A. Fatih Aydın

Effect of carnosine against thioacetamide-induced liver cirrhosis in rat.

Carnosine (beta-alanyl-L-histidine) is a dipeptide with antioxidant properties. Oxidative stress has been proposed to be involved in thioacetamide (TAA)-induced liver cirrhosis in rats, that is similar to human disease. In this study we aimed to investigate the role of carnosine on the development of TAA-induced cirrhosis. 200mg TAA/kg body weight has been given i.p. twice a week for three months to female wistar rats. Another group received same dose of TAA in the same pattern plus 2g carnosine/L of drinking water for three months. TAA administration resulted in hepatic fibrosis, significant increases in plasma transaminase activities as well as hepatic hydroxyproline and lipid peroxide levels, while liver glutathione (GSH) and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) protein expressions and activities decreased. Carnosine was found to behave as an antioxidant reducing malondialdehyde (MDA) and diene conjugate (DC) levels although it was not effective on increased transaminase activities and decreased antioxidants. It also did not affect the histopathological changes observed in TAA group. Thus our findings indicate that carnosine appears to attenuate peroxidation as an antioxidant itself but does not seem to prevent the development of TAA-induced cirrhotic process.

Blueberry treatment attenuates D-galactose-induced oxidative stress and tissue damage in rat liver.

d‐galactose (GAL) causes aging‐related changes and oxidative stress in the organism. We investigated the effect of whole fresh blueberry (BB; Vaccinium corymbosum L.) treatment on oxidative stress in age‐related liver injury model.

Betaine treatment decreased oxidative stress, inflammation, and stellate cell activation in rats with alcoholic liver fibrosis

The aim of this study was to investigate the effect of betaine (BET) on alcoholic liver fibrosis in rats. Fibrosis was experimentally generated with ethanol plus carbon tetrachloride (ETH+CCl4) treatment. Rats were treated with ETH (5% v/v in drinking water) for 14 weeks. CCl4 was administered intraperitoneally (i.p.) 0.2mL/kg twice a week to rats in the last 6 weeks with/without commercial food containing BET (2% w/w). Serum hepatic damage markers, tumor necrosis factor-α, hepatic triglyceride (TG) and hydroxyproline (HYP) levels, and oxidative stress parameters were measured together with histopathologic observations. In addition, α-smooth muscle-actin (α-SMA), transforming growth factor-β1 (TGF-β1) and type I collagen (COL1A1) protein expressions were assayed immunohistochemically to evaluate stellate cell (HSC) activation. mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were also determined. BET treatment diminished TG and HYP levels; prooxidant status and fibrotic changes; α-SMA, COL1A1 and TGF-β protein expressions; MMP-2, TIMP-1 and TIMP-2 mRNA expressions in the liver of fibrotic rats. In conclusion, these results indicate that the antifibrotic effect of BET may be related to its suppressive effects on oxidant and inflammatory processes together with HSC activation in alcoholic liver fibrosis.

High-fat diet plus carbon tetrachloride-induced liver fibrosis is alleviated by betaine treatment in rats.

Steatosis, the first lesion in non-alcoholic fatty liver disease (NAFLD), may progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Steatosis predisposes the liver to oxidative stress, inflammation, and cytokines. Betaine (BET) has antioxidant, antiinflammatory and hepatoprotective effects. However, the effects of BET on liver fibrosis development are unknown. Rats were treated with high-fat diet (60% of total calories from fat) for 14weeks. Carbon tetrachloride (0.2mL/kg; two times per week; i.p.) was administered to rats in the last 6weeks with/without commercial food containing BET (2%; w/w). Serum liver function tests and tumor necrosis factor-α, insulin resistance, hepatic triglyceride (TG) and hydroxyproline (HYP) levels and oxidative stress parameters were determined along with histopathologic observations. Alpha-smooth muscle-actin (α-SMA), transforming growth factor-β1 (TGF-β1) and type I collagen (COL1A1) protein expressions and mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were evaluated. BET decreased TG and HYP levels, prooxidant status and fibrotic changes in the liver. α-SMA, COL1A1 and TGF-β1 protein expressions, MMP-2, TIMP-1, and TIMP-2 mRNA expressions diminished due to BET treatment. BET has an antifibrotic effect and this effect may be related to its antioxidant and antiinflammatory actions together with suppression on HSC activation.

Protective effects of carnosine alone and together with alpha-tocopherol on lipopolysaccharide (LPS) plus ethanol-induced liver injury

The aim of this study was to investigate the effect of carnosine (CAR) alone and together with vitamin E (Vit E) on alcoholic steatohepatitis (ASH) in rats. ASH was induced by ethanol (3 times; 5 g/kg; 12 h intervals, via gavage), followed by a single dose of lipopolysaccharide (LPS; 10 mg/kg; i.p.). CAR (250 mg/kg; i.p.) and Vit E (200 mg D-α-tocopherol/kg; via gavage) were administered 30 min before and 90 min after the LPS injection. CAR treatment lowered high serum transaminase activities together with hepatic histopathologic improvements in rats with ASH. Reactive oxygen species formation, malondialdehyde levels, myeloperoxidase activities and transforming growth factor β1 (TGF-β1) and collagen 1α1 (COL1A1) expressions were observed to decrease. These improvements were more remarkable in CAR plus Vit E-treated rats. Our results indicate that CAR may be effective in suppressing proinflammatory, prooxidant, and profibrotic factors in the liver of rats with ASH.

