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<p>Gastric ulcer (GU) is primarily caused by <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection, ethanol-induced oxidative stress, and excessive gastric acid secretion. This is a significant global health burden. Lifetime prevalence of peptic ulcer disease (including GU and duodenal ulcer) in the general population has been estimated to be about 5–10%, and incidence 0.1–0.3% per year. Kahweol (a coffee-derived diterpene) exhibits broad pharmacological effects. Although Kahweol has strong antioxidant, anti-inflammatory and cytoprotective effects, its gastroprotective potential against ethanol-induced GU has remained unexplored. This is the first study demonstrating the multifaceted gastroprotective effects of Kahweol using an integrated computational, in vitro, and in vivo approaches, including direct comparison with omeprazole and evidence of dual acid-suppressive and anti-<i>H. pylori</i> activity. Molecular docking and 100&#xa0;ns molecular dynamics simulations demonstrated stable Kahweol binding to H⁺/K⁺-ATPase, nuclear factor-kappa B, NOD-like receptor protein 3, and cyclooxygenase-2. Kahweol exhibits inhibition of inflammatory pathways and acid secretion, having the highest affinity for H<sup>+</sup>/K<sup>+</sup>-ATPase (-7.92&#xa0;kcal/mol). In vitro assays revealed that Kahweol has dose-dependent antibacterial activity against <i>H. pylori</i> clinical isolates. In vivo<i>,</i> Kahweol significantly decreased the ethanol-induced ulcer index in a dose-dependent manner. Kahweol pretreatment inhibited GU up to 80% with 10&#xa0;mg/kg dose, which was comparable to that of omeprazole (85%). Histopathological analysis in Kahweol-treated groups confirmed preserved mucosal architecture, reduced vacuolation, and restored epithelial boundaries, which were comparable to those of omeprazole. Biochemical assays of Kahweol-treated groups showed enhanced antioxidant defenses, with increased levels of reduced glutathione, glutathione S-transferase, and catalase, along with decreased levels of nitric oxide and malondialdehyde. Results from the enzyme-linked immunosorbent assay of the Kahweol-treated group showed that the pro-inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha were suppressed, confirming anti-inflammatory effects. Quantitative real-time polymerase chain reaction verified that the expression of H⁺/K⁺-ATPase was downregulated by Kahweol, indicating the acid-inhibition effect of Kahweol. These findings suggest Kahweol is the potential natural agent for the prevention and treatment of ethanol-induced GU, highlighting the comprehensive gastroprotective effects of Kahweol through its antioxidant, anti-inflammatory, anti-secretory, and anti-<i>H. pylori</i> activity.</p>

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Gastroprotective effect of Kahweol against ethanol-induced gastric ulcer by employing in silico, in vitro and in vivo approaches

  • 期刊论文

  • 发表日期：

    2026年2月4日

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  • Shahid Khan,
  • Abdul Qadir,
  • Jawad Azam,
  • Muhammad Noman,
  • Nadeem Ahmad,
  • Zaheer Ul-Haq,
  • Kashif Bashir,
  • Tajamul Hussain,
  • Salman Alrokayan,
  • Muhammad Latif,
  • Hussain Ali,
  • Yousaf Kamal,
  • Nadeem Irshad

摘要

Gastric ulcer (GU) is primarily caused by Helicobacter pylori (H. pylori) infection, ethanol-induced oxidative stress, and excessive gastric acid secretion. This is a significant global health burden. Lifetime prevalence of peptic ulcer disease (including GU and duodenal ulcer) in the general population has been estimated to be about 5–10%, and incidence 0.1–0.3% per year. Kahweol (a coffee-derived diterpene) exhibits broad pharmacological effects. Although Kahweol has strong antioxidant, anti-inflammatory and cytoprotective effects, its gastroprotective potential against ethanol-induced GU has remained unexplored. This is the first study demonstrating the multifaceted gastroprotective effects of Kahweol using an integrated computational, in vitro, and in vivo approaches, including direct comparison with omeprazole and evidence of dual acid-suppressive and anti-H. pylori activity. Molecular docking and 100 ns molecular dynamics simulations demonstrated stable Kahweol binding to H⁺/K⁺-ATPase, nuclear factor-kappa B, NOD-like receptor protein 3, and cyclooxygenase-2. Kahweol exhibits inhibition of inflammatory pathways and acid secretion, having the highest affinity for H+/K+-ATPase (-7.92 kcal/mol). In vitro assays revealed that Kahweol has dose-dependent antibacterial activity against H. pylori clinical isolates. In vivo, Kahweol significantly decreased the ethanol-induced ulcer index in a dose-dependent manner. Kahweol pretreatment inhibited GU up to 80% with 10 mg/kg dose, which was comparable to that of omeprazole (85%). Histopathological analysis in Kahweol-treated groups confirmed preserved mucosal architecture, reduced vacuolation, and restored epithelial boundaries, which were comparable to those of omeprazole. Biochemical assays of Kahweol-treated groups showed enhanced antioxidant defenses, with increased levels of reduced glutathione, glutathione S-transferase, and catalase, along with decreased levels of nitric oxide and malondialdehyde. Results from the enzyme-linked immunosorbent assay of the Kahweol-treated group showed that the pro-inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha were suppressed, confirming anti-inflammatory effects. Quantitative real-time polymerase chain reaction verified that the expression of H⁺/K⁺-ATPase was downregulated by Kahweol, indicating the acid-inhibition effect of Kahweol. These findings suggest Kahweol is the potential natural agent for the prevention and treatment of ethanol-induced GU, highlighting the comprehensive gastroprotective effects of Kahweol through its antioxidant, anti-inflammatory, anti-secretory, and anti-H. pylori activity.