Apigenin role against thioacetamide-triggered liver fibrosis: Deciphering the PPARγ/TGF-β1/NF-κB and the HIF/FAK/AKT pathways

Abstract

Introduction: Liver tissue malfunction is a severe worldwide health concern that arises from various chronic liver conditions. The goal of this investigation was to look into the anti-fibrotic effect of apigenin (APG), an antioxidant found in various plants, versus thioacetamide (TAA)-triggered hepatic scarring in rats and the potential mechanisms behind it. Methods: TAA was administered thrice weekly (100 mg/kg, i.p.) for two weeks to produce hepatic scarring. APG was administered after TAA for 14 days (5 or 10 mg/kg, orally). Thereafter, hepatic liver enzymes, inflammatory markers, fibrotic indicators, and histopathological changes were evaluated. Results: TAA increased the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), reduced albumin and total protein, elevated hepatic level of lipid peroxidation, focal adhesion kinase (FAK), hypoxia-inducible factor-1α (HIF-1α), and inflammatory cytokines, decreased interleukin-10 (IL-10), reduced hepatic expression of peroxisome proliferator-activated receptor gamma (PPARγ) and nuclear factor-erythroid factor 2-related factor 2 (Nrf2), and elevated serine-threonine protein kinase (AKT) expression. Furthermore, TAA increased hepatic contents of collagen I, connective tissue growth factor (CTGF), hydroxyproline, and alpha-smooth muscle actin. On the other hand, APG evaded these changes and mitigated the harmful effects of TAA in a dose-dependent way. Histopathological and immunohistochemical observations reinforced these biochemical outcomes. Conclusion: APG can potentially alleviate liver fibrosis mediated via FAK and HIF1 inhibiting signaling pathways.

Hepatoprotective activity of Lactéol® forte and quercetin dihydrate against thioacetamide‐induced hepatic cirrhosis in male albino rats

“…Furthermore, TASO2 binds to hepatic macromolecules as proteins and lipid-producing centrilobular necrosis so that TAA, unlike most hepatotoxins that produce periportal hepatocellular necrosis. The histopathological changes were in harmony with Al-Attar and Al-Rethea, 24 Shareef et al 21 and Abdel-Rahman et al 35,36 Lesions in TAA + QD-treated group were lesser in the extent than those of the TAA-treated rats but most severe than those reported in the TAA + LF-treated group. The findings of QD treatment came in accordance with Afifi et al 39 and Salama et al 31 In the present work, the administration of LF resulted in the improvement of the histoarchitecture of the liver with increasing the reactivity of inflammatory and immune cells against TAA-harmful effects as documented previously by Bahr et al 38 Moreover, Moro-García et al 44 and Garcia-Castillo et al 45 showed the immunostimulant effect of L. delbrueckii and L. fermentum, respectively.…”

“…Additionally, Ogaly et al 34 and Abdel-Rahman et al 35 showed a substantial increment in the serum levels of ALT and AST after intraperitoneal injection of TAA at a dose of 100 mg/ kg 3 times for 2 weeks. Additionally, Abdel-Rahman et al 36 detected a substantial increment in activities of AST and ALT with a reduction in albumin and total protein levels after TAA injection for 14 days (5 or 10 mg/kg, orally). This variation may be due to the strain of animals, the dose of TAA and/or conditions of the experiment.…”

Nrf2/HO‐1, NF‐κB and PI3K/Akt signalling pathways decipher the therapeutic mechanism of pitavastatin in early phase liver fibrosis in rats

“…ALT and AST are cytoplasmic in origin, and elevated serum levels, as shown in the TAA group, reflect cell membrane destruction and hepatocyte death. 32 , 37 , 38 , 39 , 40 , 41 Our results indicated that, unlike all other statins, Pit undergoes minimal hepatic metabolism 42 and does not cause any elevation in aminotransferase levels. Infect, Pit is a highly lipophilic agent that undergoes glucuronic acid conjugation, and a recent meta‐analysis study demonstrated that only hydrophilic statins result in the risk of aminotransferase elevation.…”

“…Importantly, despite the variability, pitavastatin treatment at both doses still significantly reduced MDA levels compared to the TAA group. 35 , 37 , 50 , 51 The lack of dose‐dependent difference in MDA suppression between the two pitavastatin doses could suggest a potential ceiling effect on lipid peroxidation inhibition even at the lower 0.4 mg/kg dose. However, further studies with larger sample sizes may be warranted to fully evaluate the dose–response relationship.…”

Erythropoietin Suppresses the Hepatic Fibrosis Caused by Thioacetamide: Role of the PI3K/Akt and TLR4 Signaling Pathways

“…Rats in Group 2 (TAA group) received an ip “injection of TAA (100 mg/kg) trice weekly for 2 consecutive weeks” [ 28 ]. The TAA, we have already published previous researches with the same dose and protocol for inducing liver injury [ 28 – 30 ]. Rats in groups 3 and 4 were given ip injections of EPO (150 and 300 IU/kg) [ 31 ] every day for “2 weeks following TAA injection,” as shown in Figure 1 .…”