基于TNF-α介导的IKK/IκB/NF-κB信号通道探讨补肾化瘀方调控多囊卵巢综合征伴胰岛素抵抗的机制研究

Polycystic ovary syndrome (PCOS) is a most common syndrome of reproductive dysfunction, abnormal glucose metabolism coexist and endocrine disorders for women of childbearing age. New research showed that the levels of proinflammatory cytokines (TNF, CRP, IL-6, etc.) in the peripheral blood is increased for patients with PCOS, and PCOS may be a low-grade chronic inflammatory disease. Insulin resistance (IR) is closely related with PCOS which IR is great significance not only for long-term health risks of PCOS patients, but also it may aggravate the inflammation of PCOS patients. The expression imbalance of IKK, IκB and NF-κB is one of the important reasons of chronic inflammatory diseases. We hypothesized that IKK / of IκB / NF-κB signal transduction may be closely related with PCOS, and blocking TNF-a-mediated of IKK /of IκB / NF-κB signaling pathway is perhaps the key part in the treatment of PCOS. Chinese medicine treatment of PCOS can gain stable efficacy and low adverse reactions. Gansu Province is located in the northwest, and cold and hypoxia special environment is prone to cause the body's blood stasis. There is the PCOS common deficiency and blood stasis permit application Invigorating Kidney significant effect.This study will discuss regulation mechanism of tonifying kidneys and activating blood for PCOS with IR on the basis of TNF-α-mediated IKK / of IκB / NF-κB signaling pathway and provide technical platform and theoretical basis.

多囊卵巢综合征（PCOS）是育龄期妇女常见的生殖功能障碍与糖代谢异常并存的内分泌紊乱综合征。研究表明PCOS患者外周血促炎细胞因子（TNF、CRP、IL-6等）水平增高，PCOS可能是一种低度慢性炎症性疾病。胰岛素抵抗（IR）与PCOS密切关系，IR不仅能影响PCOS的远期健康风险，而且能加重炎症表现。IKK，IκB和NF-κB的表达失衡是慢性炎症性疾病发生发展的重要原因之一，因此我们推测IKK/IκB/NF-κB信号转导与PCOS密切相关，阻断TNF-α介导的IKK/IκB/NF-κB信号通路可能是治疗PCOS的关键环节。甘肃地处西北，寒冷、缺氧的特殊环境致使PCOS患者以血脉瘀阻，肾虚血瘀证多见，以补肾活血法治疗此病切合病机，故疗效显著。本研究基于TNF-α介导的IKK/IκB/NF-κB信号通路探讨补肾化瘀方对PCOS伴IR的调控作用，为PCOS的诊治提供技术平台和奠定理论基础。

目的：基于TNF-α介导的IKK/IκB/NF-κB信号通道探讨补肾化瘀方调控多囊卵巢综合征伴胰岛素抵抗的机制研究。方法：利用免疫组化、Western Blot、 RT-PCR等多种细胞分子生物学技术和方法，通过临床病例采集和动物实验，从整体、细胞及分子水平等不同层面探讨TNF-α介导的IKK/IκB/NF-κB信号通路对PCOS伴IR的调控机制，并阐明中药阻断IKK/IκB/NF-κB信号通路的分子生物学机制。结果：多囊卵巢综合征伴IR与不伴IR两组患者在中医证型分布上无明显差异，TNF-α介导的IKK/IκB/NF-κB炎症信号通路可能参与了多囊卵巢综合征IR的病理进程，补肾化瘀方具有阻断PCOS伴IR大鼠模型IKK/IκB/NF-κB信号通路转导系统的作用，补肾化瘀颗粒能有效调节炎性因子TNF-α、NF-κB、IκBα，抑制PCOS形成，明显改善卵巢细胞的形态，TNF-α与NF-κB呈正反馈，而IκBα与TNF-α、NF-κB呈负反馈调节PCOS，且IκBα可能是造成PCOS的靶细胞。结论：通过对补肾化瘀颗粒成分-靶点-信号通路研究发现，补肾化瘀颗粒主要活性成分作用于多个靶点，从而发挥抗多囊卵巢作用，但补肾化瘀颗粒的活性成分对靶点IκBα的作用，需要后续进一步研究。