Modified Shenlingbaizhu decoction reduces intestinal adenoma formation in adenomatous polyposis coli multiple intestinal neoplasia mice by suppression of hypoxia-inducible factor 1 alpha-induced CD4+CD25+forkhead box P3 regulatory T cells
Modified Shenlingbaizhu decoction reduces intestinal adenoma formation in adenomatous polyposis coli multiple intestinal neoplasia mice by suppression of hypoxia-inducible factor 1 alpha-induced CD4+CD25+forkhead box P3 regulatory T cells
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加味参苓白术汤通过抑制缺氧诱导因子1α诱导的CD4 CD25叉头盒P3调节性T细胞减少腺瘤性大肠杆菌多发性肠肿瘤小鼠肠腺瘤形成
DOI：
10.1016/j.jtcm.2018.01.004
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发表时间：
2018
影响因子：
2.6
通讯作者：
Sun Xuegang
中科院分区：
文献类型：
--
作者：
Xu Wenjuan;Han Qinrui;Liang Shuntian;Li Lu;Shao Meng;Yao Xueqing;Sun Xuegang
目的验证参灵白术汤加味通过下调缺氧诱导因子1α (HIF-1α)，调节CD4+CD25+叉形盒P3 （FoxP3）调节性T细胞（Tregs）的激活，从而减缓肠腺瘤形成的假说。方法以人参皂苷Rb1、人参皂苷Rc、芍药苷和薯蓣皂苷的化学指纹图谱作为MSD的物质基础。大肠腺瘤性息肉病多发肠瘤（ApcMin/+）小鼠携带大肠腺瘤性息肉病突变，被用来宿主肠腺瘤。用流式细胞术分析外周血和脾脏treg。免疫组织化学和Western blotting分析蛋白表达。结果MSD治疗组肠腺瘤的数量和大小均明显减少。粘膜增厚和脾脏大小也明显减少。ApcMin/+小鼠的癌变过程与人类结直肠癌相似。肿瘤分子标志物，如β-catenin、环氧化酶-2、增殖细胞核抗原和p53，在MSD治疗后显著改善。此外，MSD下调外周和脾脏CD4 + CD25+FoxP3+Tregs，降低肠腺瘤中CD4、CD25和FoxP3的原位表达。MSD还抑制了肠腺瘤中HIF-1α的表达，HIF-1α的抑制降低了缺氧条件下Jurkat T细胞中FoxP3的表达。结论msd是控制ApcMin/+小鼠肠腺瘤形成的有效方药。在体内和体外，它通过抑制HIF-1α诱导CD4+CD25+FoxP3+ Tregsin的激活来发挥抗癌作用。
OBJECTIVETo test the hypothesis that modified Shenlingbaizhu decoction (MSD) attenuates the formation of intestinal adenomas by regulating activation of CD4+CD25+ forkhead box P3 (FoxP3) regulatory T cells (Tregs) by downregulation of hypoxia-inducible factor 1α (HIF-1α).METHODSChemical fingerprints of ginsenoside Rb1, ginsenoside Rc, paeoniflorin, and dioscin in standard extractions were used as material bases of MSD. Adenomatous polyposis coli multiple intestinal neoplasia (ApcMin/+) mice, which harbor a mutation in adenomatous polyposis coli, were used to host intestinal adenomas. Peripheral blood and spleen Tregs were analyzed by flow cytometry. Protein expression was analyzed by immunohistochemistry and Western blotting.RESULTSThe number and size of intestinal adenomas were significantly reduced by MSD treatment. Mucosal thickening and the spleen size were also substantially decreased by MSD. The carcinogenesis process in ApcMin/+mice resembled that of human colorectal cancer. Molecular markers of neoplasms, such as β-catenin, cyclooxygenase-2, proliferating cell nuclear antigen, and p53, were substantially ameliorated by MSD treatment. Moreover, MSD downregulated peripheral and spleen CD4 + CD25+FoxP3+Tregs and reduced in situ expression of CD4, CD25, and FoxP3 in intestinal adenomas. MSD also suppressed HIF-1α expression in the intestinal adenomas, and HIF-1α inhibition decreased expression of FoxP3 in Jurkat T cells under hypoxic conditions.CONCLUSIONMSD is a valid prescription to control the formation of intestinal adenomas in ApcMin/+mice. It exerts anti-cancer effects partially through suppression of HIF-1α that induced activation of CD4+CD25+FoxP3+ Tregsin vivoandin vitro.