Protective role of S-adenosylmethionine on high fat/high cholesterol diet-induced hepatic and aortic lesions and oxidative stress in guinea pigs.

S-adenosylmethionine (SAM) is the main methyl group donor and has antioxidant potential. In this study, preventive and regressive potential of SAM were investigated in high fat/high cholesterol (HFHC) diet-induced non-alcoholic fatty liver disease (NAFLD) in guinea pigs. They were injected with SAM (50 mg/kg, i.p.) for 6 weeks along with HFHC diet or 4 weeks after HFHC diet. Serum transaminase activities, total cholesterol (TC), triglyceride (TG), cytochrome p450-2E1 (CYP2E1) and hydroxyproline (Hyp) levels, prooxidative and antioxidative parameters, protein expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1) together with histopathological changes were examined in the liver. SAM treatment diminished HFHC diet-induced increases in serum transaminase activities and hepatic TC, TG, CYP2E1, Hyp, α-SMA and TGF-ß1 expressions and ameliorated prooxidant-antioxidant balance. Histopathological scores for hepatic steatosis, inflammation, and fibrosis were decreased by SAM treatment. Increases in TC, diene conjugate levels, and lipid vacuoles within the tunica media of the aorta were reduced in HFHC-fed animals treated with SAM. These protective effects were also detected in the regression period of HFHC-guinea pigs due to SAM. In conclusion, SAM treatment was found to be effective in prevention and regression of HFHC-induced hepatic and aortic lesions together with decreases in oxidative stress in guinea pigs with NAFLD.

The effect of glycine on oxidative stress, inflammation and renin-angiotensin system in kidneys and aorta of cyclosporine-administered rats.

Cyclosporine A (CsA) is an immunosuppressive drug, used in organ transplantations. Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in CsA-toxicity. Glycine (Gly) has antioxidant and anti-inflammatory effects. In this study, Gly was investigated for its protective role against CsA-induced toxicity. CsA (20 mg/kg/day; subcutaneously) was administered to rats along with Gly injection (250 or 1000 mg/kg; intraperitoneally) for 21 days. Renal function markers [serum urea and creatinine and urinary protein and kidney injury molecule levels and creatinine clearance values] together with histopathological examinations were performed. Oxidative stress (reactive oxygen species, thiobarbutiric acid reactive substances, advanced oxidation products of protein, glutathione, ferric reducing anti-oxidant power and 4-hydroxynonenal levels), and inflammation (myeloperoxidase activity) were determined in kidney tissue. The RAS system [angiotensin II (Ang II) levels, and mRNA expressions of angiotensin converting enzyme (ACE), angiotensin II type-I receptor (AT1R)] and NADPH-oxidase 4 (NOX4) were measured in kidney and aorta. CsA caused significant disturbances in renal function markers, increases in oxidative stress and inflammation parameters and renal damage. Serum angiotensin II levels and mRNA expressions of ACE, AT1R and NOX4 elevated in the aorta and kidney of CsA-rats. Gly, especially its high-dose, alleviated renal function markers, oxidative stress, inflammation and renal damage in CsA-rats. Moreover, serum Ang II levels and mRNA expressions of ACE, AT1R and NOX4 decreased significantly in aorta and kidney in CsA-rats due to Gly treatment. Our results indicate that Gly may be useful for the prevention of CsA-induced renal and vascular toxicity.

The effect of 1,25-dihydroxyvitamin D3 on liver damage, oxidative stress, and advanced glycation end products in experimental nonalcoholic- and alcoholic- fatty liver disease

