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<p>The incidence of inflammatory bowel disease (IBD) is increasing in developed nations, leading to a significant increase in healthcare expenses. It is characterized by chronic intestinal inflammation driven by excessive oxidative stress and dysregulated immune responses, leading to epithelial injury and impaired mucosal healing. Existing treatments have adverse effects, patient noncompliance issues, and high costs, emphasizing the need for new treatments. Pyrazole derivatives are promising antioxidant and anti-inflammatory bioactive compounds. This study uses zebrafish to test 1H-pyrazol-1-yl benzenesulfonamide derivatives for IBD treatment. Through network pharmacology and molecular docking, various 1H-pyrazol-1-yl benzenesulfonamide derivatives were screened, and T8 (4-(5-(4-chlorophenyl)-3-(2-(4-phenoxybenzylidene)hydrazine-1-carbonyl)-1H-pyrazol-1-yl)benzenesulfonamide) was chosen for in vitro and in vivo evaluation. T8 at 200&#xa0;μM exhibited dose-dependent antioxidant (&gt; 80%) and anti-inflammatory (&gt; 85%) activities&#xa0;in vitro. In the zebrafish intestine, administering T8 at 150&#xa0;μM led to a reduction in reactive oxygen species (ROS) (2.97-fold), lipid peroxidation, cellular apoptosis (2.30-fold), and macrophage accumulation. It restored superoxide dismutase (SOD) (19.49 U/mg) and catalase (CAT) (0.54 U/mg) levels while reducing malondialdehyde (MDA) (0.44&#xa0;μmol), lactate dehydrogenase (LDH) (0.23 U/mg), and nitric oxide (NO) (3.61&#xa0;μmol) levels. The expression levels of proinflammatory cytokines in zebrafish intestines were significantly reduced due to T8 suppressing the PI3K/Akt/mTOR signaling pathway. The gut histoarchitecture was restored after T8 treatment, as shown by histological analysis. By modulating the PI3K/Akt/mTOR signaling pathway, T8 reduced inflammation and oxidative stress in zebrafish, reducing IBD symptoms.</p>

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Evaluation of 1H-pyrazol-1-yl benzenesulfonamide derivatives in alleviating inflammatory bowel disease via PI3K/Akt/mTOR signaling pathway in zebrafish models

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • S. P. Ramya Ranjan Nayak,
  • D. Priya,
  • V. Chitra,
  • Ajay Guru,
  • Mohamed Farouk Elsadek,
  • Mohamed S. Elshikh,
  • Selvaraj Arokiyaraj,
  • M. K. Kathiravan,
  • Jesu Arockiaraj

摘要

The incidence of inflammatory bowel disease (IBD) is increasing in developed nations, leading to a significant increase in healthcare expenses. It is characterized by chronic intestinal inflammation driven by excessive oxidative stress and dysregulated immune responses, leading to epithelial injury and impaired mucosal healing. Existing treatments have adverse effects, patient noncompliance issues, and high costs, emphasizing the need for new treatments. Pyrazole derivatives are promising antioxidant and anti-inflammatory bioactive compounds. This study uses zebrafish to test 1H-pyrazol-1-yl benzenesulfonamide derivatives for IBD treatment. Through network pharmacology and molecular docking, various 1H-pyrazol-1-yl benzenesulfonamide derivatives were screened, and T8 (4-(5-(4-chlorophenyl)-3-(2-(4-phenoxybenzylidene)hydrazine-1-carbonyl)-1H-pyrazol-1-yl)benzenesulfonamide) was chosen for in vitro and in vivo evaluation. T8 at 200 μM exhibited dose-dependent antioxidant (> 80%) and anti-inflammatory (> 85%) activities in vitro. In the zebrafish intestine, administering T8 at 150 μM led to a reduction in reactive oxygen species (ROS) (2.97-fold), lipid peroxidation, cellular apoptosis (2.30-fold), and macrophage accumulation. It restored superoxide dismutase (SOD) (19.49 U/mg) and catalase (CAT) (0.54 U/mg) levels while reducing malondialdehyde (MDA) (0.44 μmol), lactate dehydrogenase (LDH) (0.23 U/mg), and nitric oxide (NO) (3.61 μmol) levels. The expression levels of proinflammatory cytokines in zebrafish intestines were significantly reduced due to T8 suppressing the PI3K/Akt/mTOR signaling pathway. The gut histoarchitecture was restored after T8 treatment, as shown by histological analysis. By modulating the PI3K/Akt/mTOR signaling pathway, T8 reduced inflammation and oxidative stress in zebrafish, reducing IBD symptoms.