ABSTRACT
Hepatic fibrosis results from chronic liver damage and is characterized by excessive accumulation of extracellular matrix (ECM). In this study, we showed that dendropanoxide (DPX), isolated from Dendropanax morbifera, had anti-fibrotic effects on hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. DPX suppressed mRNA and protein expression of α-SMA, fibronectin, and collagen in activated HSCs. Moreover, DPX (40 mg/kg) treatment significantly lowered levels of liver injury markers (aspartate aminotransferase and alanine transaminase), expression of fibrotic markers, and deposition of ECM in a carbon tetrachloride-induced mouse model. Anti-fibrotic effects of DPX were comparable to those of silymarin in a hepatic fibrosis mouse model. As a possible mechanism of anti-fibrotic effects, we showed that DPX inhibited autophagosome formation (LC3B-II) and degradation of p62, which have important roles in HSC activation. These findings suggest that DPX inhibits HSC activation by inhibiting autophagy and can be utilized in hepatic fibrosis therapy.
Subject(s)
Hepatic Stellate Cells/drug effects , Liver Cirrhosis/prevention & control , Triterpenes/pharmacology , Animals , Araliaceae/chemistry , Carbon Tetrachloride Poisoning , Cell Line , Dose-Response Relationship, Drug , Humans , Liver Cirrhosis/chemically induced , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Plant Components, Aerial/chemistry , Protective Agents/chemistry , Protective Agents/pharmacology , Random Allocation , Silymarin/pharmacology , Triterpenes/administration & dosage , Triterpenes/chemistryABSTRACT
The aim of this study was to investigate the protective effects of dendropanoxide (DPx) isolated from Dendropanax morbifera against cis-diamminedichloroplatinum (II) (CDDP)-induced nephrotoxicity in NRK-52E cells and in Sprague-Dawley rats. DPx was administered to Sprague-Dawley rats by oral gavage (5 and 10 mg/kg) for 7 consecutive days, 24 h after intraperitoneal injection with CDDP (6 mg/kg). All rats were euthanized 24 h after the last DPx administration, and histopathological damage, acute kidney injury (AKI) biomarkers, inflammatory cytokines, and oxidative damages were evaluated. DPx (5 and 10 µg/mL) was found to protect against CDDP-induced cytotoxicity and apoptotic cell death in NRK-52E cells. CDDP-induced serum blood urea nitrogen (BUN), creatinine (sCr), and pro-inflammatory cytokines levels were significantly ameliorated by DPx in a dose-dependent manner. Furthermore, excretion of kidney injury molecules (KIM-1), selenium binding protein-1 (SBP-1), and neutrophil gelatinase-associated lipocalin (NGAL) in the urine was significantly reduced in response to DPx administration in CDDP-treated rats. Activities of antioxidant enzymes and lipid peroxidation levels were markedly altered in the kidney of CDDP-treated rats in response to DPx administration. Serum pro-inflammatory cytokine levels were dramatically suppressed by DPx in CDDP-treated rats. DPx also restored renal-cell apoptosis via regulation of AMPK/mTOR signaling in CDDP-treated rats. Our results clearly suggest that DPx ameliorates CDDP-induced nephrotoxicity in vitro and in vivo by inhibiting oxidative stress, inflammation, and apoptosis. Overall, our data demonstrates that DPx may serve as a therapeutic agent in patients with solid tumors to prevent CDDP-induced AKI.