Background/aim: Oxidative stress and advanced glycation end products (AGEs) formation are proposed as effective mechanisms in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). 1,25(OH)2D3 was proposed to have antioxidant, antiinflammatory and antiglycation properties. In this study, the effect of 1,25(OH)2D3 treatment on oxidative stress parameters and AGEs levels together with hepatic histopathology was investigated in high fructose (HFr) or ethanol (EtOH)-treated rats. Materials and methods: Rats were treated with fructose (30%) or ethanol (5-20%) in drinking water with and without 1,25(OH)2D3 treatment (5 µg/kg two times a week) for 8 weeks. Insulin resistance (IR), oxidative stress parameters, AGEs, triglyceride (TG), and hydroxyproline (Hyp) levels together with histopathology were investigated in the liver. Results: 1,25(OH)2D3 decreased hepatic reactive oxygen species, lipid and protein oxidation products together with histopathological improvements in HFr- and EtOH-treated rats. 1,25(OH)2D3 treatment was observed to decrease significantly serum and hepatic AGEs in HFr group, and hepatic AGEs in EtOH group. Conclusion: Our results clearly show that 1,25(OH)2 D3 treatment may be useful in the alleviation of hepatic lesions by decreasing glycooxidant stress in both NAFLD and ALD models created by HFr- and EtOH-treated rats, respectively.

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system.

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.

N-Acetylcysteine supplementation decreased brain lipid and protein oxidations produced by experimental homocysteine thiolactone exposure: Relevance to neurodegeneration.

High levels of homocysteine (Hcy) have neurotoxic effects. Homocysteine thiolactone (HcyT), a thioester of Hcy, plays a role in Hcy-induced toxicity. In this study, effects of HcyT treatment (500 mg/kg body weight/day in drinking water) for 6 weeks on serum Hcy levels and brain prooxidant-antioxidant balance were investigated in rats. The effect of N-acetylcysteine (NAC) treatment (1 g/kg body weight/day in chow) for 6 weeks on HcyT-induced neurotoxicity was evaluated. Reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), diene conjugate (DC), protein carbonyl (PC) and advanced oxidation protein products (AOPP) were determined in the brain tissue. Ferric reducing antioxidant power (FRAP) and non-protein sulfydryl groups (NPSH) levels as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were also measured to evaluate the antioxidant potential of brain the tissue. HcyT elevated serum Hcy levels and brain ROS, TBARS, DC, PC and AOPP levels. However, HcyT did not affect FRAP levels and SOD, and GSH-Px activities. NAC treatment decreased serum Hcy and brain ROS, TBARS, DC, PC and AOPP levels in HCyT-treated rats. Our results indicate that NAC supplementation may be effective in decreasing serum Hcy levels and HcyT-induced oxidative stress in brain of rats.

Effects of resveratrol on high-fructose-induced testis injury in rats.

This study investigated whether a high-fructose (HFr) diet changes the morphology of seminiferous tubules (ST) in rats and resveratrol (RES) has a possible restoring effect in this sense. Fructose (30%; w/v) was administered to rats alone or together with RES (50 mg/L) in drinking water for 8 weeks. In the HFr group, destruction of the germinal epithelium led to the detection of immature germ cells in the lumen. HFr diet gave rise to a decrease in the ST diameters (p < 0.05), Johnsen's tubular biopsy score values (p < 0.001), and an increase in the apoptotic index (p < 0.05). Ultrastructurally, HFr feeding increased lipid accumulation (p < 0.01), mitochondrial damage, and acrosomal abnormalities in spermatogenic cells. Treatment of HFr -fed rats with RES improved the reduced ST diameters and overall general histological and ultrastructural abnormalities of the STs, but did not change the increased apoptotic index.

Effect of betaine treatment on the regression of existing hepatic triglyceride accumulation and oxidative stress in rats fed on high fructose diet.

