1. Huperzine A targets Apolipoprotein E: A potential therapeutic drug for diabetic nephropathy based on omics analysis.
- Author
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Chen X, Zhang Y, Cao Z, Wang Y, Liao M, Guan Y, Zhu C, Wang W, Huang W, Li W, Xiao Y, Li Y, Yin J, Ding Y, Peng Q, and Hu L
- Subjects
- Animals, Male, Humans, Rats, Mice, Kidney drug effects, Kidney metabolism, Kidney pathology, Transcriptome drug effects, Mice, Inbred C57BL, Network Pharmacology, Metabolomics, Middle Aged, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Female, Diabetic Nephropathies drug therapy, Diabetic Nephropathies metabolism, Diabetic Nephropathies genetics, Alkaloids pharmacology, Alkaloids therapeutic use, Sesquiterpenes pharmacology, Sesquiterpenes therapeutic use, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism, Rats, Sprague-Dawley, Apolipoproteins E genetics
- Abstract
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., Conclusions: Collectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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