黄连解毒汤对白念珠菌组蛋白ε乙酰化信号途径的调控研究

In recent years, with the increasing application of hormone, immunosuppressive agents, tumor radiotherapy and chemotherapy, and other treatment methods, the clinical infection rate of Candida albicans is growing up, and in some cases it is serious life-threatening. At present, triazole drugs were first applied medcine for prevention and control of Candida albicans, but due to the long-term application and single target effect mode of triazole drugs, drug-resistant Candida albicans strains are increasing year by year. In the previous study, we found that Huanglian detoxification decoction has a good clinical anti-fungal effect, and can increase the sensitivity of triazole drugs against Candida albicans, and apart from this, it was also found that Huanglian detoxification decoction was involved in 26 signal pathways, including DNA replication and transfer protein activity, which suggesting that the effect of Huanglian detoxification decoction is acting on multiple signal pathways, but the clear mechanism in it still need further studies. Research works have shown that histone acetylation and histone deacetylation are related to the pathogenicity and virulence of Candida albicans, histone deacetylase inhibitors have a synergistic effect on the in vitro sensitivity of azole drugs. We speculate that Huanglian detoxification decoction may play an anti-fungal and sensitizing effect by regulating the acetylation-related signal pathways. The research target of this project is to study the regulation of signal pathways based on acetylation, and to discuss the possible mechanism of Huanglian detoxification decoction in inhibiting Candida albicans and the possible mechanism of west medicine sensibilization，and provide the theoretical basis for clinical application of Huanglian detoxification decoction.

近年来随着激素、免疫抑制剂、肿瘤放化疗等诊疗方法的应用，临床白色念珠菌感染率不断增加，严重时可危及生命。目前主要以三唑类药物进行防治，但是作为一线使用的三唑类药物由于长期应用和作用靶点的单一性，耐药菌株逐年增多。在前期研究中我们发现黄连解毒汤具有较好临床抗真菌作用，同时能增加三唑类药物的抗白念珠菌敏感性，通过转录组研究发现黄连解毒汤参与了包括DNA复制、转运蛋白活性在内的26个信号通路，提示黄连解毒汤的抑菌作用是同时作用于多个信号途径，但具体机制有待进一步明确。目前基本明确的是，白念珠菌乙酰化水平高低，能够显著影响其致病能力和耐药性，我们推测黄连解毒汤可能通过调控乙酰化相关信号途径发挥抗菌和增敏作用。本项目拟通过分析黄连解毒汤对白念珠菌乙酰化水平的调控，以及对白念珠菌毒力和药物敏感性的作用规律，阐明黄连解毒汤抗白念菌株以及药物增敏的可能机制和信号传导途径，为其临床应用提供理论依据。

近年来随着三唑类药物的长期使用，白色念珠菌的耐药菌株发现的越来越多，耐药性越来越强，因此选择合适的药物治疗念珠菌耐药菌株引起的感染，成为日益严峻的问题。白念珠菌感染的诊治已经成为医学上备受关注的问题。本课题计划从组蛋白乙酰化角度对黄连解毒汤抗白念珠菌及其与三唑类药物联用的协同效应的分子机制和信号传导途径进行研究和解读。着力于阐明白念珠菌乙酰化的相关酶的催化特点；揭示组蛋白乙酰化位点和水平影响念珠菌毒力、耐药性的机制和规律；阐明黄连解毒汤 “协同效应”所依赖的信号传导途径。但是由于实验过程，随着各层面管理的加强，白念菌株实验不能在我校和我院一级实验室完成，在联系合适的二级实验室过程中花费较为大的周折，同时由于新冠肺炎疫情的原因，我们的实验出现耽误，目前主要发现白念珠菌毒性和氟康唑耐药性可能与蛋白乙酰化水平有关；黄连解毒汤可能通过降低蛋白乙酰化水平来抑制白念珠菌毒性和氟康唑耐药性，且高剂量黄连解毒汤调节作用更强，同时检测了高剂量黄连解毒汤对白念菌株毒力基因和耐药基因的表达有明显的抑制作用，但是黄连解毒汤对白念菌作用前后的蛋白乙酰化分析和转录组测序尚未完全完成，预期在后续2个月内可以完成相应的内容。