Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.
Beijing University of Chinese Medicine, Beijing, People's Republic of China.
Drug Des Devel Ther. 2020 Jun 9;14:2207-2219. doi: 10.2147/DDDT.S247958. eCollection 2020.
Gastric cancer is a leading cause of cancer death worldwide. In-depth research of precancerous lesions of gastric carcinoma (PLGC) with malignant transformation potential is a key measure to prevent the development of gastric carcinoma. Recently, calycosin has been shown to have anticancer effects in vitro and in vivo. The molecular mechanism by which calycosin affects PLGC, however, has not yet been elucidated. The purpose of this study was to evaluate the effect and mechanism of calycosin in -methyl-'-nitro--nitrosoguanidine (MNNG)-induced PLGC rats.
The effects of calycosin in the gastric mucosa of rats with PLGC were evaluated using histopathology and transmission electron microscopy (TEM). For further characterization, the expression levels of integrin β1, nuclear factor kappa B (NF-κB), p-NF-κB, DARPP-32 and signal transducer and activator of transcription 3 (STAT3) were determined by Western blot assay and immunohistochemistry.
Hematoxylin-eosin and high iron diamine-Alcian blue-periodic acid-Schiff (HID-AB-PAS) staining showed that intestinal metaplasia and dysplasia were significantly ameliorated in the calycosin intervention groups compared with the model group. Further, TEM results showed that calycosin intervention tempered microvascular abnormalities and cell morphology of primary and parietal cells in PLGC tissues. The results suggested that calycosin had gastro-protective effects in MNNG-induced PLGC rats. Western blot and immunohistochemistry analysis showed that the increased protein expression levels of NF-κB, p-NF-κB, DARPP-32 and STAT3 in the model group were downregulated by calycosin. The upregulation of integrin β1 expression induced by MNNG was decreased in the calycosin groups.
Collectively, calycosin protected against gastric mucosal injury in part via regulation of the integrin β1/NF-κB/DARPP-32 pathway and suppressed the expression of STAT3 in PLGC. The elucidation of this effect and mechanism of calycosin in PLGC provides a potential therapeutic strategy for treatment of gastric precancerous lesions.
胃癌是全球癌症死亡的主要原因。深入研究具有恶性转化潜能的胃癌前病变（PLGC）是预防胃癌发展的关键措施。最近，毛蕊异黄酮已被证明具有体内外的抗癌作用。然而，毛蕊异黄酮影响 PLGC 的分子机制尚未阐明。本研究旨在评估毛蕊异黄酮在 1-甲基-3-硝基-1-亚硝基胍（MNNG）诱导的 PLGC 大鼠中的作用和机制。
采用组织病理学和透射电镜（TEM）评估毛蕊异黄酮对 PLGC 大鼠胃黏膜的影响。为了进一步表征，通过 Western blot 分析和免疫组织化学法测定整合素β1、核因子κB（NF-κB）、磷酸化 NF-κB（p-NF-κB）、多巴胺和环磷酸腺苷反应元件结合蛋白 32（DARPP-32）和信号转导和转录激活因子 3（STAT3）的表达水平。
苏木精-伊红和高铁二胺-阿尔辛蓝-过碘酸-雪夫（HID-AB-PAS）染色显示，与模型组相比，毛蕊异黄酮干预组的肠上皮化生和异型增生明显改善。进一步的 TEM 结果显示，毛蕊异黄酮干预减轻了 PLGC 组织中原发性和壁细胞的微血管异常和细胞形态。结果表明，毛蕊异黄酮对 MNNG 诱导的 PLGC 大鼠具有胃保护作用。Western blot 和免疫组织化学分析显示，模型组中 NF-κB、p-NF-κB、DARPP-32 和 STAT3 的蛋白表达水平升高，毛蕊异黄酮可下调其表达。MNNG 诱导的整合素β1表达上调在毛蕊异黄酮组中减少。
综上所述，毛蕊异黄酮通过调节整合素β1/NF-κB/DARPP-32 通路和抑制 PLGC 中 STAT3 的表达，部分保护胃黏膜免受损伤。阐明毛蕊异黄酮在 PLGC 中的这种作用和机制为治疗胃前病变提供了一种潜在的治疗策略。