We investigated whether betaine has any regressive effect on existing high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, inflammation as well as hepatic steatosis and oxidative stress. Rats were fed a HFrD containing 60% fructose for 8 weeks. After 8 weeks, rats were divided into two groups and fed a control diet for an additional 4-week period (regression groups). One of the regression groups received drinking water containing betaine (1%; w/v), having antioxidant and anti-inflammatory actions. HFrD feeding caused insulin resistance, elevated triglyceride (TG) and tumor necrosis factor-alfa (TNF-α) levels, alanine aminotransferase (ALT) and aspartate transaminase (AST) activities in serum. This diet increased hepatic TG, thiobarbituric acid reactive substances (TBARS) and diene conjugate (DC) levels, decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Marked macro-vesicular steatosis were detected. Serum TNF-α and ALT, hepatic TG, TBARS and DC levels and steatosis scores decreased in regression period of HFrD-fed rats. Additionally, serum TNF-α, hepatic TG, TBARS and DC levels significantly lower in betaine-treated regressed rats than non-treated regressed group. Our results indicate that betaine treatment may accelerate regression of HFrD-induced hepatic TG accumulation and oxidative stress in rats.

Carnosine decreased oxidation and glycation products in serum and liver of high-fat diet and low-dose streptozotocin-induced diabetic rats.

High-fat diet (HFD) and low-dose streptozotocin (STZ)-treated rats provide useful animal model for type II diabetes mellitus. Oxidative stress and advanced glycation end products (AGEs) play a role in the development of diabetic complications. Carnosine (CAR) has anti-oxidant and anti-glycating properties. We investigated the effects of CAR on oxidation and glycation products in HFD+STZ rats. Rats were fed with HFD (60% of total calories from fat) for 4 weeks, and then a single dose of STZ (40 mg/kg; i.p.) was applied. Rats with blood glucose levels above 200 mg/dl were fed with HFD until the end of the 12th week. CAR (250 mg/kg body weight; i.p.; five times a week) was administered to the rats for the last four weeks. CAR significantly decreased serum triglyceride (TG) (57.7%), cholesterol (35.6%) levels and hepatic marker enzyme activities of HFD+STZ rats. It significantly reduced serum reactive oxygen species (ROS) (23.7%), AGEs (13.4%) and advanced oxidized protein products (AOPP) (35.9%) and hepatic TG (59%), ROS (26%), malondialdehyde (MDA) (11.5%), protein carbonyl (PC) (19.2%) and AGE (20.2%) levels. Liver steatosis and hepatocyte ballooning were also significantly reduced. However, CAR treatment did not alter serum glucose and blood glycated haemoglobin and hepatic anti-oxidant enzyme activities/mRNA expressions in HFD+STZ rats. Our results indicate that CAR decreased accumulation of oxidation and glycation products, such as MDA, AGE, AOPP and PC in the serum and liver and ameliorated hepatic dysfunction in HFD+STZ rats. This effect may be related to its anti-oxidative, anti-glycating, and anti-lipogenic potential.

Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin.

Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic, exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase 1 HO-1) induction influenced kidney and vascular function in GM-administered rats. GM (100 mg·kg-1·day-1; i.p.) was given to rats alone or together with hemin (20 mg·kg-1 on alternate days; i.p.) for 14 days. Plasma and kidney l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathological examinations of kidney and relaxation and contraction responses of aorta were also examined. GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathological alterations in the kidney. GM elevated HO-1 protein and mRNA expressions, 4-HNE level, and MPO activity and decreased antioxidant enzyme activities and l-arginine levels in the kidney. Decreased relaxation and contraction were detected in the aorta. Hemin restored renal oxidative stress and inflammatory changes together with vascular dysfunction, but did not affect SDMA, BUN, or creatinine levels. We conclude that HO-1 induction may be effective in improving renal oxidative stress, inflammation, and vascular dysfunction mediated by GM.

