20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway.
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ABSTRACT:
SUBMITTER: Zhang F
PROVIDER: S-EPMC4539091 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:The replicative senescence of human dermal fibroblasts (HDFs) is accompanied by growth arrest. In our previous study, the treatment of senescent HDFs with Rg3(S) lowered the intrinsic reactive oxygen species (ROS) levels and reversed cellular senescence by inducing peroxiredoxin-3, an antioxidant enzyme. However, the signaling pathways involved in Rg3(S)-induced senescence reversal in HDFs and the relatedness of the stereoisomer Rg3(R) in corresponding signaling pathways are not known yet. Methods:We performed senescence-associated ?-galactosidase and cell cycle assays in Rg3(S)-treated senescent HDFs. The levels of ROS, adenosine triphosphate (ATP), and cyclic adenosine monophosphate (cAMP) as well as the mitochondrial DNA copy number, nicotinamide adenine dinucleotide (NAD)+/1,4-dihydronicotinamide adenine dinucleotide (NADH) ratio, and NAD-dependent sirtuins expression were measured and compared among young, old, and Rg3(S)-pretreated old HDFs. Major signaling pathways of phosphatidylinositol 3-kinase/Akt, 5' adenosine monophosphate-activated protein kinase (AMPK), and sirtuin 1/3, including cell cycle regulatory proteins, were examined by immunoblot analysis. Results:Ginsenoside Rg3(S) reversed the replicative senescence of HDFs by restoring the ATP level and NAD+/NADH ratio in downregulated senescent HDFs. Rg3(S) recovered directly the cellular levels of ROS and the NAD+/NADH ratio in young HDFs inactivated by rotenone. Rg3(S) mainly downregulated phosphatidylinositol 3-kinase/Akt through the inhibition of mTOR by cell cycle regulators like p53/p21 in senescent HDFs, whereas Rg3(R) did not alter the corresponding signaling pathways. Rg3(S)-activated sirtuin 3/PGC1? to stimulate mitochondrial biogenesis. Conclusion:Cellular molecular analysis suggests that Rg3(S) specifically reverses the replicative senescence of HDFs by modulating Akt-mTOR-sirtuin signaling to promote the biogenesis of mitochondria.
| S-EPMC7031753 | biostudies-literature
Project description:The angio-suppressive effect of 20(R)-ginsenoside Rg3 (Rg3-R) has been previously demonstrated, and microRNAs (miRNAs) are a vital group of small non-coding RNAs that function as post-transcriptional modulator of gene expression. Thus, using human umbilical vein endothelial cells (HUVEC) as model, we compared the microRNA (miRNA) expression profile of vascular endothelial growth factor (VEGF)-induced cells with the profile of the cell co-treated with VEGF and Rg3-R. Among the screened 553 human miRNAs, 6 up-regulated (miR-520h, miR-487b, miR-197, miR-524*, miR-342 and miR-219) and 3 down-regulated (miR-23a, miR-489 and miR-377) miRNAs were detected in Rg3-R treated vascular endothelial growth factor (VEGF)-induced HUVECs compared to VEGF alone. Real time RT-PCR was subsequently performed to verify the miRNA microarray result. Two condition experiment: VEGF-induced HUVEC and VEGF-induced HUVEC treated with Rg3-R. Three independent microarray experiments, with triplicate per microarray.
2011-09-09 | E-GEOD-31959 | biostudies-arrayexpress
Project description:The angio-suppressive effect of 20(R)-ginsenoside Rg3 (Rg3-R) has been previously demonstrated, and microRNAs (miRNAs) are a vital group of small non-coding RNAs that function as post-transcriptional modulator of gene expression. Thus, using human umbilical vein endothelial cells (HUVEC) as model, we compared the microRNA (miRNA) expression profile of vascular endothelial growth factor (VEGF)-induced cells with the profile of the cell co-treated with VEGF and Rg3-R. Among the screened 553 human miRNAs, 6 up-regulated (miR-520h, miR-487b, miR-197, miR-524*, miR-342 and miR-219) and 3 down-regulated (miR-23a, miR-489 and miR-377) miRNAs were detected in Rg3-R treated vascular endothelial growth factor (VEGF)-induced HUVECs compared to VEGF alone. Real time RT-PCR was subsequently performed to verify the miRNA microarray result.
