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<p>Methotrexate (MTX), a chemotherapeutic and immunosuppressive drug, is well known to cause salivary gland (SG) toxicity. Although <i>Withania somnifera</i> (WS) exhibits strong antioxidant and cytoprotective properties, its potential to counteract MTX-induced SG injury remains poorly explored. The current study aimed to assess the protective effect of WS supplementation against MTX-induced toxicity in rat parotid and submandibular glands and to explore the underlying mechanisms. Forty adult male albino rats, each weighing ~ 200&#xa0;g, were randomly allocated into four groups (<i>n</i> = 10): Control (distilled water orally/8 days), WS (300&#xa0;mg/kg orally/8 days), MTX (single intraperitoneal injection of 60&#xa0;mg/kg on day 4), and WS + MTX (WS/8 days with MTX on day 4). Glandular injury was assessed histologically using hematoxylin and eosin staining and immunohistochemically for cyclooxygenase-2 (COX-2) and cleaved caspase-3. Biochemical assays measured malondialdehyde (MDA) and total antioxidant capacity (TAC). p38 mitogen-activated protein kinase (p38 MAPK) and transient receptor potential canonical channel 1 (TRPC1) were quantified using ELISA. Gene expression of nuclear factor-κB (NF-κB) and C/EBP homologous protein (CHOP) was analyzed by qPCR. MTX induced acinar and ductal degeneration, cytoplasmic vacuolization, and nuclear pyknosis; increased MDA; reduced TAC; activated the p38 MAPK/NF-κB/COX-2 inflammatory axis; ER stress through the TRPC1/CHOP pathway; and elevated cleaved caspase-3 expression. Co-treatment with WS preserved glandular architecture, restored antioxidant balance, attenuated oxidative, inflammatory, and ER-stress responses, and suppressed the apoptosis. This demonstrates that WS supplementation provided protection against MTX-induced toxicity in both the parotid and submandibular glands largely through modulation of p38 MAPK/NF-κB/COX-2 and TRPC1/CHOP pathways.</p>

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Modulatory effects of Withania somnifera supplementation on p38 MAPK/NF-κB/COX-2 and TRPC1/CHOP signaling pathways in methotrexate-induced parotid and submandibular salivary gland toxicity in rats

  • 期刊论文

  • 发表日期：

    2026年1月23日

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  • Hanaa Salem Moubarak,
  • Abdelaleem Abdelnour Mohamed,
  • Sayed Fouad El-sheikh Ali,
  • Ahlam M. Abdallah,
  • Walaa Yehia Abdelzaher

摘要

Methotrexate (MTX), a chemotherapeutic and immunosuppressive drug, is well known to cause salivary gland (SG) toxicity. Although Withania somnifera (WS) exhibits strong antioxidant and cytoprotective properties, its potential to counteract MTX-induced SG injury remains poorly explored. The current study aimed to assess the protective effect of WS supplementation against MTX-induced toxicity in rat parotid and submandibular glands and to explore the underlying mechanisms. Forty adult male albino rats, each weighing ~ 200 g, were randomly allocated into four groups (n = 10): Control (distilled water orally/8 days), WS (300 mg/kg orally/8 days), MTX (single intraperitoneal injection of 60 mg/kg on day 4), and WS + MTX (WS/8 days with MTX on day 4). Glandular injury was assessed histologically using hematoxylin and eosin staining and immunohistochemically for cyclooxygenase-2 (COX-2) and cleaved caspase-3. Biochemical assays measured malondialdehyde (MDA) and total antioxidant capacity (TAC). p38 mitogen-activated protein kinase (p38 MAPK) and transient receptor potential canonical channel 1 (TRPC1) were quantified using ELISA. Gene expression of nuclear factor-κB (NF-κB) and C/EBP homologous protein (CHOP) was analyzed by qPCR. MTX induced acinar and ductal degeneration, cytoplasmic vacuolization, and nuclear pyknosis; increased MDA; reduced TAC; activated the p38 MAPK/NF-κB/COX-2 inflammatory axis; ER stress through the TRPC1/CHOP pathway; and elevated cleaved caspase-3 expression. Co-treatment with WS preserved glandular architecture, restored antioxidant balance, attenuated oxidative, inflammatory, and ER-stress responses, and suppressed the apoptosis. This demonstrates that WS supplementation provided protection against MTX-induced toxicity in both the parotid and submandibular glands largely through modulation of p38 MAPK/NF-κB/COX-2 and TRPC1/CHOP pathways.