A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver

Abstract

NADPH oxidases (NOXs) are a predominant mediator of redox homeostasis in hepatic stellate cells (HSCs), and oxidative stress plays an important role in the pathogenesis of liver fibrosis. Ursolic acid (UA) is a pentacyclic triterpenoid with various pharmacological activities, but the molecular targets and underlying mechanisms for its antifibrotic effect in the liver remain elusive. This study aimed to computationally predict the molecular interactome and mechanistically investigate the antifibrotic effect of UA on oxidative stress, with a focus on NOX4 activity and cross-linked signaling pathways in human HSCs and rat liver. Drug–drug interaction via chemical–protein interactome tool, a server that can predict drug–drug interaction via chemical–protein interactome, was used to predict the molecular targets of UA, and Database for Annotation, Visualization, and Integrated Discovery was employed to analyze the signaling pathways of the predicted targets of UA. The bioinformatic data showed that there were 611 molecular proteins possibly interacting with UA and that there were over 49 functional clusters responding to UA. The subsequential benchmarking data showed that UA significantly reduced the accumulation of type I collagen in HSCs in rat liver, increased the expression level of MMP-1, but decreased the expression level of TIMP-1 in HSC-T6 cells. UA also remarkably reduced the gene expression level of type I collagen in HSC-T6 cells. Furthermore, UA remarkably attenuated oxidative stress via negative regulation of NOX4 activity and expression in HSC-T6 cells. The employment of specific chemical inhibitors, SB203580, LY294002, PD98059, and AG490, demonstrated the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in the regulatory effect of UA on NOX4 activity and expression. Collectively, the antifibrotic effect of UA is partially due to the oxidative stress attenuating effect through manipulating NOX4 activity and expression. The results suggest that UA may act as a promising antifibrotic agent. More studies are warranted to evaluate the safety and efficacy of UA in the treatment of liver fibrosis.

Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways

“…As a traditional Chinese medicine, UA can inhibit the proliferation of activated HSCs, induce apoptosis, and protect liver cells to exert anti-fibrotic effects [ 41 ]. We conducted a preliminary exploration of the target of UA in HSCs and found that UA can inhibit the proliferation and migration of HSCs by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, and this result was further verified in vivo.…”

Schisandrin B Prevents Hind Limb from Ischemia-Reperfusion-Induced Oxidative Stress and Inflammation via MAPK/NF-κB Pathways in Rats

“…P38MAPK and ERK1/2 may regulate oxidative stress and inflammatory responses [34, 35]. It is known that many I/R injury models elicited the activation of p38MAPK and ERK1/2 pathways [36–38].…”

Protective Effect of Ursolic Acid on the Intestinal Mucosal Barrier in a Rat Model of Liver Fibrosis

“…Other researchers subsequently corroborated that UA selectively induces the apoptosis of activated HSCs without inducing liver or quiescent HSC apoptosis (Wang et al, 2011). Furthermore, we observed that UA inhibited the leptin-mediated expression of the NOX subunits NOX2, P67phox and NOX4 in an activated rat HSC cell line (HSC-T6), resulting in the accumulation of extracellular matrix (ECM) proteins (Wang et al, 2011; He et al, 2015). In addition, the results of another study suggested that UA attenuates experimental colitis in mice via its anti-inflammatory and antioxidant activities (Chun et al, 2014; Liu et al, 2016).…”