Resveratrol suppresses cholestasis‐induced liver injury and fibrosis in rats associated with the inhibition of TGFβ1–Smad3–miR21 axis and profibrogenic and hepatic injury biomarkers

Abstract

Cholestasis caused by slowing or blockage of bile flow is a serious liver disease that can lead to liver fibrosis and cirrhosis. The link between transforming growth factor beta 1 (TGFβ1), Smad family member 3 (Smad3), and microRNA 21 (miR21) in bile duct ligation (BDL)‐induced liver fibrosis in the presence and absence of the anti‐inflammatory and antioxidant compound, resveratrol (RSV), has not been previously studied. Therefore, we tested whether RSV can protect against BDL‐induced liver fibrosis associated with the inhibition of the TGFβ1–Smad3–miR21 axis and profibrogenic and hepatic injury biomarkers. The model group of rats had their bile duct ligated (BDL) for 3 weeks before being killed, whereas, the BDL‐treated rats were separated into three groups that received 10, 20, and 30 mg/kg RSV daily until the end of the experiment. Using light microscopy and ultrasound examinations, we documented in the BDL group, the development of hepatic injury and fibrosis as demonstrated by hepatocytes necrosis, bile duct hyperplasia, collagen deposition, enlarged liver with increased echogenicity, irregular nodular border and dilated common bile duct, which were more effectively inhibited by the highest used RSV dosage. In addition, RSV significantly (p ≤ 0.0027) inhibited BDL‐induced hepatic TGFβ1, Smad3, miR21, the profibrogenic biomarker tissue inhibitor of metalloproteinases‐1 (TIMP‐1), malondialdehyde (MDA), interleukin‐17a (IL‐17a), and blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. These findings show that RSV at 30 mg/kg substantially protects against BDL‐induced liver injuries, which is associated with the inhibition of TGFβ1‐Smad3‐miR21 axis, and biomarkers of profibrogenesis, oxidative stress, and inflammation.

Roles of MicroRNA-21 in Skin Wound Healing: A Comprehensive Review

“…Increasing evidence has demonstrated the potential value of miR-21 in organ injuries, i.e., cerebral injury (Yan et al, 2021), myocardial ischemia/reperfusion injury (Yuan and Fu 2021), and liver injury (ShamsEldeen et al, 2021). Besides, numerous studies have also identified the critical roles of miR-21 in cutaneous damage and wound healing (Abdel-Gawad et al, 2021;Ma et al, 2020).…”

“…As reported, miR-21 may regulate multiple target genes, including phosphatase and Tensin Homolog (PTEN), Transcription Factor Dp Family Member 3 (TFDP3), HMG-Box Transcription Factor 1 (HMG-Box Transcription Factor 1), Fatty Acid Binding Protein 7 (Fatty Acid Binding Protein 7), Hypoxia-inducible factor 1-alpha (HIF-α), Programmed Cell Death 4 (PDCD4), Transforming growth factor-beta (TGF-β), SMAD Family Member 7 (SMAD), Interleukin 12 (IL-12), and Tissue inhibitors of metalloproteinases 3 (TIMP-3), etc ( Zhang T et al, 2020 ). Increasing evidence has demonstrated the potential value of miR-21 in organ injuries, i.e., cerebral injury ( Yan et al, 2021 ), myocardial ischemia/reperfusion injury ( Yuan and Fu 2021 ), and liver injury ( ShamsEldeen et al, 2021 ). Besides, numerous studies have also identified the critical roles of miR-21 in cutaneous damage and wound healing ( Abdel-Gawad et al, 2021 ; Ma et al, 2020 ).…”

MiR-155 Dysregulation Is Associated with the Augmentation of ROS/p53 Axis of Fibrosis in Thioacetamide-Induced Hepatotoxicity and Is Protected by Resveratrol

“…Previous reports documented a beneficial role of resveratrol on the liver. For example, resveratrol (i) inhibits liver steatosis [ 22 ]; (ii) inhibits the proliferation of rat HSCs [ 23 ]; (iii) inhibits liver p53 gene expression in paracetamol-mediated acute hepatic injury in rats [ 24 ]; (iv) inhibits lipopolysacharride-induced inflammation and hepatic fibrosis in mice [ 25 ]; (v) suppresses cholestasis-induced liver injury and fibrosis [ 26 ]; and (vi) reduces miR-155 induced cardiac hypertrophy [ 27 ]. Therefore, these reports urged us to speculate that the modulation of miR-155 and activation of ROS/p53-mediated hepatic fibrosis by TAA, which could be prevented by resveratrol.…”

Combination of resveratrol and luteolin ameliorates α-naphthylisothiocyanate-induced cholestasis by regulating the bile acid homeostasis and suppressing oxidative stress

“…13 Resveratrol (RES), which is a non-flavonoid polyphenol with a stilbene structure, is thought to have beneficial effects on the liver and to protect the liver against various injuries. [14][15][16] Previous studies have shown that RES protects against cholestasis by decreasing the accumulation of BAs and suppressing neutrophil infiltration, 17 regulating the farnesoid X receptor and BA homeostasis, 18 inhibiting profibrogenic effects, oxidative stress and inflammation, 19 and downregulating NF-κB. 20 Meanwhile, luteolin (LUT), which is a naturally occurring flavonoid, is abundantly present in a broad range of plants and has a variety of biological activities.…”