基于“糖代谢重编码”探索健脾化浊法恢复“脾气散精”抑制CAG胃上皮恶性转化的分子机制

Blocking the malignant transformation of chronic atrophic gastritis (CAG) is of great significance in the prevention of gastric cancer. "Spleen to disperse essence" is essential for maintaining the balance of glucose metabolism. "Spleen failing to disperse essence" resembles glycometabolic disturbance "Pentose Phosphate Pathway (PPP) is active while Oxidative Phosphorylation is suppressive", which was considered as the core event in CAG malignant transformation. Sustained G6PD/ROS up-regulation is closely linked to the phenomenon of "Pentose Phosphate Pathway (PPP) is active while Oxidative Phosphorylation is suppressive". A recent study found that inactivated TIGAR, as the "valve" of glucose metabolism and the upstream of this cascade reaction, induced the above molecular events. Based on the previous study demonstrating that "invigorating spleen and resolve turbidity" method was effective in blocking CAG malignant transformation, we hypothesized that"invigorating spleen and resolve turbidity" method could reprogram glucose metabolism by regulating TIGAR/G6PD/ROS which inhibits the active PPP and restores normal oxidative phosphorylation, thereby restoring "spleen to disperse essence" and regaining normal glucose metabolism to suppress malignant transformation. This study, using a classical CAG malignant transformation rat model, is to explore the effect of "invigorating spleen and resolve turbidity" method on glycometabolic disturbance in which "Pentose Phosphate Pathway (PPP) is active while Oxidative Phosphorylation is suppressive", and how the method affect TIGAR/G6PD/ROS reprogramming glucose metabolism to inhibit malignant transformation. Finally, the present study is trying to enrich the TCM theoretical connotation of "spleen to disperse essence" and provide scientific evidence for "invigorating spleen and resolve turbidity" in CAG treatment.

阻遏慢性萎缩性胃炎（CAG）恶变对防治胃癌意义重大。“脾气散精”是维持糖代谢平衡的关键，而“脾不散精”与CAG恶变的核心事件—“PPP旁路活跃-氧化磷酸化低下”糖代谢紊乱状态相契合。G6PD/ROS持续上调与“PPP旁路活跃-氧化磷酸化低下”关系密切，而最新研究发现这一级联反应的上游，糖代谢“阀门”TIGAR的失活诱导了上述分子事件。基于前期研究健脾化浊法方药干预CAG恶性转化有效。据此，我们提出科学假说：健脾化浊法通过调控TIGAR/G6PD/ROS继而重编码糖代谢（抑制PPP旁路活跃，恢复氧化磷酸化），恢复“脾气散精”回归正常糖代谢格局而阻遏癌变。本项目拟用经典CAG恶变大鼠模型探索：健脾化浊法对“PPP旁路活跃-氧化磷酸化低下”糖代谢紊乱的影响；健脾化浊法如何调控TIGAR/G6PD/ROS继而重编码糖代谢抗癌变。丰富中医“脾气散精”理论内涵，为健脾化浊法干预CAG提供科学依据。

慢性萎缩性胃炎(CAG) 是以胃黏膜固有腺体萎缩、减少，常并发肠化生、异型增生病变，被视为胃癌前疾病，早期干预可有效逆转胃上皮恶性转化，从而阻遏胃癌的发生。根据我们的科学假说：健脾化浊法通过调控TIGAR /G6PD/ROS继而重编码糖代谢（抑制PPP旁路活跃，恢复氧化磷酸化），恢复“脾气散精”回归正常糖代谢格局而阻遏癌变，项目复制CAG恶变大鼠模型并采用健脾化浊方药胃痞方进行干预。研究结果表明：胃痞方可显著改善CAG恶性大鼠胃黏膜上皮腺体结构、排列紊乱和细胞异型性等病理表现；可抑制肠上皮化生病变的范围及程度。胃痞方可显著减少CAG恶性转化大鼠胃黏膜上皮的CD4+细胞、Ki67阳性细胞数量，促进TUNEL凋亡细胞数量增加；胃痞方可调节CAG恶性转化大鼠胃黏膜上皮细胞的ATP含量、ATP合成酶含量；胃痞方可下调CAG恶性转化大鼠胃黏膜上皮的NADP含量、GSH含量、TKT含量。机制方面，胃痞方对TP53转录水平无干预作用；胃痞方下调CAG恶性转化大鼠胃黏膜上皮细胞的TIGAR蛋白水平，降低胃黏膜上皮细胞的G6PDH含量，增加ROS含量，从而调控 TIAGR/G6PD/ROS重编码糖代谢，发挥了抑制胃上皮细胞分化、增殖、凋亡异常，阻遏 CAG 癌变的作用。本项目丰富了中医“脾气散精”理论内涵，为健脾化浊法在临床干预CAG提供了科学依据。

内容获取失败，请点击重试