Dapagliflozin alleviates thioacetamide induced-liver fibrosis in rats via controlling the Nrf2/HO-1 and TLR4/TGF-β1/PI3K signaling pathways

Apr 29, 2025Immunopharmacology and immunotoxicology

Dapagliflozin reduces liver scarring in rats by affecting antioxidant and inflammation-related pathways

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Abstract

Dapagliflozin treatment significantly reduced the increase in liver fibrosis markers induced by thioacetamide in male rats.

Thioacetamide injections elevated levels of toll-like receptor 4 (TLR4) by 509.6%, tumor necrosis factor (TNF-) by 298.8%, and interleukin-6 (IL-6) by 330.9%.
Dapagliflozin administration lowered these elevated markers and restored levels of reduced glutathione (GSH) and superoxide dismutase (SOD).
Gene expression analysis showed increased levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme-oxygenase 1 (HO-1) in Dapa-treated groups.
Histopathological examinations confirmed reduced expression of caspase-3 and alpha-smooth muscle actin (SMA) following Dapa treatment.
The findings suggest that Dapa's protective effects may be linked to its interaction with the Nrf2/HO-1 and TLR4 pathways.

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OBJECTIVES: Because liver fibrosis causes several insults that can result in death, it is regarded as an epidemic health issue. As "an inhibitor of the sodium-glucose cotransporter-2 (SGLT2)," Dapagliflozin (Dapa) is one of the newest anti-diabetic drugs used to treat type 2 diabetes mellitus. Dapa's antioxidant, anti-inflammatory, and antifibrotic properties produced positive impacts in numerous human and animal models. Due to Dapa's previously documented properties, we planned this investigation to elucidate the protective function of Dapa in male rat liver fibrosis caused by thioacetamide (TAA) as well as the expected pathways.

METHODS: There were four groups of 24 rats: a control group, a TAA group that received (100 mg/kg b.wt intraperitoneally twice a week for 6 weeks), "TAA + Dapa" groups that given oral Dapa at (1 and 2 mg/kg b.wt. for 4 weeks in addition to TAA injections).

RESULTS: It was shown that TAA injections increased toll-like receptor 4 (TLR4) (509.6%), tumor necrosis factor (TNF-) (298.8%), alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), interleukin-6 (IL-6) (330.9%), phosphotidylinositol-3-kinase (PI3K) (428.9% %), and transforming growth factor-beta (TGF-1) (416.6%) levels. All of these markers were considerably reduced by Dapa treatment. In addition, reduced glutathione (GSH), nuclear factor erythroid 2-related factor 2 (Nrf2) (79%), albumin, Heme-oxygenase 1 (HO-1) (69%), and superoxide dismutase (SOD) were all decreased after TAA injection; however, they were restored by Dapa administration. The Dapa-treated groups had higher Nrf2 and HO-1 gene expressions, based on the results of PCR. Biochemical outcomes were validated by histopathological results. Immunohistopathological study revealed that DAPA treatment decreased caspase-3 and alpha-smooth Muscle Actin (SMA) expression. α β α

CONCLUSION: Due to its interactions with the Nrf2/HO-1 and TLR4 pathways, our research showed that Dapa had antioxidant and anti-inflammatory qualities against TAA-induced liver fibrosis.

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Dapagliflozin alleviates thioacetamide induced-liver fibrosis in rats via controlling the Nrf2/HO-1 and TLR4/TGF-β1/PI3K signaling pathways

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