatonin are important in protecting the heart from Dox‐induced damage in rats. It would seem valuable to test melatonin in clinical trials for prevention of possible heart damage associated with Dox.

Protective effects of ascorbic acid on hepatotoxicity and oxidative stress caused by carbon tetrachloride in the liver of Wistar rats

This study was planned to investigate the protective effect of l(+)‐ascorbic acid (Vit C) on CCl4‐induced hepatotoxicity and oxidative stress in the liver of Wistar rats (Rattus Norvegicus, strain Wistar). Twenty‐four adult male Wistar rats were fed with standard rat chow diet for 10 days and randomly were divided into four groups of six each as follows: (1) control, (2) CCl4, (3) “CCl4 + Vit C”, (4) Vit C groups. CCl4 was applied to rats belonging to CCl4 and “CCl4 + Vit C” groups subcutaneously at 1 mg kg−1 dose CCl4 for 3 days. Vit C applied to “CCl4 + Vit C” and “Vit C” group rats intraperitoneally at 300 mg kg−1 dose for 3 days. All rats were sacrificed and livers were quickly removed on the fourth day of the experiment. MDA, total glutathione (T.GSH) levels and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‐PX) activities were measured in the liver of all groups of rats and also serum alanine amino transferase (ALT) and aspartate amino transferase (AST) activities were detected to determine liver functions in all groups of rats. Histopathological changes were evaluated by light and transmission electron microscopes. In “CCl4 + Vit C” group, MDA level was significantly decreased (p < 0.05) and SOD, CAT, GSH‐PX activities were significantly increased (p < 0.005, 0.01, 0.05) respectively, T.GSH level was significantly increased (p < 0.005) and serum ALT and AST activities were significantly decreased (p < 0.01, 0.05), respectively, when compared with CCl4 group. These results show that Vit C has a highly protective effect on hepatotoxicity and oxidative stress caused by CCl4. Copyright

Protective effect of apricot (Prunus armeniaca L.) on hepatic steatosis and damage induced by carbon tetrachloride in Wistar rats.

The present study was planned to investigate the protective effect of 10 % and 20 % apricot-containing feed on carbon tetrachloride (CCl4)-induced hepatic steatosis and damage. Adult male Wistar rats (n 42) were divided into six groups of seven each, as follows: control group; CCl4 group; CCl4+10 % apricot group; CCl4+20 % apricot group; 10 % apricot group; 20 % apricot group. All apricot groups were fed with 10 % or 20 % apricot-containing feed for 5 months. CCl4 injections were applied to the CCl4 groups at the dose of 1 mg/kg for 3 d at the end of 5 months. In the CCl4 group, vacuolated hepatocytes and hepatic necrosis were seen, especially in the centrilobular area. Hepatocytes showed an oedematous cytoplasmic matrix, large lipid globules and degenerated organelles. The area of liver injury was found significantly decreased with apricot feeding. Malondialdehyde and total glutathione levels and catalase, superoxide dismutase and glutathione peroxidase activities were significantly changed in the CCl4 group and indicated increased oxidative stress. Apricot feeding decreased this oxidative stress and ameliorated histological damage. We concluded that apricot feeding had beneficial effects on CCl4-induced liver steatosis and damage probably due to its antioxidant nutrient (beta-carotene and vitamin) contents and high radical-scavenging capacity. Dietary intake of apricot can reduce the risk of liver steatosis and damage caused by free radicals.

Beneficial role of aminoguanidine on acute cardiomyopathy related to doxorubicin-treatment

Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic that has cardiotoxicity as a major side effect. One mechanism of this toxicity is believed to involve the reactive oxygen radical species (ROS); these agents likely account for the pathophysiology of DOX-induced cardiomyopathy. Aminoguanidine (AG) is an effective antioxidant and free radical scavenger which has long been known to protect against ROS formation. We investigated the effects of AG on DOX-induced changes in thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content. The rats were divided into four groups:1) Control; 2) DOX group; injected intraperitoneally (i.p.) with DOX 20 mg/kg in a single dose 3) AG-treated group; injected i.p. in single dose of 20 mg/kg DOX plus 100 mg/kg AG 1 h before the DOX for 3 days, 4) AG group; injected i.p. with AG 100 mg/kg for 3 days. DOX administration to control rats increased TBARS and decreased GSH levels. AG administration before DOX injection caused significant decrease in TBARS and increase in GSH levels in the heart tissue when compared with DOX only. Morphological changes, including severe myocardial fibrosis and inflammatory cell infiltration were clearly observed in the DOX-treated heart. AG reversed the DOX-induced heart damage. Therefore AG could protect the heart tissue against free radical injury. The application of AG during cancer chemotherapy may attenuate tissue damage and improve the therapeutic index of DOX.

The contradictory effects of nitric oxide in caerulein-induced acute pancreatitis in rats

This study was planned to observe the effects of nitric oxide synthesis on the antioxidative defense enzymes and pancreatic tissue histology in caerulein-induced acute pancreatitis. Acute pancreatitis was induced by intraperitoneal injections of 50 µg/kg caerulein, L-arginine used for NO induction and Nω-nitro-L-arginine methyl ester (L-NAME) used for NO inhibition. In the caerulein group acinar cell degeneration, interstitial inflammation, oedema and haemorrhage were detected. Pancreatic damage scores were decreased with both NO induction and inhibition (p<0.05). MDA, GSH-Px, CAT, GSH and SOD activities were significantly changed in the caerulein group and indicated increased oxidative stress. Both NO induction and inhibition decreased this oxidative stress. It is concluded that both nitric oxide induction and inhibition ameliorated caerulein-induced acute pancreatitis. The findings indicate that a certain amount of NO production has beneficial effects in experimental acute pancreatitis, but uncontrolled over-production of NO may be detrimental.