2011-09-10 | GSE31959 | GEO
Project description:BackgroundGinsenoside-Rg3, the pharmacologically active component of red ginseng, has been found to inhibit tumor growth, invasion, metastasis, and angiogenesis in various cancer models. Previously, we found that 20(R)-ginsenoside-Rg3 (Rg3) could inhibit angiogenesis. Since microRNAs (miRNAs) have been shown to affect many biological processes, they might play an important role in ginsenoside-mediated angiomodulation.MethodsIn this study, we examined the underlying mechanisms of Rg3-induced angiosuppression through modulating the miRNA expression. In the miRNA-expression profiling analysis, six miRNAs and three miRNAs were found to be up- or down-regulated in vascular-endothelial-growth-factor-induced human-umbilical-vein endothelial cells (HUVECs) after Rg3 treatment, respectively.ResultsA computational prediction suggested that mature hsa-miR-520h (miR-520h) targets ephrin receptor (Eph) B2 and EphB4, and hence, affecting angiogenesis. The up-regulation of miR-520h after Rg3 treatment was validated by quantitative real-time polymerase chain reaction, while the protein expressions of EphB2 and EphB4 were found to decrease, respectively. The mimics and inhibitors of miR-520h were transfected into HUVECs and injected into zebra-fish embryos. The results showed that overexpression of miR-520h could significantly suppress the EphB2 and EphB4 protein expression, proliferation, and tubulogenesis of HUVECs, and the subintestinal-vessel formation of the zebra fish.ConclusionThese results might provide further information on the mechanism of Rg3-induced angiosuppression and the involvement of miRNAs in angiogenesis.
| S-EPMC4845046 | biostudies-literature
Project description:BackgroundThymic stromal lymphopoietin (TSLP) acts as a master switch for inflammatory responses. Ginsenoside Rg3 (Rg3) which is an active ingredient of Panax ginseng Meyer (Araliaceae) is known to possess various therapeutic effects. However, a modulatory effect of Rg3 on TSLP expression in the inflammatory responses remains poorly understood.MethodsWe investigated antiinflammatory effects of Rg3 on an in vitro model using HMC-1 cells stimulated by PMA plus calcium ionophore (PMACI), as well as an in vivo model using PMA-induced mouse ear edema. TSLP and vascular endothelial growth factor (VEGF) levels were detected using enzyme-linked immunosorbent assay or real-time PCR analysis. Murine double minute 2 (MDM2) and hypoxia-inducible factor 1α (HIF1α) expression levels were detected using Western blot analysis.ResultsRg3 treatment restrained the production and mRNA expression levels of TSLP and VEGF in activated HMC-1 cells. Rg3 down-regulated the MDM2 expression level increased by PMACI stimulation. The HIF1α expression level was also reduced by Rg3 in activated HMC-1 cells. In addition, Rg3-administered mice showed the decreased redness and ear thickness in PMA-irritated ear edema. Rg3 inhibited the TSLP and VEGF levels in the serum and ear tissue homogenate. Moreover, the MDM2 and HIF1α expression levels in the ear tissue homogenate were suppressed by Rg3.ConclusionTaken together, the current study identifies new mechanistic evidence about MDM2/HIF1α pathway in the antiinflammatory effect of Rg3, providing a new effective therapeutic strategy for the treatment of skin inflammatory diseases.
