中药配伍组分调控非酶蛋白糖基化及细胞转导通路改善糖尿病血管病变的机理研究

Diabetic vascular disease is one of the most important complications of diabetes, to bring great harm to health. Recent studies found, advanced glycation end products ( AGEs ) and receptor ( RAGE ) combined with the activation of mitogen-activated protein kinase ( MAPK ) signal transduction pathways leading to oxidative stress, inflammatory reaction, growth factors, cell proliferation, apoptosis and vascular disease closely related. Chinese medicine composition consists of Ophiopogon japonicus polysaccharide of Rhizoma Coptidis alkaloids, saponins, three seven. Our previous study showed that, the inhibition of protein non enzymatic glycosylation, reduce AGEs, improve endothelial function, antioxidant and inflammatory reaction, vascular disease, delay the reversal process. However, at present there is no compatibility of traditional Chinese medicine composition regulation of the AGEs-RAGE/MAPK pathway is reported. The research group of " Chinese medicine component through the regulation of AGEs-RAGE/MAPK pathway system in the prevention of diabetic vascular disease " hypothesis, by animal experiments and in vitro cell culture, to observe its effect on AGEs-RAGE/MAPK pathway system related protein and its downstream signaling mediated by oxidative stress, inflammation, proliferation, apoptosis, tissue factor and pathological changes of influence, a new target to explore and explain the compatibility of traditional Chinese medicine components of prevention and treatment of diabetic vascular disease and the possible mechanism.

糖尿病血管病变是糖尿病最重要并发症，给健康带来极大危害。近来研究发现，糖基化终末产物（AGEs）与受体（RAGE）结合激活丝裂原活化蛋白激酶（MAPK）细胞转导通路导致氧化应激、炎症反应、生长因子、细胞增殖、凋亡与血管病变密切相关。中药配伍组分由麦冬多糖、黄连生物碱、三七总皂苷组成。我们既往研究表明，其可抑制蛋白非酶糖基化，减少AGEs，改善血管内皮功能，抗氧化及炎症反应，延缓、逆转血管病变进程。然而目前尚无中药配伍组分调控AGEs-RAGE/MAPK通路报道。本课题组设"中药配伍组分通过调控AGEs-RAGE/MAPK通路系统防治糖尿病血管病变"假说，采用动物实验及体外细胞培养，观察其对AGEs-RAGE/MAPK通路系统相关蛋白及其下游信号介导的氧化应激、炎症反应、生长因子及细胞增殖、凋亡、组织病理结构改变的影响，探究并阐释中药配伍组分防治糖尿病血管病变的新靶点和可能机制。

糖尿病血管病变是糖尿病最重要并发症，给健康带来极大危害。近来研究发现，糖基化终末产物（AGEs）与受体（RAGE）结合激活丝裂原活化蛋白激酶（MAPK）细胞转导通路导致氧化应激、炎症反应、生长因子、细胞增殖、凋亡与糖尿病血管病变密切相关。中药配伍组分由麦冬多糖、黄连生物碱、三七总皂苷组成。我们既往研究表明，其可抑制蛋白非酶糖基化，减少AGEs，改善血管内皮功能，抗氧化及炎症反应，延缓、逆转血管病变进程。.本课题组采用动物实验及体外细胞培养，观察其对AGEs-RAGE/MAPK通路系统相关蛋白及其下游信号介导的氧化应激、炎症反应、生长因子及细胞增殖、凋亡、组织病理结构改变的影响，. 结果显示：中药配伍组分可明显降低糖尿病动脉硬化兔AGEs的表达，可降低DA兔心肌及主动脉平滑肌细胞中MAPK信号传导通路中ERK、p38MAPK、ERK5、JNK 、CREB蛋白水平及AP-1、ATF-1、ATF-2蛋白水平；改善了糖尿病动脉粥样硬化兔心肌病变并抑制主动脉VSMC的增殖；可降低模型兔FBG、GHB、GSP、AR、FRA含量，降低空腹血糖，改善糖耐量异常；降低IRI、INS含量，改善胰岛素抵抗；降低TC、TG、LDL-C，升高HDL-C，调整血脂紊乱；降低AGEs、MDA、NO、NOS、升高SOD、GSH-PX含量，改善氧化应激损伤；降低降低hs-CRP、IL-6、TNF-α、ET、TGF-β1、PDGF、ICAM-1、VCAM-1、PAI-1，升高bFGF，缓解炎症反应；调控Caspase-3、bcl-2途径，有效抑制了心肌细胞凋亡。.结论：中药组分可能通过调控AGEs-RAGE/MAPK通路系统改善其下游信号介导的氧化应激、炎症反应、细胞增殖、凋亡、组织病理结构改变等糖尿病血管病变，这为中药配伍组分防治糖尿病血管病变找到了新靶点，并阐明了其部分作用机制。