The results of the present study suggest that the cardioprotective effect of sitagliptin is mediated partly, but not solely, through the BNP/cGMP/PKG survival signaling pathway.

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Background: Non alcoholic fatty liver disease (NAFLD) is an increasing health problem which affects about 1/3 of the population worldwide, it is strongly associated with metabolic syndrome with oxidative stress and insulin resistance are the mechanisms mostly involved in its pathogenesis. Dipeptidyl peptidase-4 inhibitors are antidiabetic agents expected to have beneficial effects beyond their glycemic control. Aim of the Study:The present work was designed to study the beneficial effects of sitagliptin (a DPP-4I) on a dietary model of NAFLD.Material and Methods: 30 male albino rats were allocated in 3 groups. The effects of sitagliptin, was assessed in groups III. Body weight and blood pressure were recorded and blood samples were tested for total cholesterol, triglycerides and liver transaminases, glucose and insulin levels. Livers for GSH, MDA, TGF-B and DPP-4 activity and for histopatholgical examination. Aortae were removed for in vitro vascular reactivity studies.Results: Induction of NAFLD model by HFD for 20 weeks resulted in significant increase in body weight, blood pressure, liver index and epididymal weight. Significant reduction of these parameters was observed with 4 week treatment with sitagliptin. There was significant increase in all biochemical parametres in HFD fed rats compared to that of normal with significant improvement in sitagliptin treated group. HFD model groups showed notable steatosis, lobular inflammation and fibrosis which was improved with sitagliptin use. Also NAFLD rats developed endothelial dysfunction which was significantly ameliorated in sitagliptin treated group. Conclusion:The results of the present work showed that the DPP4Is have the potential to favorably influence the course of NAFLD process and its complications. DPP4I (sitagliptin) has many beneficial effects including scavenging of free radicals, and enhancing the activity of antioxidant effects. Large clinical trials are needed to determine the effectiveness of DPP-4 inhibitors for the prevention and treatment of NAFLD

BACKGROUND: The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease. Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury. AIM: In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury. METHODS: Twenty-six rats had bile duct ligation co-treated with silymarin and AM1241 for 3 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. RESULTS: Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers. CONCLUSION: In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.

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