| S-EPMC8587510 | biostudies-literature
Project description:Inflammation and autophagy occur during hepatic fibrosis development caused by various pathogens, and effectively curbing of autophage may delay the occurrence of hepatic fibrosis. The current study aimed to unravel the inhibitory effects of Ginsenoside Rg3 (G-Rg3) on inflammation-mediated hepatic autophagy to curb hepatic fibrosis caused by thioacetamide (TAA)-induced subacute and chronic hepatic injury. TAA is mainly metabolized in the liver to cause liver dysfunction. After intraperitoneal injection of TAA for 4 or 10 weeks (TAA-chronic mouse models), severe inflammatory infiltration and fibrosis occurred in the liver. Treatment with G-Rg3 alleviated hepatic pathological changes and reversed hepatic fibrosis in the TAA-chronic models with decreased deposition of collagen fibers, reduced expression of HSCs activation marker (α-SMA), and reduced secretion of profibrogenic factors (TGF-β1). G-Rg3 decreased expressions of autophagy-related proteins in mice of TAA-chronic models. Notably, G-Rg3 inhibited the survival of activated rat hepatic stellate cells (HSC-T6), but had no cytotoxicity on human hepatocytes (L02 cell lines). G-Rg3 dose-dependently inhibited autophagy in vitro with less expression of p62 and fewer LC3a transformation into LC3b in inflammatory inducer lipopolysaccharide (LPS)-induced rat HSC-T6 cells. Furthermore, G-Rg3 enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) in vivo and in vitro. Besides, mTOR inhibitor Rapamycin and PI3K inhibitors LY294002 were employed in LPS-treated HSC-T6 cell cultures to verify that Rg3 partially reversed the increase in autophagy in hepatic fibrosis in vitro. Taken together, G-Rg3 exerted anti-fibrosis effect through the inhibition of autophagy in TAA-treated mice and LPS-stimulated HSC-T6 cells. These data collectively unravel that G-Rg3 may serve a promising anti-hepatic fibrosis drug.
| S-EPMC7293224 | biostudies-literature
Project description:20(S)-Ginsenoside Rg3 (20(S)-Rg3) has been shown to induce apoptosis by interfering with several signaling pathways. Furthermore, it has been reported to have anticancer and antidiabetic effects. In order to detect the protective effect of 20(S)-Rg3 on diabetic kidney disease (DKD), diabetic rat models which were established by administering high-sugar, high-fat diet combined with intraperitoneal injection of streptozotocin (STZ), and age-matched wild-type (WT) rat were given 20(S)-Rg3 for 12 weeks, with three groups: control group (normal adult rats with saline), diabetic group (diabetic rats with saline), and 20(S)-Rg3 treatment group (diabetic rats with 20(S)-Rg3 (10 mg/kg body weight/day)). The biochemical indicators and the changes in glomerular basement membrane and mesangial matrix were detected. TUNEL staining was used to detect glomerular and renal tubular cell apoptosis. Immunohistochemical staining was used to detect the expression of fibrosis factors and inflammation factors in rat kidney tissues. Through periodic acid-Schiff staining, we observed that the change in renal histology was improved and renal tubular epithelial cell apoptosis decreased significantly by treatment with 20(S)-Rg3. Plus, the urine protein decreased in the rats with the 20(S)-Rg3 treatment. Fasting blood glucose, creatinine, total cholesterol, and triglyceride levels in the 20(S)-Rg3 treatment group were all lower than those in the diabetic group. Mechanistically, 20(S)-Rg3 dramatically downregulated the expression of TGF-β1, NF-κB65, and TNF-α in the kidney. These resulted in a significant prevention of renal damage from the inflammation. The results of the current study suggest that 20(S)-Rg3 could potentially be used as a novel treatment against DKD.
