Abstract
Obacunone, a limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-fibrosis ones. However, the anti-fibrotic effect of obacunone and the detailed underlying mechanism in liver fibrosis remain unclear. Liver fibrosis is a debilitating disease threatening human health. Transforming growth factor (TGF)-β/P-Smad is a major pathway of fibrosis featured with epithelia mesenchymal transformations (EMT) and collagen depositions, accompanying with excessive oxygen-free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the glutathione peroxidase family that directly inhibits phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of obacunone in mouse liver fibrosis model induced by carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-β. Obacunone demonstrated potent ameliorative effects on liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and vimentin. Obacunone also remarkably suppressed the TGF-β/P-Smad signals and EMT process. Meanwhile, obacunone exerted a potent anti-oxidation effect by reducing the levels of reactive oxygen species (ROS) in both models. The antioxidant effect of obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the therapeutic effect of obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that obacunone is able to attenuate liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-β/P-Smad pathway and EMT process.
Highlights
Since the activated Hepatic stellate cells (HSCs) played a critical role in liver fibrosis [3], we firstly observed the effects of Oba on liver fibrosis in aHSCs
The LX-2 cells were stimulated with 10 ng/mL Transforming growth factor (TGF)-β for 24 h and treated with Oba or not. the protein expression of α-Smooth muscle actin (α-SMA) was effectively inhibited at concentrations of
HSCs are activated with aberrant productions of a variety of fibrogenic factors and extracellular matrix (ECM) depositions [2,3]
Summary
Chronic hepatitis is usually caused by virus hepatitis, nonalcoholic steatitis, alcoholic hepatitis, and autoimmune hepatitis. Liver fibrosis is a type of wound non-healing response under the continuous injury factors characterized by the exaggerated accumulation of extracellular matrix (ECM) and scar formation [2]. Hepatic stellate cells (HSCs) are usually in a rest state under normal conditions, they became aberrantly activated under chronic liver injury and featured with high proliferation and secretions of ECM [3], denoted as myofibroblasts [4]. Understanding the mechanism of HSCs activation is of great value for the development of novel therapeutics for treating hepatic fibrosis
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