Vascular endothelial growth factor G+405C polymorphism may contribute to the risk of developing papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Vascular endothelial growth factor (VEGF) is a mediator implicated with cell proliferation, differentiation and migration, and monocyte/macrophage chemotaxis. In present study, we aimed to investigate the relationship between VEGF gene polymorphisms (G+405C, T-460C, and A-2578C) and PTC susceptibility. METHODS: DNA was isolated from peripheral blood leukocytes of 127 patients with PTC and 203 healthy controls. Genotyping was performed by real-time PCR. Association of genotypes with susceptibility of PTC was analyzed with multivariate logistic regression adjusted for age, gender and smoking status. RESULTS AND CONCLUSION: In G+405C polymorphism, the frequencies of C allele (related with increased VEGF production) and combined CG+CC genotype were found to be higher (3.5 and 5-fold, respectively) among patients with PTC than controls (P<.001). However, VEGF T-460C and A-2578C polymorphisms are not associated with PTC risk. There was no relationship between VEGF polymorphisms and clinical/laboratory parameters of PTC. Haplotype analysis demonstrated that there was a strong linkage disequilibrium (LD) between -460/-2578 (D'=.89, r2 =.79), weak LD between +405/-460 (D'=.422, r2 =.035), and +405/-2578 (D'=.43, r2 =.038) locuses. Additionally, the +405/-460/-2578 GTA haplotype was found to be protective, whereas CTA haplotype to be related with increased PTC risk. As a conclusion, we suggest that VEGF G+405C polymorphism is associated with increased risk of PTC.

Carnosine and taurine treatments diminished brain oxidative stress and apoptosis in D-galactose aging model.

D-galactose (GAL) has been used as an animal model for brain aging and antiaging studies. GAL stimulates oxidative stress in several tissues including brain. Carnosine (CAR; ß-alanil-L-histidine) and taurine (TAU; 2-aminoethanesulfonic acid) exhibit antioxidant properties. CAR and TAU have anti-aging and neuroprotective effects. We investigated the effect of CAR and TAU supplementations on oxidative stress and brain damage in GAL-treated rats. Rats received GAL (300 mg/kg; s.c.; 5 days per week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days per week) or TAU (2.5% w/w; in rat chow) for 2 months. Brain malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione transferase (GST) and acetylcholinesterase (AChE) activities were determined. Expressions of B cell lymphoma-2 (Bcl-2), Bax and caspase-3 were also evaluated in the brains by immunohistochemistry. GAL treatment increased brain MDA and PC levels and AChE activities. It decreased significantly brain GSH levels, SOD and GSH-Px but not GST activities. GAL treatment caused histopathological changes and increased apoptosis. CAR and TAU significantly reduced brain AChE activities, MDA and PC levels and elevated GSH levels in GAL-treated rats. CAR, but not TAU, significantly increased low activities of SOD and GSH-Px. Both CAR and TAU diminished apoptosis and ameliorated histopathological findings in the brain of GAL-treated rats. Our results indicate that CAR and TAU may be effective to prevent the development of oxidative stress, apoptosis and histopathological deterioration in the brain of GAL-treated rats.

Circulating levels of apelin, glucagon-like peptide and visfatin in hypercholesterolemic-hyperhomocysteinemic guinea-pigs: their relation with NO metabolism.

The aim of this study was to determine the levels of regulatory peptides apelin, glucagon-like peptide (GLP-1) and visfatin in hypercholesterolemic and hyperhomocysteinemic state and to examine their relation with nitric oxide (NO) metabolism. 32 Male guinea pigs were divided into four groups and each group was fed as follows: (a) commercial chow, (b) cholesterol (chol)-rich diet, (c) methionine (meth)-rich diet, and (d) chol + meth-rich diet. Blood samples were drawn at the end of 10 weeks, and abdominal aorta was dissected for histopathological examination. Serum insulin, GLP-1, apelin, visfatin, and nitrotyrosine concentrations were measured by the manufacturer's kits based on ELISA; asymmetric dimethylarginine (ADMA) and arginine levels were measured by the high performance liquid chromatography. Homocysteine level was measured by the chemiluminescence immunoassay; glucose, total chol and triglyceride levels were measured by the autoanalyzer. The microscopic examination of aorta indicated varying degrees of vascular disturbance in chol- and chol + meth-fed groups. High levels of chol and homocysteine, accompanied with significantly low levels of apelin and GLP-1 were detected in the plasma. Visfatin, ADMA, and nitrotyrosine levels both in chol- and chol + meth-fed groups were significantly higher than those in control animals, whereas arginine and arginine/ADMA ratio were lower. This study indicated that circulating levels of apelin, GLP-1, and visfatin are markedly altered during the development of atherosclerotic changes in close association with chol, homocysteine, NO, and ADMA levels. The measurements of these peptides in serum may help for the diagnosis and follow-up of vascular dysfunction.

Blueberry treatment decreased D-galactose-induced oxidative stress and brain damage in rats.

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 brain damage model. Rats received GAL (300 mg/kg; s.c.; 5 days per week) alone or together with 5 % (BB1) and 10 % (BB2) BB containing chow for two months. Malondialdehyde (MDA),protein carbonyl (PC) and glutathione (GSH) levels, and Cu Zn-superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities as well as acetylcholinesterase (AChE) activities were determined. Expressions of B cell lymphoma-2 (Bcl-2), Bax and caspase-3 were also evaluated in the brain by immunohistochemistry. MDA and PC levels and AChE activity increased, but GSH levels, SOD and GSH-Px activities decreased together with histopathological structural damage in the brain of GAL-treated rats. BB treatments, especially BB2 reduced MDA and PC levels and AChE activity and elevated GSH levels and GSH-Px activity. BB1 and BB2 treatments diminished apoptosis and ameliorated histopathological findings in the brain of GAL-treated rats. These results indicate that BB partially prevented the shift towards an imbalanced prooxidative status and apoptosis together with histopathological amelioration by acting as an antioxidant (radical scavenger) itself in GAL-treated rats.

Effect of rosiglitazone on asymmetric dimethylarginine metabolism in thioacetamide-induced acute liver injury.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is metabolized in the liver by dimethylarginine dimethylaminohydrolase (DDAH). We aimed to investigate the effect of rosiglitazone, a peroxysome proliferator-activated receptor-gamma (PPAR-γ) agonist, on ADMA metabolism in acute liver injury. Male Sprague Dawley rats were injected thioacetamide (TAA; 500mgkg(-1)) intraperitoneally in order to induce acute liver injury. ADMA, SDMA and arginine levels were determined in plasma by the HPLC. Liver DDAH activity and malondialdehyde (MDA) levels were measured by spectrophotometric procedures. TAA injection caused marked increases in ALT and AST activities. Plasma ADMA levels were increased, while arginine levels and arginine/ADMA ratio were decreased. Liver DDAH activity was significantly diminished and MDA levels were elevated. In another group of animals which were treated with a PPAR-γ agonist (rosiglitazone, 5mgkg(-1)) daily via gastric intubation for a week prior to TAA injection, significant recoveries in DDAH activity and antioxidant status were observed when compared with solely TAA-injected animals. Rosiglitazone pretreatment improved the plasma arginine/ADMA ratio. Our findings indicated that PPAR-γ agonist rosiglitazone beneficially influenced hepatic metabolism of ADMA in TAA-induced acute liver damage.

Effect of olive leaf extract treatment on doxorubicin-induced cardiac, hepatic and renal toxicity in rats.

Doxorubicin (DOX) is known to increase in oxidative stress in several organs. Olive leaf extract (OLE) has potent antioxidant effects; therefore, we evaluated the ability of OLE to reduce DOX-induced toxicity in the heart, liver, and kidneys of rats. DOX (30mg/kg; i.p.) was administered to rats, which were sacrificed 4 days after DOX. The rats received OLE (6 and 12mL/L in drinking water) for 12 days. Serum cardiac troponin I (cTnI) levels, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities, urea and creatinine levels, as well as prooxidant and antioxidant status in organs were measured. DOX was found to increase serum markers that indicate tissue injury, malondialdehyde (MDA), diene conjugate (DC), and protein carbonyl (PC) levels, and to decrease glutathione (GSH) levels in organs. Histopathologic changes were also evaluated. OLE, especially OLE 1000, led to decreases in serum cTnI and urea levels, ALT and AST activities, and amelioration in histopathologic findings. Decreases in MDA, DC, and PC, and increases in GSH levels were observed in organs of DOX-treated rats due to OLE. We conclude that OLE treatment may be effective in decreasing DOX-induced cardiac, hepatic and renal oxidative stress and injury.

Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer.

The etiopathogenesis of thyroid cancer has not been clearly elucidated although the role of chronical inflammation and the imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with papillary thyroid cancer (PTC), and to evaluate the relationship between genotypes and clinical/laboratory manifestation of PTC. Tumor necrosis factorα (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 A-1082G (rs 1800896) single nucleotide polymorphisms in DNA from peripheral blood leukocytes of 190 patients with thyroid cancer and 216 healthy controls were investigated by real-time PCR combined with melting curve analysis. There was no notable risk for PTC afflicted by TNFα-308 and IL-6-174 alone. However, IL-10-1082 G allele frequency were higher among PTC patients than healthy controls (p=0.009). The patients with IL-10-1082 GG geotype have twofold increased risk of developing thyroid cancer according to AA genotype (OR 2.07, 95% CI 1.21-3.55). In addition, the concomitant presence of IL-10-1082 G allele (GG+AG genotypes) together with IL-6 -174 GG genotype has a nearly twofold increased risk for thyroid cancer (OR 1.75 with 95% CI 1.00-3.05, p=0.049). We suggest that IL-10-1082 G allele is associated with an increased risk of PTC. The polymorphism of IL-10 gene can improve our knowledge about the pathogenesis of PTC, and could provide to estimate people at the increased risk for PTC.

Resveratrol improves high-fructose-induced vascular dysfunction in rats.

High levels of fructose in the diet results in metabolic abnormalities and vascular disorders. In this study, the effect of resveratrol (RES) on vascular relaxation and contraction responses was examined in the aorta of high-fructose (HFr)-fed rats. mRNA expressions of aortic sirtuin 1 (SIRT1), GLUT5, and aldolase B were also investigated. Rats were given fructose (30%) and (or) RES (50 mg · L(-1)) in their drinking water for 8 weeks. In the HFr-fed rats, plasma levels of arginine and the ratio of arginine:asymmetric dimethylarginine (ADMA) decreased, whereas leptin levels increased. Decreased relaxation and increased contractile responses were detected in aortic rings. However, the aortic expressions of SIRT1, GLUT5, and aldolase B remained unchanged. RES treatment restored HFr-induced vascular dysfunction without improvements in insulin resistance. Treatment of HFr-fed rats with RES increased plasma levels of arginine and the L-arginine:ADMA ratio, and decreased plasma levels of leptin. RES increased SIRT1 expression, but decreased the expression of GLUT5 and aldolase B in aortas from HFr-fed rats. These results suggest that RES contributes to the restoration of HFr-induced vascular dysfunction in rats, at least in part, by up-regulation of SIRT 1 and down-regulation of GLUT5 and aldolase B in the aorta. Moreover, RES may have a positive influence on vasculature by partly restoring the plasma arginine:ADMA ratio and leptin levels.

Effects of Ginkgo biloba extract on spinal cord ischemia-reperfusion injury in rats.

BACKGROUND: We aimed to assess the biochemical and histopathologic effects of Ginkgo biloba extract (EGb) in an ischemia-reperfusion (IR) model of spinal cord ischemia induced by cross-clamping of the infrarenal abdominal aorta. METHODS: A total of 24 Sprague-Dawley rats were divided into 3 groups as group 1: control (sham laparotomy), group 2: IR, and group 3: IR+EGb treatment (IR+T) group. All subjects were euthanized 2 days postsurgery and their spinal cords were removed. Tissue malondialdehyde, superoxide dismutase, glutathione (GSH), and glutathione peroxidase levels were measured, and the spinal cord tissue samples were examined histopathologically. RESULTS: No significant difference was detected in ischemia markers between control, IR, and IR+T groups, with the exception of GSH, which was significantly lower in the IR group. GSH levels in group 1 and group 3 were similar. The group 2 displayed significant ischemic damage to the medulla spinalis. This damage was less pronounced in group 3 compared with group 2 only, but in extent and intensity comparable with the controls. CONCLUSIONS: Although we were not able to demonstrate a uniform effect of EGb on biochemical markers of IR injury, the histopathologic data appear to show a protective effect conferred on the spinal cord tissue by EGb.

