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Association of resveratrol with the suppression of TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and systemic hypertension in thioacetamide-induced liver injury


Chronic liver injury can lead to hepatic failure and the only available method of treatment would be liver transplantation. The link between inflammation (TNF-α), nuclear factor-kappa B (NF-kB), nitrosative stress (iNOS) and hypoxia-inducible factor-1α (HIF-1α) in thioacetamide (TAA) induced liver fibrosis, and hypertension with and without the incorporation of the anti-inflammatory and antioxidant resveratrol (RES) has not been investigated before. Consequently, we injected rats with either 200 mg/kg TAA for 8 weeks starting at week 2 (model group) or pretreated them before TAA injections with RES (20 mg/kg) for 2 weeks and continued them on RES and TAA until being culled at week 10 (protective group). In the model group, we documented the induction of hepatic fibrosis and upregulation of tumor necrosis factor-α (TNF-α), NF-kB, inducible nitric oxide synthase (iNOS), HIF-1α and the profibrotic biomarkers alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-9 (MMP-9) that was significantly (p ≤ 0.0014) ameliorated by RES. RES also significantly (p ≤ 0.0232) reduced triglycerides (TG), cholesterol (CHOL), very low-density lipoprotein (vLDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure, and heart rate (HR) induction by TAA. Also, a significant (p < 0.0001) positive correlation between TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and hypertension and liver injury biomarkers was observed. These findings suggest that in the hepatotoxic compound, TAA is associated with TNF-α/NF-kB/iNOS/HIF-1α-mediated fibrosis and hypertension, whilst being inhibited by RES.

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Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to confidential handling of our materials because this manuscript data is part of a big project which is underway.


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We are grateful to Dr Mariam Al-Ani from Face Studio Clinic, 90 Hagley Road, Edgbaston, Birmingham, B16 8LU, UK, for proofreading the manuscript.


This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Funding Program (Grant No# FRP – 1442—5).

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Authors and Affiliations



Conceived and designed the experiments: B. A.-A. and A. F. D.; performed the experiments: H. A. E., S. S. K., N. S. A. L., A. M. S. and M. A. E.; analyzed the data: H. A. E., M. D., M. A. H., A. F. D. and B. A.-A.; wrote the manuscript: B. A.-A., A. F. D. and H. A. E. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Amal F. Dawood.

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Ebrahim, H.A., Kamar, S.S., Haidara, M.A. et al. Association of resveratrol with the suppression of TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and systemic hypertension in thioacetamide-induced liver injury. Naunyn-Schmiedeberg's Arch Pharmacol (2022).

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  • Thioacetamide
  • Liver fibrosis
  • Hypertension
  • Rat model
  • Resveratrol
  • TNF-α/NF-kB/iNOS/HIF-1α axis