Effective Inhibition of TNF-α/mTOR Axis-Mediated Liver Inflammation and Fibrosis Induced by TAA Using a Combination of Metformin and Resveratrol in Association with the Inhibition of the Profibrotic Gene and Protein Expression

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Mohammad Y. Alshahrani; Hasnaa A. Ebrahim; Faris Almasabi; Muath Suliman; Thoraya M. E. A-Elgadir; Mohamed Abd Ellatif; Norah M. Alzamil; Fahad S. Al Amri & Bahjat Al-Ani


The response of the immune system to harmful stimuli leads to inflammation, and the adverse effects of the toxic hepatitis chemical, thioacetamide (TAA) on the human body are well documented. This article investigated the degree of protection provided by the combined pleotropic drug, metformin (Met) and the plant polyphenolic and the antiinflammatory compound, resveratrol (Res) on liver tissue exposed to TAA possibly via the inhibition of the inflammatory cytokine, tumor necrosis factor-α (TNF-α) / mammalian target of rapamycin (mTOR) axis-mediated liver fibrosis, as well as amelioration of profibrotic gene and protein expression. Rats were either given TAA (200 mg/kg via intraperitoneal injection) for 8 weeks beginning at the third week (experimental group) or received during the first two weeks of the experiment combined doses of metformin (200 mg/kg) and resveratrol (20 mg/kg) and continued receiving these agents and TAA until experiment completion at week 10 (treated group). A considerable damage to hepatic tissue in the experimental rats was observed as revealed by tissue collagen deposition in the portal area of the liver and a substantial increase (p<0.0001) in hepatic levels of the inflammatory marker, tumor necrosis factor-α (TNF-α), as well as blood levels of hepatocellular injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TAA also augmented hepatic tissue levels of the signalling molecule that promotes liver fibrosis (mTOR), and profibrogenic markers; alpha-smooth muscle actin (α-SMA) protein, tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA, and matrix metalloproteinase-9 (MMP-9) mRNA. All these parameters were protected (p≤0.0016) by Met+Res. In addition, a significant correlation was detected between liver fibrosis score and inflammation, liver injury enzymes, mTOR, and profibrogenesis markers. Thus, these findings suggest that Met+Res effectively protect the liver against damage induced by thioacetamide in association with the downregulation of the TNF-α/mTOR/fibrosis axis.

KEY WORDS: Thioacetamide; Inflammation; mTOR; Profibrosis; Liver fibrosis; Metformin; Resveratrol.

How to cite this article

ALSHAHRANI, M. Y.; EBRAHIM, H. A.; ALMASABI, F.; SULIMAN, M.; A-ELGADIR, T. M. E.; ABD ELLATIF, M.; ALZAMIL, N. M.; AL AMRI, F. S. & AL-ANI, B. Effective inhibition of TNF-α/mTOR axis-mediated liver inflammation and fibrosis induced by TAA using a combination of metformin and resveratrol in association with the inhibition of the profibrotic gene and protein expression. Int. J. Morphol., 42(2):249-255, 2024.