ICAM1 K469E and E-selectin S128R polymorphisms could predispose to increased autoantibody production and TSH suppression in Graves' disease.

The etiopathogenesis of Graves' disease (GD) has not been clearly elucidated although the role of chronical inflammation and endothelial dysfunction has been established. Adhesion molecules such as intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and E-selectin are secreted from vascular endothelium and promote accumulation of leukocytes in damaged endothelial areas. This study examined the possible association of ICAM1 (G241R and K469E), VCAM1 (T-1591C and T-833C), and E-selectin (S128R) single nucleotide polymorphisms (SNPs) with the occurrence of GD. ICAM1 (G241R and K469E), VCAM1 (T-1591C and T-833C), and E-selectin (S128R) SNPs in DNA from peripheral blood leukocytes of 171 patients with GD and 259 healthy controls were investigated by real-time PCR combined with melting curve analysis using fluorescence-labeled hybridization probes. We did not find significant differences in the distributions of studied polymorphisms, nor in the haplotype frequencies between patients with GD and healthy control. However, the anti-TPO levels in E-selectin 128R allele carrying subjects (SR + RR) were higher than S128S genotype (p < 0.05). In addition, the decline of TSH levels was more prominent in ICAM1 469 E carrying subjects (KE + EE) in comparison with wild homozygotes (p < 0.05). Although there is not association between ICAM1 (G241R and K469E), VCAM1 (T-1591C and T-833C), and E-selectin (S128R) SNPs and susceptibility to GD, higher anti-TPO in E-selectin 128 SR + RR, and lower TSH in ICAM1 469 KE + EE subjects suspect that these genotypes are prone to increased antithyroid autoantibody production with more accentuated TSH suppression in GD. Further studies with a larger cohort, analyzing other polymorphisms in ICAM, VCAM1 and E-selectin genes are necessary to support our observations.

The protection by heme oxygenase-1 induction against thioacetamide-induced liver toxicity is associated with changes in arginine and asymmetric dimethylarginine.

This study was designed to investigate the role of HO-1 induction in prevention of thioacetamide (TAA)-induced oxidative stress, inflammation and liver damage. The changes in hepatic dimethylarginine dimethylaminohydrolase (DDAH) activity as well as plasma arginine and asymmetric dimethylarginine (ADMA) levels were also measured to evaluate nitric oxide (NO) bioavailability. Rats were divided into four groups as control, hemin, TAA and hemin + TAA groups. Hemin (50 mg kg(-1) , i.p.) was injected to rats 18 h before TAA treatment to induce HO-1 enzyme expression. Rats were given TAA (300 mg kg(-1) , i.p.) and killed 24 h after treatment. Although TAA treatment produced severe hepatic injury, upregulation of HO-1 ameliorated TAA-induced liver damage up to some extent as evidence by decreased serum alanine transaminase, aspartate transaminase and arginase activities and histopathological findings. Induction of HO-1 stimulated antioxidant system and decreased lipid peroxidation in TAA-treated rats. Myeloperoxidase activity and inducible NO synthase protein expression were decreased, whereas DDAH activity was increased by hemin injection in TAA-treated rats. Induction of HO-1 was associated with increased arginine levels and decreased ADMA levels, being the main determinants of NO production, in plasma of TAA-treated rats. In conclusion, our results indicate that HO-1 induction alleviated increased oxidative stress and inflammatory reactions together with deterioration in NO production in TAA-induced liver damage in rats.