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Simultaneous Modulation of NLRP3 Inflammasome and Nrf2/ARE Pathway Rescues Thioacetamide-Induced Hepatic Damage in
Durgesh Kumar Dwivedi1, G B Jena2
1Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S., Nagar, Punjab, 160062, India.
Abstract:
Chronic tissue injury resulting in fibrosis of multiple organs, responsible for one-third of the death globally. Liver fibrosis is a common pathway/condition involved in all chronic liver diseases. Thioacetamide (TAA), a hepatotoxicant, was used to induce hepatic fibrosis. Anti-diabetic drug glibenclamide (GLB) possesses anti-inflammatory properties and inhibits NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation. Dimethyl fumarate (DMF), a multiple sclerosis drug, activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and maintains the antioxidant status in the cell. The present study was designed to investigate (i) role of NLRP3 inflammasome and Nrf2/ARE pathway in TAA-induced hepatotoxicity and liver fibrosis, (ii) mechanism involved in GLB and DMF mediated hepatoprotection against TAA-induced hepatotoxicity, and (iii) additional/synergistic hepatoprotective effect of combination treatment with NLRP3 inhibition + Nrf2 activation or GLB + DMF or MCC950 + 4OI to reverse/ameliorate the experimental liver fibrosis completely. TAA was administered intraperitoneally to mice for seven consecutive weeks, and treatments of GLB, DMF, GLB + DMF, MCC950, 4OI, and MCC950 + 4OI were provided for the last three consecutive weeks. The intervention with GLB, DMF, GLB + DMF, MCC950, 4OI, and MCC950 + 4OI significantly protected TAA-induced oxidative stress and inflammatory conditions by improving biochemical, histological, and immunoexpression changes in mice. The GLB, DMF, and GLB + DMF intervention exhibited a better protective effect compared with MCC950, 4OI, and MCC950 + 4OI, which revealed that this specific inhibitor/activator possesses only NLRP3 inflammasome inhibitory/Nrf2 activatory properties. In contrast, the clinical drug GLB and DMF have several other beneficial effects, which are independent of NLRP3 inhibition and Nrf2 activation.
Insights
Chronic liver injury causes fibrosis, a global health issue. This study shows anti-diabetic glibenclamide (GLB) and multiple sclerosis drug dimethyl fumarate (DMF) protect against liver damage by targeting inflammation and oxidative stress pathways.
Area of Science:
- * Pharmacology and Toxicology
- * Cellular and Molecular Biology
- * Pathology
Background:
- * Chronic tissue injury leading to fibrosis affects multiple organs and is a leading global cause of death.
- * Liver fibrosis is a common endpoint for many chronic liver diseases.
- * Thioacetamide (TAA) is a known hepatotoxicant used to induce experimental liver fibrosis.
Purpose of the Study:
- * To investigate the roles of the NLRP3 inflammasome and Nrf2/ARE pathway in TAA-induced liver injury and fibrosis.
- * To elucidate the mechanisms behind the hepatoprotective effects of glibenclamide (GLB) and dimethyl fumarate (DMF) against TAA-induced hepatotoxicity.
- * To evaluate the potential synergistic or additive hepatoprotective effects of combined treatments targeting NLRP3 inhibition and Nrf2 activation, including GLB + DMF.
Main Methods:
- * Hepatic fibrosis was induced in mice using intraperitoneal administration of Thioacetamide (TAA) for seven weeks.
- * Various treatment groups received GLB, DMF, GLB + DMF, MCC950 (NLRP3 inhibitor), 4OI (Nrf2 activator), or MCC950 + 4OI for the final three weeks.
- * Hepatoprotective effects were assessed through biochemical, histological, and immunoexpression analyses to evaluate oxidative stress and inflammation.
Main Results:
- * All tested interventions, including GLB, DMF, GLB + DMF, MCC950, 4OI, and MCC950 + 4OI, significantly protected against TAA-induced oxidative stress and inflammation.
- * Treatments with GLB, DMF, and their combination demonstrated superior hepatoprotective effects compared to MCC950, 4OI, and MCC950 + 4OI.
- * The superior efficacy of GLB and DMF suggests they possess additional beneficial mechanisms beyond direct NLRP3 inhibition or Nrf2 activation.
Conclusions:
- * Both the NLRP3 inflammasome and Nrf2/ARE pathways are implicated in TAA-induced liver injury and fibrosis.
- * Glibenclamide (GLB) and Dimethyl Fumarate (DMF) offer significant hepatoprotection against TAA-induced liver damage, with combined treatment showing enhanced effects.
- * Clinical drugs GLB and DMF exhibit broader hepatoprotective benefits independent of solely targeting NLRP3 inhibition or Nrf2 activation, highlighting their therapeutic potential.
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