Ginsenoside Rg1 Nanoparticles Induce Demethylation of H3K27me3 in VEGF-A and Jagged 1 Promoter Regions to Activate Angiogenesis After Ischemic Stroke

Abstract

Background Compared with traditional drugs, nanomaterial drugs have the benefits of improving the solubility, bioavailability, and absorption rate of insoluble drugs. Nanoporous complexes can increase the efficiency with which drugs can penetrate the blood-brain barrier and reach target organs. Ginsenoside Rg1 is an effective drug that promotes angiogenesis. Ginsenoside Rg1 composite nanoparticles were employed to induce the expression of several key epigenetic enzymes and then activate the VEGF and Notch pathways after the onset of ischemic brain lesions. Methods We constructed nanoparticles to fully encapsulate the therapeutic drug (ginsenoside Rg1), which can be transferred into brain tissue via the receptor-mediated transfer of drug-encapsulated nanoparticles. Evaluation of the therapeutic effect of ginsenoside Rg1 complex nanovesicles (CNV) was performed by in vitro and in vivo experiments. Real-time polymerase chain reaction (RT- PCR), Western blot, immunohistochemistry staining (IHC), and Co-immunoprecipitation (co-IP) were employed to screen for epigenetic enzymes with an up-regulated expression post ginsenoside Rg1-CNV intervention. RNA sequencing, shRNA knockdown, and chromatin Immunoprecipitation (ChIP) sequencing were performed to detect the target genes of ginsenoside Rg1-CNV that regulate angiogenesis. Then, bioinformatic analysis was performed to investigate the mechanism of action of epigenetic modifying enzymes in regulating target genes. Results The average of the synthesized ginsenoside Rg1-CNV was 203.78±6.83 nm, the polydispersion index was 0.135±0.007, and the Zeta potential was 23.13±1.65 mV. Through in vivo and in vitro experiments, we found that it promotes the proliferation, migration, and tubular formation of brain microvascular endothelial cells (BMECs). Meanwhile, the intervention of ginsenoside Rg1-CNV promoted the demethylation of H3K27me3 within the promoter region of VEGF-A and Jagged1 genes and reduced the H3K27me3 modification within this region. Conclusion The ginsenoside Rg1 nanoparticles may be an available blood-brain barrier penetrating agent for ischemic stroke.

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…Ginsenoside nanoparticles induce the expression of histone demethylases JMJD3 and UTX to increase the levels of demethylation in the promoter regions of VEGF-A and Jagged1, thereby promoting angiogenesis in rats with ischemic stroke [ 108 ]. Highly expressed DNMT1 and DNMT3A were detected in the spinal cord and skeletal muscle of mice with amyotrophic lateral sclerosis; however, treatment with the DNMT inhibitor RG108 improved motor function and prolonged survival in the affected mice [ 109 ].…”

Natural products for the treatment of chemotherapy-related cognitive impairment and prospects of nose-to-brain drug delivery

“…They discovered that administrating PHRO injection via tail venous could effectively penetrate the BBB, resulting in the sustained release of Rg1, which ultimately decreased the volume of cerebral infarction and enhanced recovery of neurons in rats suffering diabetes and cerebral infarction ( Shen et al, 2017 ; Shen et al, 2019 ). Additionally, Rg1-loaded complex nanovesicles could also across BBB and promote angiogenesis ( Shang et al, 2022 ). Notably, Li et al developed self-assembled Dox@Rg1 nanoparticles that not only mitigated DOX-induced cardiotoxicity but also enhanced its antitumor efficacy ( Li et al, 2021 ).…”

Recent advances in tissue repair of the blood-brain barrier after stroke

“… 146 Ginsenoside Rg1, which is completely encapsulated by nanoparticles, and notoginsenoside R1, a unique component of Panax notoginseng, can promote the proliferation, migration of HBMEC and tube formation during the treatment of cerebral ischemia. 147 , 148 Among them, notoginsenoside R1 shows pro-angiogenic effects partly dependent on the activation of the NAMPT-SIRT1 cascade, 148 while the therapeutic effects of ginsenoside Rg1 nanoparticles are achieved by inducing the demethylation of H3K27me3 within the promoter region of VEGF-A and Jagged1 genes. 147 In the regulation of angiogenesis in the treatment of cerebral ischemia, the mechanism of action of Astragaloside IV lies in the HIF/VEGF/Notch signaling pathway activated by miRNA-210.…”

“… 147 , 148 Among them, notoginsenoside R1 shows pro-angiogenic effects partly dependent on the activation of the NAMPT-SIRT1 cascade, 148 while the therapeutic effects of ginsenoside Rg1 nanoparticles are achieved by inducing the demethylation of H3K27me3 within the promoter region of VEGF-A and Jagged1 genes. 147 In the regulation of angiogenesis in the treatment of cerebral ischemia, the mechanism of action of Astragaloside IV lies in the HIF/VEGF/Notch signaling pathway activated by miRNA-210. 149 The pro-angiogenic process of Shengui Sansheng San (SSS) extract is associated with Akt/mTOR and ERK1/2 signaling pathways.…”