Cardioprotective potential of azaleatin against sodium arsenite instigated sub-chronic cardiotoxicity via targeting TLR4/MyD88, JAK1/STAT3, and NF-κB in Sprague Dawley rats

  • J Trace Elem Med Biol. 2025 Dec:92:127763. doi: 10.1016/j.jtemb.2025.127763.
Hesham M Hassan  1 ,  Aqsa Bibi  2 ,  Muhammad Faisal Hayat  3 ,  Khalid J Alzahrani  4 ,  Fuad M Alzahrani  4 ,  Meshari A Alsuwat  5 ,  Maha A Al-Aream  6
Affiliations
  • 1. Department of Pathology, Faculty of Medicine, Assiut University, Egypt.
  • 2. Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250061, China.
  • 3. Department of Zoology, Wildlife and Fisheries, University of Agriculture Faisalabad, Pakistan. Electronic address: [email protected].
  • 4. Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
  • 5. Department of Basic Sciences, College of Nursing, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
  • 6. Department of Pathology, College of Medicine, King Khalid University, Saudi Arabia.
PMID: 41015022 DOI: 10.1016/j.jtemb.2025.127763
Abstract

Background: Sodium arsenite (SA) is a potent carcinogenic compound which is evident to prompt multiple organs damage including the heart. Azaleatin (AZA) is a novel therapeutic agent with excellent biological properties.

Objectives: The current investigation was executed to evaluate the mitigative efficacy of AZA against SA induced sub-chronic cardiotoxicity in rats through the evaluation of biochemical and histological parameters.

Methodology: Thirty-two rats were apportioned into control, SA (10 mg kg-1), SA (10 mg kg-1) + AZA (25 mg kg-1), and AZA (25 mg kg-1) exposed group. Biochemical parameters were evaluated through different techniques including qRT-PCR, ELISA and already reported standard assays. Histological analysis was performed to validate the tissue damage. The curative potential of AZA was re-validated through in-silico approaches.

Findings: SA intoxication upregulated the expression of nuclear factor-kappa B (NF-κB), myeloid differentiation primary response 88 (MyD88), janus kinase 1 (JAK1), Toll-like Receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), signal transducer and activator of transcription 3 (STAT3), interleukin-1β (IL-1β), interleukin-6 (IL-6), & cyclooxygenase-2 (COX-2) while increasing the levels of Reactive Oxygen Species (ROS) and malondialdehyde (MDA). Moreover, the enzymatic activities Glutathione Peroxidase (GPx), glutathione reductase (GSR), Glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), heme-oxygenase-1 (HO-1) and glutathione (GSH) were lowered whereas the levels of Troponin I, ProBNP, C-reactive protein, LDH, troponin-T, BNP and CPK were exacerbated following the SA exposure. Furthermore, SA intoxication promoted the levels of Bax, Caspase-9, and Caspase-3 while lowering the levels of Bcl-2. Cardiac tissues showed impaired histology after SA administration. Nonetheless, AZA therapy excellently ameliorated cardiac toxicity owing to its anti-inflammatory, antioxidative and anti-apoptotic potential.

Conclusion: SA intoxication induced severe cardiac toxicity via disrupting biochemical and histological parameters while AZA excellently restored cardiac health profile. Collectively, AZA may serve as a cardioprotective agent in counteracting SA induced sub-chronic cardiotoxicity.

Keywords
Azaleatin; Cardiotoxicity; Inflammation; Oxidative stress; Sodium arsenite.
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