Gentamicin-induced nephrotoxicity and protective effect of caffeic acid phenethyl ester in rats

The objective of this study was to investigate the beneficial effects of caffeic acid phenethyl ester (CAPE) on gentamicin (GM)‐induced nephrotoxicity in Wistar rats. Twenty‐one adult Wistar rats were divided into three groups as follows: control group, GM and GM + CAPE group. Control group rats were injected with 5% ethanol, GM group rats were treated with 100 mg/kg GM and GM + CAPE group were pretreated with 10 μmol/kg CAPE for 2 days, then exposed to GM at the same dose. Drug injections were applied for 12 days. Twenty‐four hours after the last injection, rats were killed and kidneys were quicky removed. Tissue malondialdehyde (MDA) measurements and microscopic examination of kidneys were performed. In the GM group, significant increases in MDA levels were observed (P < 0.05). These changes were found to be normalized in the GM + CAPE group. Exposure to GM caused necrosis of tubular epithelial cells. Necrosis of tubules were found to be prevented by CAPE pretreatment. In conclusion, CAPE exerted an improvement on GM‐induced nephrotoxicity, possibly, at least in part through inhibition of the production of oxygen free radicals that cause lipid peroxidation.

Protective effect of oral L-arginine supplementation on cyclosporine induced nephropathy in rats.

Background: One of the major adverse effects of long term cyclosporine A (CyA) administration is chronic nephrotoxicity. Several studies have suggested that alterations of the L-arginine (L-Arg) nitric oxide (NO) pathway may be involved in the pathogenesis of CyA-induced kidney damage. Aim: We postulated that in vivo activation of L-Arg-NO pathway might have a beneficial effect on CyA-induced renal damage. Conditions of chronic NO enhancement was established with L-Arg supplementation and chronic NO blockade with N-nitro-L-Arg methyl ester (L-NAME). We tested the hypothesis that, if CyA administration alters intrarenal NO synthesis, then exogenous L-Arg supplementation could limit renal injury, on the contrary, L-NAME, a potent competitive inhibitor of NO synthesis, could enhance CyA nephrotoxicity. Harmful effect of NO blockade indirectly supports the beneficial effect of NO in a model of CyA nephrotoxicity. Methods: Rats were administered vehicle (VH), CyA (7.5 mg/kg/day), CyA + L-Arg (2g/kg/day), CyA + L-NAME (5 mg/100 ml/day), CyA + L-Arg + L-NAME, VH + L-Arg, VH + L-NAME and were sacrificed at the end of the experiment. Body weight, serum creatinine, blood urea nitrogen (BUN) and NO levels were determined. Tubular injury and interstitial fibrosis were evaluated semiquantitatively using scoring systems on paraffin sections stained with hematoxylin/eosin (H/E), Masson’s trichromic and periodic acid-Schiff (PAS). Results: The CyA group developed marked renal injury, characterized by a significant increase in serum creatinine and BUN, and histopathological alterations including tubular dilatation, vacuolization, necrosis, interstitial cell infiltration and tubulointerstitial fibrosis. CyA reduced serum NO level. L-Arg treatment significantly enhanced NO biosynthesis and protected animals from CyA-induced kidney damage. In contrast L-NAME strikingly reduced serum NO level, and worsened biochemical and histopathological alterations. Conclusion: Chronic CyA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement suggesting that L-Arg supplementation may be protective in CyA nephrotoxicity.

The effect of melatonin on 7,12-dimethyl- benz[a]anthracene injury in comparison with vitamin E + selenium in mouse kidneys

The aims of this study were to observe the changes in antioxidative defense enzymes and renal morphology after 7,12‐dimethyl‐benz[a]anthracene (7,12‐DMBA) administration in mice and to investigate the possible protective effects of melatonin against 7,12‐DMBA‐induced renal damage in comparison with vitamin E + selenium (vit E + Se). Forty female mice were divided into four groups: control, DMBA, DMBA + vit E + Se and DMBA + melatonin. In the DMBA group, mice were given injections of 7,12‐DMBA (20 mg/kg). DMBA + vit E + Se group mice received injections of 7,12‐DMBA + vit E + Se (20 mg/kg + 90 mg/kg + 1.8 μg/kg). In the melatonin group, mice were given injections of 7,12‐DMBA + melatonin (20 mg/kg + 4.2 mg/kg). The experiment lasted for 21 days. Mice were killed and the kidneys were taken for enzyme analyses and histologic examination. Catalase (CAT) and glutathione peroxidase (GSH‐Px) activities were found significantly decreased in the DMBA group and in the DMBA + vit E + Se group when compared with the control group (P < 0.05), whereas CAT and GSH‐Px activities were found significantly elevated in the DMBA + melatonin group when compared with the control (P < 0.05) and the DMBA group (P < 0.01). Exposure to DMBA resulted in tubular alterations in renal cortex. Morphometric analysis revealed proximal and distal tubular damage (P < 0.05). These alterations were found to be prevented by melatonin but not with vit E + Se administration. These results reveal that melatonin stimulates CAT and GSH‐Px activities and prevents renal injury better than vit E + Se combination in mice kidneys.