Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT

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.

Effects of Traditional Chinese Medicine for Vaginal Lavage Combined with Psychological Intervention in Postoperative Patients with Cervical Cancer

“…Pharmacological studies show that matrine in Sophora flavescens can effectively sterilize without damaging normal vaginal flora [24]. e dione, dictamnine, and obacunone in Cortex Dictamni have more potent antibacterial, anti-inflammatory, antianaphylaxis, anticancer, and insecticidal pharmacological activities [25][26][27]. Cnidium cnidii, fructus kochiae, and rhizome smilacis glabrae have anti-inflammatory, antiviral, and antitumor effects [28][29][30], and the therapeutic effects are mainly achieved by promoting the apoptosis of corresponding cells.…”

Triterpenoids as Reactive Oxygen Species Modulators of Cell Fate

“…Obacunone (compound 37 , Figure 1 ), a triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, showed anti-inflammatory, antineoplastic, antioxidant, and antifibrotic effects, among various pharmacological effects. 47 However, the mechanism of how compound 37 mediates antifibrotic effects in liver fibrosis models remains unclear. Liver fibrosis is a debilitating human disease, and while various inflammatory pathways are activated, it is known to be accompanied by excessive ROS.…”

Evaluation of the Mechanism of Jiedu Huazhuo Quyu Formula in Treating Wilson’s Disease-Associated Liver Fibrosis by Network Pharmacology Analysis and Molecular Dynamics Simulation

“…Luteolin exerts its therapeutic effect on liver fibrosis by promoting extracellular matrix degradation in fibrotic liver tissue and strongly enhancing the hepatic regeneration capability [ 37 ]. Obacunone is able to alleviate liver fibrosis by enhancing the antioxidant effects of glutathione peroxidase 4 (GPx-4) and inhibiting EMT [ 38 ]. These findings suggest that JHQ may exert its anti-liver fibrosis effect via these active compounds.…”