| S-EPMC7106937 | biostudies-literature
Project description:BackgroundGinsenoside 20(S)-Rg3 shows promising tumor-suppressive effects in ovarian cancer via inhibiting NF-κB signaling. This study aimed to explore the downstream tumor suppressive mechanisms of ginsenoside Rg3 via this signaling pathway.Materials and methodsA systematical screening was applied to examine the expression profile of 41 kinesin family member genes in ovarian cancer. The regulatory effect of ginsenoside Rg3 on KIF20A expression was studied. In addition, we explored interacting proteins of KIF20A and their molecular regulations in ovarian cancer. RNA-seq data from The Cancer Genome Atlas (TCGA) was used for bioinformatic analysis. Epithelial ovarian cancer cell lines SKOV3 and A2780 were used as in vitro and in vivo cell models. Commercial human ovarian cancer tissue arrays were used for immunohistochemistry staining.ResultsKIF20A is a biomarker of poor prognosis among the kinesin genes. It promotes ovarian cancer cell growth in vitro and in vivo. Ginsenoside Rg3 can suppress the transcription of KIF20A. GST pull-down and co-immunoprecipitation (IP) assays confirmed that KIF20A physically interacts with BTRC (β-TrCP1), a substrate recognition subunit for SCFβ-TrCP E3 ubiquitin ligase. In vitro ubiquitination and cycloheximide (CHX) chase assays showed that via interacting with BTRC, KIF20A reduces BTRC-mediated CDC25A poly-ubiquitination and enhances its stability. Ginsenoside Rg3 treatment partly abrogates KIF20A overexpression-induced CDC25A upregulation.ConclusionThis study revealed a novel anti-tumor mechanism of ginsenoside Rg3. It can inhibit KIF20A transcription and promote CDC25A proteasomal degradation in epithelial ovarian cancer.
| S-EPMC10785255 | biostudies-literature
Project description:Ginsenoside Rg3 is a steroidal saponin isolated from Panax ginseng. Previous studies have shown that Rg3 treatment downregulates the activity of rapamycin complex 1 (mTORC1) activity and inhibits the growth of cancer cells. However, the inhibitory effect of Rg3 on cancer cells is associated with high concentrations of Rg3 that are difficult to achieve in vivo. The human cervix adenocarcinoma HeLa cells were treated with Rg3. The protein levels of AMP-activated protein kinase alpha (AMPKα), protein kinase B(Akt), ribosomal S6 protein(S6), and Erk were determined by immunoblotting analyses. We used a fluorescent probe to detect reactive oxygen species (ROS) production in living cells. The oxygen consumption rate (OCR) was examined by the Seahorse Extracellular Flux Analyzer. The content of adenosine triphosphate (ATP) was measured by ATPlite kit and Mitotracker was applied to detect the mitochondria. We showed that at lower concentrations, Rg3 activates mTORC1 independent of AKT and AMP-activated protein kinase (AMPK). Rg3 promotes mitochondrial biogenesis and function, increases the oxygen consumption of mitochondria and the content of ATP. This effect is in contrast to that of high concentrations of Rg3, which inhibits cell growth. These findings demonstrate a pro-growth activity of Rg3 that acts through mTORC1 and mitochondrial biogenesis and suggest a dose-dependent effect of Rg3 on tumor cell growth.
| S-EPMC8473834 | biostudies-literature
Project description:Ginsenoside Rg3 extracted from Panax notoginseng has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy (DCM) remains unclear. 24-week-old diabetic db/db mice were treated with ginsenoside Rg3 for 12 weeks, then body weight, serum lipids, adiponectin levels, as well as cardiac function and pathological morphology, were measured. The targets of ginsenoside Rg3 and its regulation of the adiponectin pathway were also evaluated on 3T3-L1 or H9c2 cells. Ginsenoside Rg3 directly bound to PPAR-γ, improving adiponectin secretion and promoting adiponectin signaling. Significantly attenuated overweight, hyperglycemia, and hyperlipidemia, as well as alleviated lipid accumulation and dysfunction in adipose, liver, and heart tissues, were observed in the ginsenoside Rg3-treated group. Ginsenoside Rg3 could be a promising drug targeting PPAR-γ to treat diabetic cardiomyopathy.
| S-EPMC10705869 | biostudies-literature