Combination of Antioxidant Cocktail and Pregabalin in the Management of Pain in Chronic Pancreatitis After Ductal Clearance: A Randomized, Double-Blinded, Placebo-Controlled Trial
2015
BACKGROUND AND AIMS: Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the anti-fibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSC). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. METHODS: Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. RESULTS: Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. PSTAT3 and downstream signals were downregulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. CONCLUSIONS: Sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a novel strategy for antifibrotic drug discovery. Combination of Antioxidant Cocktail and Pregabalin in the Management of Pain in Chronic Pancreatitis After Ductal Clearance: A Randomized, Double-Blinded, Placebo-Controlled Trial R. Talukdar, S. Lakhtakia, R. Pradeep, G. V. Rao, and D. N. Reddy
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