Resveratrol Alleviates Hepatic Fibrosis in Associated with Decreased Endoplasmic Reticulum Stress-Mediated Apoptosis and Inflammation

Abstract

Abstract—Hepatic fibrosis (HF) is the typical response to chronic liver disease and is characterized by deposition of abundant extracellular matrix. The aim of the present study was to investigate the protective effect of resveratrol (RSV) in a CCl4-induced rat model of HF. We demonstrate that the administration of RSV effectively improves liver function and ameliorates liver fibrosis by reducing collagen deposition and reversing the expression of COL1A1 and PPAR-γ. Treatment efficacy of RSV could be attributed to reversed epithelial-mesenchymal transition progress with upregulated expression of E-cadherin and downregulated N-cadherin, vimentin, and α-SMA. Moreover, RSV significantly decreased the levels of endoplasmic reticulum stress (ERS)-related proteins CHOP; Bip; cleaved caspase-3, caspase-7, and caspase-12; Bax; and Bak while promotes the expression of anti-apoptosis protein Bcl2. The important role of ERS in HF was confirmed by using 4-PBA, an ERS inhibitor, which markedly ameliorated CCl4-induced HF. Further, mechanistic studies demonstrated that RSV significantly decreased CCl4-induced transforming growth factor-β synthesis and inflammatory factor (tumor necrosis factor-α and interleukin-6) expression and reduced the inflammation of hepatic stellate cells by inhibiting the NF-κB pathway in vivo and in vitro. In conclusion, the results suggested that RSV ameliorated HF in associated with decreased ERS-induced apoptosis and inflammation in rats.

Emerging Therapeutic Targets for Portal Hypertension

“…Other strategies targeting oxidative stress were based on the inhibition of NADPH, such as GKT137831 [ 161 ], angiotensin blocking agents (discussed in functional targets below). Resveratrol, a natural anti-oxidant with multiple effects on vascular biology, has also been found to decrease portal pressure, decrease fibrosis, and improve NO availability in rats with experimental cirrhosis [ 47 , 162 ].…”

Protective role of resveratrol against VCM-induced hepatotoxicity in male wistar rats

“…As well as protecting cells from oxidative stress, resveratrol also promotes the expression of antioxidative enzymes and their substrates ( Miguel et al, 2021 ; Santos et al, 2021 ). Recently, it has been suggested that resveratrol has hepatoprotection properties through its anti-inflammatory and antioxidant effects ( Chupradit et al, 2022 ; Ma et al, 2022 ; Tong et al, 2022 ). It has also been reported that resveratrol attenuates acetaminophen toxic metabolite N-acetyl-p-benzoquinone-imine and facilitates liver regeneration by modulating the silent mating type information regulation two homolog (SIRT1), tumor protein P53, and Tumor Necrosis Factor-alpha (TNF-α) ( Sener et al, 2006 ; Wang et al, 2015 ).…”

Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways

“…Recent reports have shown that resveratrol can prevent or slow the progression of various brotic diseases, including cardiac brosis [9], pulmonary brosis [10], renal brosis [11], prostate brosis [12] and systemic sclerosis [13]. In liver brosis, resveratrol provides signi cant protection against brosis induced by carbon tetrachloride (CCl 4 ) [14,15], dimethylnitrosamine [16], bile duct ligation [17], and Schistosoma japonicum [18]. In fact, resveratrol reduces portal pressure, HSC activation, in ammatory cell in ltration of liver tissue, and brosis and improves hepatic endothelial function in cirrhotic rats [19].…”

“…In liver fibrosis, resveratrol provides significant protection against fibrosis induced by carbon tetrachloride (CCl 4 ) (Li, Zhang, Zhan, & Zheng, 2021; Ma et al, 2022), dimethylnitrosamine (Abdu & Al-Bogami, 2019), bile duct ligation (ShamsEldeen et al, 2021), and Schistosoma japonicum (Chen et al, 2019). In fact, resveratrol reduces portal pressure, HSC activation, inflammatory cell infiltration of liver tissue, and fibrosis and improves hepatic endothelial function in cirrhotic rats (Izzo et al, 2021).…”

“…Recent reports have shown that resveratrol can prevent or slow the progression of various fibrotic diseases, including cardiac fibrosis (Zivarpour, Reiner, Hallajzadeh, & Mirsafaei, 2022), pulmonary fibrosis (Wang et al, 2021), renal fibrosis (Liu et al, 2019), prostate fibrosis (Vicari et al, 2020), and systemic sclerosis (Yao et al, 2020). In liver fibrosis, resveratrol provides significant protection against fibrosis induced by carbon tetrachloride (CCl 4 ) (Li, Zhang, Zhan, & Zheng, 2021; Ma et al, 2022), dimethylnitrosamine (Abdu & Al‐Bogami, 2019), bile duct ligation (ShamsEldeen et al, 2021), and Schistosoma japonicum (Chen et al, 2019). In fact, resveratrol reduces portal pressure, HSC activation, inflammatory cell infiltration of liver tissue, and fibrosis and improves hepatic endothelial function in cirrhotic rats (Izzo et al, 2021).…”