sildenafil-citrate and Cholestasis

Intrahepatic cholestasis is a common pathological condition of several types of liver disorders. In this study, we aimed to investigate the regulatory effects of quercetin (QU) on selected phosphodiesterase inhibitors against alpha-naphthyl isothiocyanate (ANIT)-induced acute intrahepatic cholestasis.. Cholestasis was induced in Wistar albino rats by ANIT as a single dose (60 mg/kg; P·O.). QU (50 mg/kg, daily, P·O.), sildenafil (Sild; 10 mg/kg, twice daily, P·O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for 10 days for their antioxidant, anti-inflammatory, and anti-pyroptotic effects.. ANIT produced a prominent intrahepatic cholestasis as evidenced by a significant alteration in liver functions, histological structure, inflammatory response, and oxidative stress biomarkers. Furthermore, up-regulation of NF-κB-p65, TLR4, NLRP3, cleaved caspase-1, IKK-β, and IL-1β concurrently with down-regulation of Nrf-2, HO-1, and PPAR-γ expressions were observed after ANIT. QU, Sild, or PTX treatment significantly alleviated the disturbance induced by ANIT. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of QU with Sild or PTX significantly improved liver defects due to ANIT as compared to the individual drugs.. Combined QU with Sild or PTX exhibited promising hepatoprotective effects and anti-cholestatic properties through modulation of Nrf2/ARE, TLR4/NF- κB, and NLRP3/IL-1β signaling pathways.

Topics: Cholestasis; Cholestasis, Intrahepatic; Interleukin-1beta; Liver; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pentoxifylline; Quercetin; Rats; Signal Transduction; Sildenafil Citrate; Toll-Like Receptor 4

Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-β content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Carbazoles; Cholestasis; Cytoprotection; Disease Models, Animal; Histone Deacetylase Inhibitors; Inflammation Mediators; Ligation; Liver; Liver Cirrhosis, Biliary; Male; Oxidative Stress; Protective Agents; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Sirtuin 1; Up-Regulation