低氧诱导因子的分子调控机制及中药的干预作用  

Molecular regulatory mechanisms of hypoxia-inducible factor and interventional effect of Chinese herbal medicine

作　　者：刘不悔 王美子 孙伟[1] 万毅刚[3] 吴薇[3] 房其军[2] 王文文 YEE Hong-yun 袁灿灿 刘莹露[3] 涂玥 CHONG Fee-lan LIU Bu-hui;WANG Mei-zi;SUN Wei;WAN Yi-gang;WU Wei;FANG Qi-jun;WANG Wen-wen;YEE Hong-yun;YUAN Can-can;LIU Ying-lu;TU Yue;CHONG Fee-lan(Nephrology Division,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China;Department of Traditional Chinese Medicine,Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210008,China;Department of Traditional Chinese Medicine,Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China;Department of Traditional Chinese Medicine Health Preservation,Acupuncture and Moxibustion and Massage College·Health Preservation and Rehabilitation College,Nanjing University of Chinese Medicine,Nanjing 210023,China;The School of Pharmacy,Management and Science University,Shah Alam 40100,Malaysia)

机构地区：[1]南京中医药大学附属医院肾内科,江苏南京210029 [2]南京中医药大学中西医结合鼓楼临床医学院中医科,江苏南京210008 [3]南京大学医学院附属鼓楼医院中医科,江苏南京210008 [4]南京中医药大学针灸推拿学院·养生康复学院中医养生学教研室,江苏南京210023 [5]The School of Pharmacy,Management and Science University,Shah Alam 40100,Malaysia

出　　处：《中国中药杂志》2020年第20期4805-4811,共7页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金面上项目(81774245,81573903);国家自然科学基金青年基金项目(81603675);江苏省自然科学基金青年基金项目(BK20161046);江苏省中医药科技发展计划项目(YB201937);南京市医学科技发展基金项目(QRX17042)。

摘　　要：低氧诱导因子(hypoxia-inducible factors,HIFs)是机体内感受和调节细胞氧浓度的关键转录因子。HIF-1由α和β等2个亚基组成,其中,HIF-1α的分子调控机制涉及其降解和活化等主要过程。HIF-1α的降解是由氧依赖性信号途径调控的,包括"希佩尔-林道病恶性肿瘤抑制蛋白(von hippel-lindau protein,pVHL)依赖通路"和"pVHL非依赖性通路";而HIF-1α的活化是由氧非依赖性信号途径调控的,包括哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)/真核生物始动因子4E结合蛋白1(eukaryotic initiation factor 4E-binding protein 1, 4EBP1)/HIF-1α通路、磷脂酰肌醇3激酶(phosph atidylinositol 3-kinase,PI3K)/丝氨酸-苏氨酸蛋白激酶(proteirrserinc-threonine kinases,Akt)/HIF-1α通路以及沉默信息调节因子1(silent information regulator1,Sirt1)/HIF-1α通路等。近年来,基于HIFs的分子调控机制,不仅研制出治疗肾性贫血的新药罗沙司他,在中药提取物中也发现了一些药理作用类似于HIFs的大分子物质,如大黄素、三七皂苷、厚朴酚以及灵仙新苷等,这些天然的大分子物质在炎症反应、自噬、表观遗传修饰以及细胞焦亡中发挥调控性作用。值得注意的是,对于常见的低氧相关疾病,如糖尿病肾病,HIFs介导的"细胞焦亡"可能是清利湿热类中药及其代表性经方(如二妙丸)干预炎症性组织、细胞损伤的新靶点。Hypoxia-inducible factors(HIFs)are the key transcription factors that sense and regulate cellular oxygen concentration in vivo. HIF-1 is composed of 2 subunits,α and β,in which,the molecular regulatory mechanism of HIF-1α involves the main processes of its degradation and activation. The degradation of HIF-1α is regulated by oxygen-dependent pathways,including "von hippel-lindau protein(pVHL)-dependent pathway" and "pVHL-independent pathway". The activation of HIF-1α is regulated by oxygen-independent pathways,including mammalian target of rapamycin(mTOR)/eukaryotic initiation factor 4 E-binding protein 1(4 EBP1)/HIF-1α pathway,phosphatidylinositol 3-kinase(PI3 K)/proteirrserinc-threonine kinases(Akt)/HIF-1α pathway and silent information regulator1(Sirt1)/HIF-1α pathway. In recent years,based on the molecular regulatory mechanism of HIFs,Roxadustat,a new drug for the treatment of renal anemia has been developed. Besides, some macromolecular substances with similar pharmacological effect to HIFs have been found in the extracts from Chinese herbal medicine(CHM),such as emodin,notoginseng triterpenes,honokiol and clematichinenoside. These natural macromolecular substances play the regulatory roles in inflammatory response,epigenetic modification and auto-phagy. It is worth noting that,for common hypoxic-related diseases including diabetic kidney disease,HIFs-mediated "pyroptosis" may be a new target of CHMs for clearing dampness and heat and its representative classical prescriptions(Ermiao Pills)in treating inflammatory injury in cells and tissues.

关 键 词：低氧诱导因子 中药 分子机制 信号通路 细胞焦亡 

分 类 号：R285[医药卫生—中药学]