Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic, paralleling the increased prevalence of obesity and diabetes, which are risk factors. In this review, we present the current pre-clinical evidence showing that GLP-1 analogues and DPP4 inhibitors can improve hepatic steatosis. Although some of the effects could be due to overall improvement in metabolic parameters, there are data to support improvements independent of weight loss, as well as direct effects on the hepatocyte in vitro. Multiple hepatocyte signal transduction pathways appear to be activated by GLP-1 and its analogues, with both AMP-activated protein kinase and Akt proposed to be key players in improving hepatic steatosis. However, it is controversial as to whether the pancreatic-type GLP-1 receptor is present or responsible for conferring the GLP-1 signal in the hepatocyte. In total, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies for treatment of NAFLD.

We investigated the anti-carcinogenic effects of a cyclooxygenase-2 inhibitor (Celecoxib) and immunosuppression drugs - Sirolimus (SIR) and Cyclosporine (CsA) - on a rat model of bladder cancer induced by N-butyl-N(4-hydroxibutil)nitrosamine (BBN).There was a statistically significant reduction in the incidence of bladder tumors in the SIR (2 mg/kg/day) and CEL (10 mg/kg/day) groups (37.5 and 12.5%. respectively: p<0.05) vs BBN (65%). with less aggressive histological changes, together with significantly lower levels of TGF-beta 1 and a better redox status (MDA/TAS). SIR 1 mg/kg/day induced a higher nr of tumors. CsA showed no significant effect on bladder carcinogenesis.In conclusion. both Sirolimus (2mg/kg/day) and Celecoxib treatments showed chemopreventive properties for urothehal bladder tumors in rats.

The purpose of this study was to compare the effects of sirolimus (SRL) vs cyclosporine (CsA) concerning the cardiovascular mechanisms hypothetically contributing to hypertension development. Three rat groups were studied: control (vehicle), CsA (5 mg/kg/d), and SRL (1 mg/kg/d). The following parameters were evaluated after 7 weeks of treatment: blood pressured (BP) and heart rate (HR; tail cuff), lipid profile, hematology, plasma and platelet 5-HT and catecholamines (HPLC-ECD), and oxidative equilibrium (serum malondialdehyde [MDA] and total antioxidant status [TAS]). Systolic (SBP) and diastolic blood pressure (DBP) values were higher (P < .001) in both the CsA (146.2 +/- 4.5 and 124.9 +/- 4.5 mm Hg) and SRL (148.9 +/- 4.8 and 126.4 +/- 6.0 mm Hg) groups vs the controls (115.9 +/- 3.3 and 99.1 +/- 2.0 mm Hg). However, HR values were elevated in CsA but not SRL animals. The dyslipidemic pattern of CsA was even more enhanced in the SRL group, with significantly higher low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels vs CsA (P < .05); red blood cells, hematocrit, hemoglobin concentration, mean platelet volume, and platelet distribution width were significantly (P < .05) higher in the SRL vs CsA group. The pro-oxidative profile (increased MDA/TAS) in the CsA group was not reproduced in the SRL cohort. While plasma and platelet 5-HT were elevated in SRL rats, catecholamine content was higher in CsA animals. In conclusion, this study demonstrated that CsA and SRL produce identical hypertensive effects. However, while CsA promotes oxidative stress and sympathetic activation, SRL mainly interferes with lipid profile and hematological parameters. Thus, the hypertensive effects of CsA, a calcineurin inhibitor, and of SRL, an mTOR inhibitor, are associated with impairment of distinct cardiovascular pathways.

This study aimed to assess the cardio-renal effects of rhEPO therapy on an animal model of moderate chronic renal failure (CRF). Four groups (n=7) of male rat were evaluated during a 12-week follow up period: control: rhEPO: 50 IU/Kg/wk. CRF: two stage 3/4 nephrectomy. CRF+ rhEPO (start after the 3rd wk of surgery). Renal function, haematology and serum inflammation and redox status were assessed. rhEPO treatment was able to partially attenuate renal function markers, totally correct anaemia, also showing a proliferative and antioxidant action, due to increased serum TGF-beta 1 and decreased 3-NT. In conclusion, rhEPO therapy might be recommended in moderate CRF stages in order to efficiently correct not only the underlying anaemia but also the deleterious cardio-renal effects, due to a proliferative and antioxidant renoprotective action.

