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<p>The exact etiology of ulcerative colitis (UC) remains incompletely understood. However, substantial evidence implicates multiple signaling pathways in its pathogenesis, including interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), wingless/Int1 (Wnt), heme oxygenase-1 (HO-1), nuclear factor erythroid 2–related factor 2 (Nrf2), adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and NLR family pyrin domain-containing 3 (NLRP3). Atorvastatin and nitazoxanide have demonstrated anti-inflammatory, antioxidant, and immunomodulatory properties that may target these signaling pathways. The aim of this study was to investigate the coloprotective effects of atorvastatin and nitazoxanide in an experimental model of UC. Colitis was induced by intracolonic administration of acetic acid (AA) in rats. A total of 32 rats were randomly assigned to four groups (<i>n</i> = 8 each): normal control, colitis, atorvastatin-treated, and nitazoxanide-treated groups. Disease severity was assessed via colon length, weight, disease activity index, and histopathological evaluation. Tissue levels of SIRT1, mTOR, HO-1, Nrf2, STAT3, AMPK, and Dickkopf-related protein 1 (DKK1) were measured, along with colonic gene expression of NLRP3, Wnt, IL-6, TNF-α, and DKK1. Additionally, TNF-α and IL-6 protein expressions were assessed by immunohistochemistry. Intracolonic AA administration caused significant biochemical, inflammatory, and structural damage to the colon. Both atorvastatin and nitazoxanide significantly attenuated colitis, as evidenced by reduced disease activity scores, histological improvement, and decreased expression of colonic mTOR, NLRP3, DKK1, IL-6, TNF-α, and STAT3. Conversely, both agents upregulated HO-1, Nrf2, SIRT1, Wnt, and AMPK levels. Histologically, treated groups exhibited partial restoration of normal mucosal architecture, with fewer irregular crypts and reduced lymphoplasmacytic infiltration. Atorvastatin and nitazoxanide ameliorated experimental colitis through modulation of inflammatory and oxidative stress pathways.</p> Graphical Abstract <p></p>

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Modulation of mTOR, NLRP3, and Nrf2/HO-1 signaling by atorvastatin and nitazoxanide in experimental ulcerative colitis

  • 期刊论文

  • 发表日期：

    2026年3月27日

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  • Hayam Ali AlRasheed,
  • Mahmoud S. Abdallah,
  • Esraa M. Mosalam,
  • Mostafa M. Bahaa,
  • Muhammed M. Salahuddin,
  • Amir O. Hamouda,
  • Sarah Alrubia,
  • Amsha S. Alsegiani,
  • Eman El-Khateeb,
  • Mohamed Kh. Elmahdy,
  • Nora Elshorbagi,
  • Abd El Razeq A. Meselhy,
  • Eman Hamza,
  • Eman Wahsh

摘要

The exact etiology of ulcerative colitis (UC) remains incompletely understood. However, substantial evidence implicates multiple signaling pathways in its pathogenesis, including interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), wingless/Int1 (Wnt), heme oxygenase-1 (HO-1), nuclear factor erythroid 2–related factor 2 (Nrf2), adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and NLR family pyrin domain-containing 3 (NLRP3). Atorvastatin and nitazoxanide have demonstrated anti-inflammatory, antioxidant, and immunomodulatory properties that may target these signaling pathways. The aim of this study was to investigate the coloprotective effects of atorvastatin and nitazoxanide in an experimental model of UC. Colitis was induced by intracolonic administration of acetic acid (AA) in rats. A total of 32 rats were randomly assigned to four groups (n = 8 each): normal control, colitis, atorvastatin-treated, and nitazoxanide-treated groups. Disease severity was assessed via colon length, weight, disease activity index, and histopathological evaluation. Tissue levels of SIRT1, mTOR, HO-1, Nrf2, STAT3, AMPK, and Dickkopf-related protein 1 (DKK1) were measured, along with colonic gene expression of NLRP3, Wnt, IL-6, TNF-α, and DKK1. Additionally, TNF-α and IL-6 protein expressions were assessed by immunohistochemistry. Intracolonic AA administration caused significant biochemical, inflammatory, and structural damage to the colon. Both atorvastatin and nitazoxanide significantly attenuated colitis, as evidenced by reduced disease activity scores, histological improvement, and decreased expression of colonic mTOR, NLRP3, DKK1, IL-6, TNF-α, and STAT3. Conversely, both agents upregulated HO-1, Nrf2, SIRT1, Wnt, and AMPK levels. Histologically, treated groups exhibited partial restoration of normal mucosal architecture, with fewer irregular crypts and reduced lymphoplasmacytic infiltration. Atorvastatin and nitazoxanide ameliorated experimental colitis through modulation of inflammatory and oxidative stress pathways.

Graphical Abstract