The effect of carnosine on methylglyoxal-induced oxidative stress in rats

Abstract Methylglyoxal (MG) is generated from glycolytic metabolites, lipid peroxidation, glucose autooxidation and protein glycation. It is a prooxidant inducing oxidative stress and formation of advanced glycation end products (AGE). Effect of carnosine (CAR) as an antioxidant on toxicity due to MG has generated interest. In this study, rats were given incrementally increased doses (100–300 mg/kg) of MG in drinking water for ten weeks. CAR (250 mg/kg i.p.) was administered with MG. Plasma thiobarbituric reactive substances (TBARS), protein carbonyl (PC), advanced oxidation protein products (AOPP) and AGE levels were elevated by MG, and CAR decreased PC, AOPP and AGE levels. MG increased liver reactive oxygen species (ROS), TBARS, PC and AOPP levels, which were decreased by CAR. Thus, in vivo role of CAR on chronic MG administration was observed to suppress the generated hepatic and plasma oxidative stress.

The effect of N-acetylcysteine supplementation on serum homocysteine levels and hepatic and renal oxidative stress in homocysteine thiolactone-treated rats.

Abstract The effect of N-acetylcysteine (NAC) (1 g/kg body weight/day) on serum homocysteine (Hcy) levels, insulin resistance (IR), and hepatic and renal prooxidant-antioxidant balance was evaluated in rats treated with homocysteine thiolactone (HcyT) (500 mg/kg body weight/day for 6 weeks). Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione, ferric reducing antioxidant power, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined in the liver and kidney. HcyT elevated serum Hcy levels and caused IR, but liver and kidney function tests remained unchanged. HcyT increased ROS and MDA without any change in hepatic antioxidants, but it elevated renal SOD and GSH-Px activities. NAC decreased serum Hcy, hepatic and renal ROS and MDA levels, and renal SOD and GSH-Px activities in rats with high Hcy levels. However, it did not ameliorate IR. Our results indicate that NAC supplementation may be effective in decreasing Hcy levels and Hcy-induced hepatic and renal oxidative stress.

Blueberry treatment attenuated cirrhotic and preneoplastic lesions and oxidative stress in the liver of diethylnitrosamine-treated rats.

Diethylnitrosamine (DEN)-induced liver cancer normally develops in stages that progress from cirrhosis and carcinoma. Increased oxidative stress is suggested to play a role in DEN-induced carcinogenicity. Blueberries (BB) contain high antioxidant capacity. We investigated the effect of BB supplementation on development of DEN-induced cirrhosis and neoplastic lesions in the liver. Rats were injected with DEN (200 mg/kg; i.p.) three times with an interval of 15 days at 4, 6, and 8 weeks and sacrificed 8 weeks after the last DEN injection. They were also fed on 8% BB (w/w) containing chow for 16 weeks. Hepatic damage markers in serum were determined together with hepatic histopathological examinations. Hydroxyproline (HYP), malondialdehyde (MDA), diene conjugate (DC), protein carbonyl (PC), and glutathione (GSH) levels, and CuZn-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and their mRNA expressions were measured. Protein and mRNA expressions of glutathione transferase-pi (GST-pi) were evaluated as a marker of preneoplastic lesions. BB supplementation decreased hepatic damage markers in serum and hepatic MDA, DC, and PC levels, but SOD, CAT, and GSH-Px activities and their mRNA expressions remained unchanged in DEN-treated rats. BB attenuated cirrhotic changes and decreased hepatic HYP levels and GST-pi expressions. Our results indicate that BB is effective in decreasing development of DEN-induced hepatic cirrhosis and preneoplastic lesions by acting as an antioxidant (radical scavenger) itself without affecting activities and mRNA expressions of antioxidant enzymes.

Antiglycation and anti-oxidant efficiency of carnosine in the plasma and liver of aged rats

Increases in oxidative stress and advanced glycation end‐products (AGE) formation play an important role in the pathogenesis of aging. Carnosine (CAR; β‐alanyl‐L‐histidine) has anti‐oxidant and antiglycating properties. We investigated the effect of CAR supplementation on AGE levels, and protein and lipid oxidation products in the serum and liver tissue in aged rats.

The effect of resveratrol on glycation and oxidation products in plasma and liver of chronic methylglyoxal-treated rats

BACKGROUND Methylglyoxal (MG) is a highly reactive dicarbonyl compound. It is produced by processes like glycolysis, glucose autooxidation, lipid peroxidation, and protein glycation. It is a major precursor of advanced glycation end products (AGE). It also exacerbates oxidative stress in the organism. Although there are some in vitro studies investigating the effect of resveratrol (RES) as an antioxidant and antiglycating agent on MG-induced toxicity, in vivo effect of RES is unknown. Therefore, we aimed to investigate the efficiency of RES in chronic MG-treated rats. METHODS Rats were given incrementally increased doses (100-300 mg/kg) of MG in drinking water for ten weeks. RES (10 mg/kg ip) was administered together with MG. Reactive oxygen species (ROS) formation, thiobarbituric reactive substances (TBARS), protein carbonyl (PC), advanced oxidation protein products (AOPP) and AGE levels as well as ferric reducing antioxidant power (FRAP) values were determined in plasma and liver. RESULTS Significant increases in plasma TBARS, PC, AOPP and AGE and fructosamine levels were detected in MG-treated rats. However, plasma ROS and FRAP levels remained unchanged. Hepatic ROS, TBARS, PC and AOPP, but not AGE and FRAP levels were also increased in MG-treated rats. RES treatment diminished high levels of plasma PC, AOPP and AGE levels in MG-treated rats. Additionally, significant decreases in hepatic ROS, TBARS, PC and AOPP levels together with histopatological amelioration were detected due to RES treatment in MG-treated rats. CONCLUSIONS Our results indicate that RES may be considered as a protective agent against glycoxidative stress generated by in vivo MG treatment.