To evaluate possible associations between serum adiponectin. CRP, PON1 activity and oxidative stress in a population sample from Portugal. The following serum parameters were assessed in a 121 patient's population: lipid profile. adiponectin and CRP levels. PON activity and lipid peroxidation (MDA content).Low adiponectin levels and PON1 activity were associated with higher MDA content and were shown in the populations with higher BMI (> 30 kg/m(2)) and CRP content (>= 2 mg/l). suggesting its association with oxidative stress obesity and inflammation in atherosclerosis.In conclusion, our results, yet preliminary, seem to support the hypothesis that adiponectin may modulate PON1 activity, which may partly explain its anti-inflammatory and antioxidant effects on atherogenesis.

Objective: In the present study we evaluated the effect of exercise on the plasma levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory molecule uric acid in the Zucker diabetic fatty (ZDF) rats that are more prone to develop type 2 diabetes mellitus.Methods: Sixteen obese ZDF(Gmi fa/fa) rats (8 wk old, 228.40 +/- 4.05 g) were randomly assigned to one of two groups (n = 8 each): an exercise-trained group and a sedentary one. In addition, 16 lean ZDF (Gmi +/+) rats (8 wk old, 199.00 +/- 3.50 g) were subjected to identical sedentary and exercise conditioning (n = 8 each). Initially, rats swam 15 min/d (5 d/wk) in a 36 degrees C bath. The exercise protocol was gradually increased by 15 min/d until a swimming period of 1 h/d (1 wk) was attained. Thereafter, rats swam 1 h/d, 3 d/wk, for an additional period of 11 wk. Rats were sacrificed 48 h after the last training period and the blood and pancreas were collected. Circulating levels of glucose, glycosylated hemoglobin, total cholesterol, triglycerides, insulin, uric acid, IL-6, and TNF-alpha were assessed. The concentrations of proinflammatory cytokines in the pancreas were also evaluated.Results: In the diabetic ZDF (fa/fa) rats, exercise decreased hyperuricemia (-37.3%) and IL-6 and TNF-alpha levels (-16.9% and -12.7% respectively) and maintained the weight of the pancreas at near normal. Immunohistochemistry revealed a marked decrease in the expression of TNF-alpha and IL-6 in the pancreatic islet cells of ZDF (fa/fa) rats.Conclusion: These results indicate that aerobic exercise is anti-inflammatory in nature. (C) 2009 Published by Elsevier Inc.

Physical exercise may improve the metabolic and haemodynamic responses, but the beneficial effects seem to depend on intensity, duration and muscular mass recruitment, which may vary between different types of protocols. This study was performed to evaluate the effects of two distinct moderate/long-term aerobic training protocols in the normal Wistar rat, the treadmill running and the swimming, on several important parameters related to cardiovascular (CV) physiological adaptations, namely: lipid profile, haemorheological measures, lipid peroxidation, peripheral serotonergic system (SS) modulation and sympathetic nervous system (SNS) activation.In both groups under training an HDL-c increment versus the sedentary control was demonstrated. There was a noticeable increase in ADP-induced platelet aggregation in the exercised rats, together with higher PDW and MPV values. The RBC patterns were altered in both groups under training; in the swimming one, however, significantly higher RBC and HCT and lower MCH and MCHC values were found, suggesting renovation of the RBCs. Plasma and platelet SS measures were generally higher in both groups under training, being noticeably relevant the 5-HT and 5-HIAA increment in the treadmill. In opposition, concerning the plasma and platelet NE and E concentrations, the rise was remarkably higher in the rats under a swimming protocol.In conclusion, this study demonstrates that, despite the similar beneficial effects on lipid profile, different aerobic exercise protocols may produce distinct CV physiological adaptations. Therefore, treadmill running was more influent than swimming concerning peripheral SS modulation while swimming was more important on SNS activation, thus recommending a judicious choice of the protocol to be tested in works which make use of rat models of exercise to study physiological or pathophysiological conditions.

The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n = 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn + CsA therapy showed, when compared with the CsA group, total prevention of CsA-induced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA + Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 ± 1.4 vs 12.78 ± 3.63 μmol/L; P < .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.