Clonidine ameliorates cisplatin-induced nephrotoxicity: impact on OCT2 and p38 MAPK pathway.

OBJECTIVES: To explore clonidine (Clon) nephroprotective effects as an inhibitor of organic cationic transporter 2 (OCT2) and p38 mitogen-activated protein kinase (p38 MAPK) against cisplatin (CP)-induced nephrotoxicity. OCT2 is mainly responsible for renal accumulation of CP. Clon has been recently recognized as an OCT2 inhibitor and exerts beneficial effects on renal function and p38 MAPK. This study further investigates its underlying anti-inflammatory, antioxidative and antiapoptotic effects. METHODS: Rats were randomly assigned into five groups: (I) CON, (II) CP, (III) CP + Clon 0.125, (IV) CP + Clon 0.25, (V) CP + Clon 0.5, and (VI) Clon 0.5 alone. Clon was administered orally at 0.125, 0.25 and 0.5 mg/kg/day dosages for 10 days. On day 7, rats in groups from (II) to (V) received a single intraperitoneal injection of CP (10 mg/kg). KEY FINDINGS: Clon 0.25 mg/kg displayed the best nephroprotective outcomes, justified by the significant amelioration of parameters like renal function, oxidative stress, and inflammatory status, as well as modulated the OCT2 expression, phosphorylation of p38 and p53, compared with Clon 0.125 and 0.5 mg/kg. CONCLUSION: This study suggests the promising nephroprotective impact of Clon as an OCT2 inhibitor against CP nephrotoxicity and its proficient role in attenuating oxidative stress, inflammatory status and apoptotic status.

Eugenol modulates insulin sensitivity by upregulating insulin receptor substrate-2 in non-alcoholic fatty liver disease in rats.

OBJECTIVES: The purpose of this study was to estimate the possible modulatory effect of Eugenol (EUG) on insulin resistance (IR) and liver fibrosis in high-fat diet (HFD)-induced experimental non-alcoholic fatty liver disease (NAFLD) in rats. It has been shown that EUG, a natural phenolic compound, has anti-hyperglycaemic, antioxidant and anti-inflammatory actions. METHODS: For 8 consecutive weeks, standard rat chow diet (control group, EUG only treated group) or HFD (HFD group and HFD+EUG-treated group) were fed to rats daily. HFD+EUG-treated group and EUG only treated group were administered EUG (10 mg/kg) orally three times per week. Various indices of hepatotoxicity, oxidative stress, indicators of inflammation and liver fibrosis were investigated. KEY FINDINGS: HFD-induced liver transaminases and triglycerides (TGs) were significantly decreased and histopathological lesions were improved with EUG treatment. EUG significantly improved IR evoked by HFD, as demonstrated by Homeostasis model assessment for insulin resistance (HOMA-IR) and increased insulin receptor substrate-2 (IRS-2) sensitivity. In addition, EUG improved oxidative stress damage elicited by HFD as shown by the restoration of reduced glutathione (GSH) level and nuclear factor erythroid-2-related factor 2 (Nrf-2) expression and plummeting lipid peroxidation. Further, EUG lessened pro-inflammatory cytokines surge [tumour necrosis factor-α (TNF-α) and IL-6] via inhibiting nuclear factor-κB (NF-κB) stimulation. As markers of fibrosis, EUG reduced collagen accumulation and smooth muscle alpha actin (SMaA) and TGF-ß expression. CONCLUSIONS: EUG may have protective effect against progression of fibrosis in NAFLD. The antifibrotic effect of EUG is probably due to EUG's antioxidant, anti-inflammatory and anti-hyperglycaemic.