文献类型： 外文期刊

作者： Chen, Xiangjun ¹ ; Zhang, Ying ² ; Cao, Zhongkai ¹ ; Wang, Yue ⁴ ; Liao, Mengqiu ¹ ; Guan, Yuelin ¹ ; Zhu, Caifeng ⁵ ; Wang, Wenmin ¹ ; Huang, Wunan ⁶ ; Li, Wei ¹ ; Xiao, Yingping ⁷ ; Li, Yayu ⁵ ; Yin, Jiazhen ⁵ ; Ding, Yuhan ⁸ ; Peng, Qinghua ³ ; Hu, Lidan ¹ ;

作者机构： 1.Zhejiang Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth, Sch Med,Dept Nephrol, Hangzhou 310052, Zhejiang, Peoples R China

2.Zhejiang Univ, Inst Translat Med, Sch Med, Hangzhou 310052, Peoples R China

3.Hunan Univ Chinese Med, Sch TCM, Changsha, Peoples R China

4.Hubei Normal Univ, Huangshi 435002, Peoples R China

5.Hangzhou TCM Hosp, Dept Nephrol, Hangzhou, Peoples R China

6.Lanzhou Univ, Clin Med Coll 1, Lanzhou 730000, Peoples R China

7.Zhejiang Acad Agr Sci, Inst Agroprod Safety & Nutr, State Key Lab Managing Biot & Chem Threats Qual &, Hangzhou, Peoples R China

8.Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China

关键词： Diabetic nephropathy; Hup A; Metabolome; Microbiome; Network pharmacology; Transcriptome

期刊名称：PHARMACOLOGICAL RESEARCH （ 影响因子：10.5； 五年影响因子：10.3 ）

ISSN： 1043-6618

年卷期： 2024 年 208 卷

页码：

收录情况： SCI

摘要： Aims: Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms Methods: We applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted. Results: Hup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings.