Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, Korea.
Am J Physiol Gastrointest Liver Physiol. 2013 Jan 15;304(2):G193-202. doi: 10.1152/ajpgi.00103.2012. Epub 2012 Nov 1.
Gastric mucosal inflammation can develop after challenge with noxious stimuli such as alcohol. Specially, alcohol stimulates the release of inflammatory cytokines but does not increase gastric acid secretion, leading to gastric mucosal damage. The plant sterol guggulsterone and its novel derivative GG-52 have been reported to inhibit nuclear factor-κB (NF-κB) signaling in intestinal epithelial cells and experimental colitis. In the present study, we investigated the anti-inflammatory effects of GG-52 on gastric epithelial cells and on ethanol-induced gastric mucosal inflammation in mice. GG-52 inhibited the expression of interleukin-8 (IL-8) in gastric epithelial AGS and MKN-45 cell lines stimulated with tumor necrosis factor (TNF)-α in a dose-dependent manner. Pretreatment with GG-52 suppressed TNF-α-induced activation of IκB kinase (IKK) and NF-κB signaling in MKN-45 cells. In contrast, the inactive analog GG-46 did not produce significant changes in IL-8 expression or NF-κB activation. In a model of ethanol-induced murine gastritis, administration of GG-52 significantly reduced the severity of gastritis, as assessed by macroscopic and histological evaluation of gastric mucosal damage. In addition, the ethanol-induced upregulation of chemokine KC, a mouse homolog of IL-8, and phosphorylated p65 NF-κB signals were significantly inhibited in murine gastric mucosa pretreated with GG-52. These results indicate that GG-52 suppresses NF-κB activation in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice, suggesting that GG-52 may be a potential gastroprotective agent.
胃黏膜炎症可在受到有害刺激后发展，如酒精。具体来说，酒精刺激炎症细胞因子的释放，但不会增加胃酸分泌，导致胃黏膜损伤。植物固醇古卡斯特隆及其新型衍生物 GG-52 已被报道可抑制肠上皮细胞中的核因子-κB（NF-κB）信号和实验性结肠炎。在本研究中，我们研究了 GG-52 对胃上皮细胞和乙醇诱导的小鼠胃黏膜炎症的抗炎作用。GG-52 以剂量依赖性方式抑制 TNF-α刺激的胃上皮 AGS 和 MKN-45 细胞系中白细胞介素-8（IL-8）的表达。GG-52 预处理可抑制 MKN-45 细胞中 TNF-α诱导的 IκB 激酶（IKK）和 NF-κB 信号的激活。相比之下，无活性类似物 GG-46 对 IL-8 表达或 NF-κB 激活没有显著变化。在乙醇诱导的小鼠胃炎模型中，GG-52 的给药显著减轻了胃黏膜损伤的严重程度，通过对胃黏膜损伤的宏观和组织学评估来评估。此外，GG-52 预处理可显著抑制乙醇诱导的趋化因子 KC（IL-8 的小鼠同源物）和磷酸化 p65 NF-κB 信号的上调。这些结果表明，GG-52 可抑制胃上皮细胞中 NF-κB 的激活，并改善乙醇诱导的小鼠胃黏膜损伤，表明 GG-52 可能是一种有潜力的胃保护剂。
