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Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis.

ABSTRACT: Ginsenoside 20(R/S)-Rg3, as a natural peroxisome proliferator-activated receptor gamma (PPAR?) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)-Rg3 and explore whether differential PPAR? activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)-Rg3 stereoisomers in the PPAR? ligand-binding domain (PPAR?-LBD) using molecular modelling and their effects on smooth muscle cell proliferation and migration induced by advanced glycation end products (AGEs). The results revealed that 20(S)-Rg3 exhibited stronger antiproliferative and antimigratory effects due to stronger PPAR? activation. To validate the in vitro results, we used a mice model with diabetic atherosclerosis and obtained that 20(S)-Rg3 markedly reduced the plaque size secondary to reducing the proliferation and migration of VSMCs, while the plaques were more stable due to improvements in other plaque compositions. The results shed light on the structural difference between Rg3 stereoisomers that can lead to significant differential physiological outcome, and the (S)-isomer seems to be the more potent isomer to be developed as a promising drug for diabetic atherosclerosis.

SUBMITTER: Guo M

PROVIDER: S-EPMC5980205 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis.

Guo Mengqi M Guo Guanlun G Xiao Jie J Sheng Xi X Zhang Xinyu X Tie Yuanyuan Y Cheng Yuen-Kit YK Ji Xiaoping X

Journal of cellular and molecular medicine 20180322 6

Ginsenoside 20(R/S)-Rg3, as a natural peroxisome proliferator-activated receptor gamma (PPARγ) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)-Rg3 and explore whether differential PPARγ activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)-Rg3 stereois ...[more]

PMID: 29566305

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Project description:Diabetic nephropathy (DN), a common diabetes-related complication, is the leading cause of progressive chronic kidney disease (CKD) and end‑stage renal disease. Despite the rapid development in the treatment of DN, currently available therapies used in early DN cannot prevent progressive CKD. The exact pathogenic mechanisms and the molecular events underlying DN development remain unclear. Ginsenoside Rg3 is a herbal medicine with numerous pharmacological effects. To gain a greater understanding of the molecular mechanism and signaling pathway underlying the effect of ginsenoside Rg3 in DN therapy, an RNA sequencing approach was performed to screen differential gene expression in a rat model of DN treated with ginsenoside Rg3. A combined bioinformatics analysis was then conducted to obtain insights into the underlying molecular mechanisms of the disease development, in order to identify potential novel targets for the treatment of DN. Six Sprague‑Dawley male rats were randomly divided into 3 groups: Normal control group, DN group and ginsenoside‑Rg3 treatment group, with two rats in each group. RNA sequencing was adopted for transcriptome profiling of cells from the renal cortex of DN rat model. Differentially expressed genes were screened out. Cluster analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to analyze the differentially expressed genes. In total, 78 differentially expressed genes in the DN control group were identified when compared with the normal control group, of which 52 genes were upregulated and 26 genes were downregulated. Differential expression of 43 genes was observed in the ginsenoside‑Rg3 treatment group when compared with the DN control group, consisting of 10 upregulated genes and 33 downregulated genes. Notably, 21 that were downregulated in the DN control group compared with the control were then shown to be upregulated in the ginsenoside‑Rg3 treatment group compared with the DN control group. In addition, 7 upregulated genes in the DN control group compared with the control were then shown to be downregulated in the ginsenoside‑Rg3 treatment group compared with the DN control group. Cluster analysis based on differentially expressed genes indicated that the transcriptomes are quite different among the samples. Distinct GO terms associated with these groups of genes were shown to be enriched. KEGG pathway analysis demonstrated that differentially expressed genes were predominantly involved in the fatty acid metabolism pathway and peroxisome proliferator‑activated receptor (PPAR) signaling pathway. To the best of our knowledge, this study was the first to present whole genome expression profiling in DN with ginsenoside‑Rg3 treatment by RNA‑Seq. A set of differentially expressed genes and pathways were identified. These data provided an insight into understanding the molecular mechanisms underlying the effect of ginsenoside‑Rg3 treatment of DN.

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Dataset Information

Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis.

Publications

Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis.

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