仁清芒觉通过cGMP-PKG/PI3K-AKT途径调节慢性萎缩性胃炎炎症-癌转移

摘要(中文译文)

慢性萎缩性胃炎（CAG）是炎症向癌症进展过程中的关键阶段，与胃癌（GC）风险增加密切相关。仁青芒觉（RQMJ）是一种传统藏药，已显示出多种药理作用，包括调节胃肠功能和抗炎作用。然而，RQMJ影响炎症向癌症转变的具体效应和机制尚不清楚。本研究旨在评估RQMJ对CAG的预防和治疗作用及其对炎症-癌症转变过程的干预，重点探索其潜在的分子机制。通过UPLC-Q-TOF-MS/MS和HPLC对RQMJ进行了化学表征。建立CAG及其炎症-癌症转变的大鼠模型，并用不同剂量的RQMJ进行治疗。通过胃黏膜大体观察、ELISA、组织病理学染色、免疫组化和Western blot分析评估RQMJ的治疗效果。在体外，采用ELISA、划痕愈合、Transwell迁移和Western blot实验评估RQMJ对胃癌前细胞模型（MC细胞）炎症和迁移的影响。随后采用RNA测序和分子生物学技术探索潜在机制，并在体内和体外实验中进一步验证关键靶点。最后，使用C型利钠肽（CNP）验证所鉴定信号通路的参与。在RQMJ中共鉴定出2780种化学成分。建立了CAG及其向GC进展的动态大鼠模型。在CAG期间，持续性炎症和PI3K-AKT的异常激活形成正反馈环路，驱动FAK过表达和上皮-间质转化（EMT）相关变化，这些变化在GC中尽管炎症部分减轻但仍保持活跃。RQMJ显著减轻胃黏膜损伤，抑制肠上皮化生，改善胃肠功能。它还减少促炎介质（TNF-α、IL-1β、CRP），增加IL-10，并下调肿瘤相关标志物（Ki-67、Vimentin、CA19-9）。在体外，RQMJ抑制MC细胞增殖和迁移，抑制炎症和EMT相关蛋白。在机制上，RQMJ激活cGMP-PKG通路并抑制PI3K-AKT信号通路，从而破坏炎症放大效应。这进一步下调细胞外基质（ECM）-受体相互作用分子（TGF-β、FAK、Itga2），最终阻断炎症-癌症转变。RQMJ可能激活cGMP-PKG信号通路同时抑制PI3K-AKT的异常激活，从而降低炎症细胞因子水平并抑制ECM重塑和EMT相关过程，进而间接中断炎症-癌症级联反应。这些发现凸显了RQMJ在炎症驱动的胃部疾病中的潜在药理价值和治疗前景。

Abstract

Chronic atrophic gastritis (CAG) is a critical stage in the progression from inflammation to cancer and is closely associated with an increased risk of gastric cancer (GC). Renqing Mangjue (RQMJ), a traditional Tibetan herbal remedy, has shown diverse pharmacological properties, including regulation of gastrointestinal function and anti-inflammatory effects. However, the specific effects and mechanisms by which RQMJ influences the transition from inflammation to cancer remain unclear. This study aimed to evaluate the preventive and therapeutic effects of RQMJ on CAG and its intervention in the inflammation-cancer transition process, with a focus on exploring the underlying molecular mechanisms. RQMJ was chemically characterized by UPLC-Q-TOF-MS/MS and HPLC. A rat model of CAG and its inflammation-cancer transition was established and treated with different doses of RQMJ. The therapeutic effects of RQMJ were evaluated by gross gastric mucosal observation, ELISA, histopathological staining, immunohistochemistry, and Western blot analysis. In vitro, the effects of RQMJ on inflammation and migration of the gastric precancerous cell model (MC cells) were assessed using ELISA, wound-healing, Transwell migration, and Western blot assays. RNA sequencing and molecular biology techniques were then employed to explore the underlying mechanisms, and key targets were further validated in both in vivo and in vitro experiments. Finally, C-type natriuretic peptide (CNP) was used to verify the involvement of the identified signaling pathway. A total of 2780 chemical constituents were identified in RQMJ. A dynamic rat model of CAG and its progression to GC was established. During CAG, persistent inflammation and aberrant PI3K-AKT activation formed a positive-feedback loop, driving FAK overexpression and epithelial-mesenchymal transition (EMT)-related changes, which remained active in GC despite partial reduction of inflammation. RQMJ markedly alleviated gastric mucosal injury, suppressed intestinal metaplasia, and improved gastrointestinal function. It also reduced pro-inflammatory mediators (TNF-α, IL-1β, CRP), increased IL-10, and downregulated tumor-related markers (Ki-67, Vimentin, CA19-9). In vitro, RQMJ inhibited MC cell proliferation and migration, suppressed inflammatory and EMT-related proteins. Mechanistically, RQMJ activated the cGMP-PKG pathway and inhibited the PI3K-AKT signaling pathway, thereby disrupting inflammatory amplification. This further downregulated extracellular matrix (ECM)-receptor interaction molecules (TGF-β, FAK, Itga2), ultimately blocking the inflammation-cancer transition. RQMJ may activate the cGMP-PKG signaling pathway while suppressing aberrant PI3K-AKT activation, thereby reducing inflammatory cytokine levels and inhibiting ECM remodeling and the EMT-associated process, and thus indirectly interrupting the inflammation-cancer cascade. These findings highlight the potential pharmacological value and therapeutic prospects of RQMJ in inflammation-driven gastric diseases.

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