Abstract
The activation of hepatic stellate cells (HSCs) is a key component of liver fibrosis. Two antifibrosis pathways have been identified, the reversion to quiescent-type HSCs and the clearance of HSCs through apoptosis. Lipopolysaccharide- (LPS-) induced HSCs activation and proliferation have been associated with the development of liver fibrosis. We determined the pharmacological effects of wild bitter melon (WM) on HSC activation following LPS treatment and investigated whether WM treatment affected cell death pathways under LPS-treated conditions, including ferroptosis. WM treatment caused cell death, both with and without LPS treatment. WM treatment caused reactive oxygen species (ROS) accumulation without LPS treatment and reversed the decrease in lipid ROS production in HSCs after LPS treatment. We examined the effects of WM treatment on fibrosis, endoplasmic reticulum (ER) stress, inflammation, and ferroptosis in LPS-activated HSCs. The western blotting analysis revealed that the WM treatment of LPS-activated HSCs induced the downregulation of the connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), integrin-β1, phospho-JNK (p-JNK), glutathione peroxidase 4 (GPX4), and cystine/glutamate transporter (SLC7A11) and the upregulation of CCAAT enhancer-binding protein homologous protein (CHOP). These results support WM as an antifibrotic agent that may represent a potential therapeutic solution for the management of liver fibrosis.
Highlights
Chronic liver fibrosis is a health problem, characterized by severe morbidity and significant mortality [1,2,3]. e underlying physiology of chronic liver fibrosis has been associated with the rapid activation and transdifferentiation of quiescent hepatic stellate cells (HSCs) fibrogenic myofibroblast-like cells following liver injury or the development of liver fibrosis [4, 5], resulting in cell proliferation, migration, extracellular matrix (ECM) accumulation [6], contraction, chemotaxis, and inflammatory signaling [7]
Our results showed that Wild bitter melon (WM) treatment induced reactive oxygen species (ROS) overproduction in HSCs relative to untreated cells (Figures 1(a) and 1(b))
Decreased HSC viability was detected after treatment with 20 μg/ml WM for 24 h compared with untreated cells (Figure 1(c)). ese results indicated that WM treatment induced ROS accumulation and cell death
Summary
Chronic liver fibrosis is a health problem, characterized by severe morbidity and significant mortality [1,2,3]. e underlying physiology of chronic liver fibrosis has been associated with the rapid activation and transdifferentiation of quiescent HSCs fibrogenic myofibroblast-like cells following liver injury or the development of liver fibrosis [4, 5], resulting in cell proliferation, migration, extracellular matrix (ECM) accumulation [6], contraction, chemotaxis, and inflammatory signaling [7]. E underlying physiology of chronic liver fibrosis has been associated with the rapid activation and transdifferentiation of quiescent HSCs fibrogenic myofibroblast-like cells following liver injury or the development of liver fibrosis [4, 5], resulting in cell proliferation, migration, extracellular matrix (ECM) accumulation [6], contraction, chemotaxis, and inflammatory signaling [7]. The full impact of WM on human health has not been thoroughly demonstrated, and systematic clinical studies remain necessary to establish the efficacy and safety of WM extract use in patients. Both in vitro and in vivo studies have demonstrated that bitter melon may elicit toxic or adverse effects under various conditions [53]
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