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Ginsenoside Rg3 protects against iE-DAP-induced endothelial-to-mesenchymal transition by regulating the miR-139-5p-NF-?B axis.

ABSTRACT: Background:Emerging evidence suggests that endothelial-to-mesenchymal transition (EndMT) in endothelial dysfunction due to persistent inflammation is a key component and emerging concept in the pathogenesis of vascular diseases. Ginsenoside Rg3 (Rg3), an active compound from red ginseng, has been known to be important for vascular homeostasis. However, the effect of Rg3 on inflammation-induced EndMT has never been reported. Here, we hypothesize that Rg3 might reverse the inflammation-induced EndMT and serve as a novel therapeutic strategy for vascular diseases. Methods:EndMT was examined under an inflammatory condition mediated by the NOD1 agonist, ?-d-glutamyl-meso-diaminopimelic acid (iE-DAP), treatment in human umbilical vein endothelial cells. The expression of EndMT markers was determined by Western blot analysis, real-time polymerase chain reaction, and immunocytochemistry. The underlying mechanisms of Rg3-mediated EndMT regulation were investigated by modulating the microRNA expression. Results:The NOD1 agonist, iE-DAP, led to a fibroblast-like morphology change with a decrease in the expression of endothelial markers and an increase in the expression of the mesenchymal marker, namely EndMT. On the other hand, Rg3 markedly attenuated the iE-DAP-induced EndMT and preserved the endothelial phenotype. Mechanically, miR-139 was downregulated in cells with iE-DAP-induced EndMT and partly reversed in response to Rg3 via the regulation of NF-?B signaling, suggesting that the Rg3-miR-139-5p-NF-?B axis is a key mediator in iE-DAP-induced EndMT. Conclusion:These results suggest, for the first time, that Rg3 can be used to inhibit inflammation-induced EndMT and may be a novel therapeutic option against EndMT-associated vascular diseases.

SUBMITTER: Lee A

PROVIDER: S-EPMC7031736 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Ginsenoside Rg3 protects against iE-DAP-induced endothelial-to-mesenchymal transition by regulating the miR-139-5p-NF-κB axis.

Lee Aram A Yun Eunsik E Chang Woochul W Kim Jongmin J

Journal of ginseng research 20190121 2

<h4>Background</h4>Emerging evidence suggests that endothelial-to-mesenchymal transition (EndMT) in endothelial dysfunction due to persistent inflammation is a key component and emerging concept in the pathogenesis of vascular diseases. Ginsenoside Rg3 (Rg3), an active compound from red ginseng, has been known to be important for vascular homeostasis. However, the effect of Rg3 on inflammation-induced EndMT has never been reported. Here, we hypothesize that Rg3 might reverse the inflammation-ind ...[more]

PMID: 32148412

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Project description:Platinum-based cytotoxic chemotherapy is considered the standard treatment for advanced gastric cancer (GC). However, cisplatin chemoresistance often occurs with the mechanisms being not well clarified, which results in the cancer recurrence and poor survival. Ginsenoside Rg3, isolated from the Chinese Herb Panax Ginseng, is recognized as an anti-cancer agent. Herein, we aimed to reveal whether Ginsenoside Rg3 alleviates cisplatin resistance and sensitizes GC cells to cisplatin-induced apoptosis, and draw out the underlying molecular mechanism in cisplatin-resistant GC cells. The lower expression of miR-429 was found in AGSR-CDDP cells; it was also in association with cisplatin-resistance in GC cells and expression of which was restored following Ginsenoside Rg3 treatment. We also demonstrated that miR-429 made a contribution toward chemosensitivity in GC cells partly through SOX2 regulation. SOX2 was found to contribute to developing platinum resistance and was an authentic target for miR-429 in AGSR-CDDP cells. Importantly, enforced expression of SOX2 with a pcDNA3-SOX2 construct lacking the 3'-UTR miRNA binding site diminished the cytotoxic effects of miR-429 in AGSR-CDDP cells. We demonstrated that Ginsenoside Rg3 enhanced chemosensitivity in AGSR-CDDP GC cells, at least in part, through up-regulating miR-429, thereby targeting SOX2 and modulating downstream PI3K/AKT/mTOR signaling. Ginsenoside Rg3 was also found to regulate apoptosis-related genes via miR-429 in cisplatin-resistant GC cells. Ginsenoside Rg3 treatment significantly suppressed the migration rate of AGSR-CDDP GC cells, while following transfection with anti-miR-429, the anti-migratory effects of Ginsenoside Rg3 was partially abolished. This data suggested that Ginsenoside Rg3 may impede the chemoresistance and migration of GC cells mainly mediated through miR-429. We concluded that miR-429-regulated SOX2 expression was one of the main mechanisms by which Ginsenoside Rg3 dramatically promoted its anticancer effects on cisplatin-resistant GC cells. We also underscored a supporting model in which miR-429 adjusted PI3K/AKT/mTOR signaling by regulating SOX2 in cisplatin-resistant GC cells.

Project description:BackgroundPrevious data have suggested that ginsenoside Rg3 (Rg3), isolated from the roots of Panax ginseng, plays a repressing role in multiple cancers, including osteosarcoma (OS). However, there is no any literature available about the role of circular RNA (circRNA) in Rg3-mediated OS development. The study aimed to explore the function of circ_0003074 in the anti-cancer effects of Rg3 on OS.MethodsRNA expression of circ_0003074, miR-516b-5p and karyopherin subunit alpha 4 (KPNA4) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was evaluated by Western blotting or immunohistochemistry assay. Cell viability, proliferation, apoptosis, migration and invasion were investigated by cell counting kit-8, 5-ethynyl-29-deoxyuridine (EdU), flow cytometry analysis, wound-healing and transwell invasion assays, respectively. Dual-luciferase reporter and/or RNA immunoprecipitation assay was performed to confirm the interplay between miR-516b-5p and circ_0003074 or KPNA4. Xenograft mouse model assay was conducted to reveal the effect of Rg3 treatment on tumor formation.ResultsCirc_0003074 and KPNA4 expression was significantly upregulated, while miR-516b-5p was downregulated in OS tissues and cells compared with controls. Rg3 treatment dramatically decreased circ_0003074 expression in OS cells. Rg3 treatment led to decreased cell proliferation, migration and invasion but increased cell apoptosis, which was attenuated after circ_0003074 overexpression. Besides, miR-516b-5p was a target miRNA of circ_0003074 and partially restored circ_0003074-mediated action under Rg3 treatment. Decreasing miR-516b-5p expression also promoted Rg3-treated OS cell malignancy through KPNA4, which was identified as a target mRNA of miR-516b-5p. Besides, circ_0003074 induced KPNA4 production owing to the decrease of miR-516b-5p expression. Furthermore, Rg3 treatment inhibited tumor formation by regulating circ_0003074 in vivo.ConclusionRg3 inhibited OS progression through circ_0003074/miR-516b-5p/KPNA4 axis, showing the potential of Rg3 as a therapeutic agent for OS.

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Dataset Information

Ginsenoside Rg3 protects against iE-DAP-induced endothelial-to-mesenchymal transition by regulating the miR-139-5p-NF-?B axis.

Publications

Ginsenoside Rg3 protects against iE-DAP-induced endothelial-to-mesenchymal transition by regulating the miR-139-5p-NF-κB axis.

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