摘要
药物重定位为现有药物提供了新的临床适应症。机体的"免疫-炎症"调节失衡是糖尿病肾病发生、发展的重要因素之一。中成药昆仙胶囊具有显著的抗炎和免疫调节作用,且有少量临床证据表明,该药具有缓解糖尿病肾病的潜能,但其作用机制尚不明确。因此,本研究整合"疾病基因-药物靶标-生物通路-功能模块"多层次关联网络分析及体内、体外实验验证,探究昆仙胶囊治疗糖尿病肾病的药理作用及其分子机制。实验方案经中国中医科学院实验动物福利与伦理委员会审查,符合实验动物福利与伦理相关规定。网络分析结果表明,昆仙胶囊干预糖尿病肾病的候选网络靶标可显著参与调节机体免疫-炎症反应、缓解肾脏基底膜病变、调节肾脏血液流变学异常、调节机体能量代谢和各类激素代谢的功能模块,且参与PI3K/AKT/NF-κB通路的网络靶标数目最多。进一步的体内、体外实验验证表明,昆仙胶囊灌胃给药可有效降低糖尿病肾病大鼠的血糖并改善胰岛素抵抗、降低血脂水平、抑制肾脏细胞外基质蛋白的生成和肾脏炎症、改善肾脏功能及病理损伤,并能够有效抑制PI3K/AKT/NF-κB/TNF-α/IL-1β通路的活性。可见,昆仙胶囊具有通过调节机体"免疫-炎症"失衡而缓解糖尿病肾病的潜能。
Drug repositioning provides new clinical indications for existing drugs.The imbalance between body’s"immune-inflammation"regulation is one of the important factors in the occurrence and development of diabetic nephropathy(DN).Chinese patent medicine Kunxian capsule is clinically used for treating rheumatoid arthritis with satisfying immune-modulatory and anti-inflammatory actions.Notably,accumulating clinical evidence based on small cohorts had shown that Kunxian capsule may be used to treat DN.But the underlying pharmacological mechanisms remain unclear.Therefore,this study integrated"drug target-disease gene-biological pathway-function module"multi-level associated network analysis,and in vivo and in vitro experiments,to verify the pharmacological effects of Kunxian capsules in DN and to elucidate its molecular mechanisms.The experimental protocol was reviewed by the Laboratory Animal Welfare and Ethics Committee of China Academy of Chinese Medical Sciences,and it complies with the relevant regulations on laboratory animal welfare and ethics.As a result,the network analysis showed that the candidate targets of Kunxian capsule against DN were significantly involved into various functional modules which were related to modulation of immune-inflammation system,basement membrane lesion,abnormal hemorheology,energy metabolism and hormone metabolism,and the number of targets enriched by PI3K/AKT/NF-κB pathway is the largest.In addition,both in vivo and in vitro experiments demonstrated that Kunxian capsule by gavage effectively reduced blood glucose,improved insulin resistance,reduced blood lipid,inhibited renal extracellular matrix protein production and renal inflammation,improved renal function and pathological damages,and inhibited the activity of PI3K/AKT/NF-κB/TNF-α/IL-1β pathway in diabetic nephropathy rats.Collectively,these findings suggest the therapeutic potentials of Kunxian capsule to alleviate DN by regulating the imbalance of immune-inflammation system.
作者
刘毓东
马兆臣
李聪翀
林雅
张彦琼
林娜
LIU Yu-dong;MA Zhao-chen;LI Cong-chong;LIN Ya;ZHANG Yan-qiong;LIN Na(College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China)
出处
《药学学报》
CAS
CSCD
北大核心
2022年第2期375-384,共10页
Acta Pharmaceutica Sinica
基金
国家重大新药创制项目(2019ZX09731-002)
中央级公益性科研院所基本科研业务费专项(ZXKT19002)。
