PMID: 

Food Funct. 2019 Dec 12. Epub 2019 Dec 12. PMID: 31830168

Abstract Title: 

Ginsenoside Rk1 induces apoptosis and downregulates the expression of PD-L1 by targeting the NF-κB pathway in lung adenocarcinoma.

Abstract: 

Ginsenoside Rk1 is a substance derived from ginseng and exhibits various activities such as anti-diabetic, anti-inflammatory and anti-cancer effects; however, its anti-tumor effect and target signaling mechanism in lung adenocarcinoma are not well understood. Here, we show that Rk1, a natural drug product, can function as an antitumor modulator that induces apoptosis in lung adenocarcinoma cells by inhibiting NF-κB transcription and triggering cell cycle arrest. Mechanistically, Rk1 suppressed the proliferation and clonal formation of two lung adenocarcinoma cell lines (A549 and PC9) in vitro and caused G1 phase cell arrest. In the A549 xenograft model, Rk1 significantly inhibited tumor growth and had fewtoxic side effects on normal organs. Western blotting results showed that Rk1 increased the protein expression of Bax, cleaved caspase-3, -8, and -9, and PARP, decreased the expression of Bcl-2 and blocked the NF-κB signaling pathway. Furthermore, ginsenoside Rk1 also reduced the high expression ofPD-L1 in lung adenocarcinoma cells by inhibiting NF-κB signaling. These data revealed a previously unreported antitumor mechanism of Rk1, providing new ideas and an experimental basis for further study of the mechanism of action of Rk1 in lung adenocarcinoma.

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PMID: 

Onco Targets Ther. 2019 ;12:10885-10895. Epub 2019 Dec 11. PMID: 31849492

Abstract Title: 

20(R)-Ginsenoside Rg3 Influences Cancer Stem Cell Properties and the Epithelial-Mesenchymal Transition in Colorectal Cancer via the SNAIL Signaling Axis.

Abstract: 

Background: Cancer stem cells (CSCs) have been proposed as central drivers of cancer relapse in many cancers. In the present study, we investigated the inhibitory effect of 20(R)-Ginsenoside Rg3 (Rg3R), a major active component of ginseng saponin, on CSC-like cells and the Epithelial-Mesenchymal Transition (EMT) in colorectal cancer (CRC).Methods: The effects of ginsenoside Rg3R on the colony-forming, migration, invasion, and wound-healing abilities of CRC cells were determined in HT29 and SW620 cell lines in vitro. Further, ginsenoside Rg3R was given intraperitoneally at 5mg/kg of mouse body weight to check its effect on the metastasis of CRC cells in vivo.Results: Ginsenoside Rg3R significantly inhibited CSC properties, but did not affect cell proliferation. Moreover, ginsenoside Rg3R treatment significantly inhibited the motility of CRC cells based on migration, invasion, and wound-healing assays. The inhibitory effects of ginsenoside Rg3R on CRC are potentially mediated by significant down-regulation of the expression of stemness genes and EMT markers in CRC cells in a SNAIL-dependent manner. Furthermore, ginsenoside Rg3R treatment decreased both the number and size of tumor nodules in the liver, lung, and kidney tissues in a metastasis mouse model.Conclusion: These findings highlighted the potential use of ginsenoside Rg3R in clinical applications for colorectal cancer treatment.

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PMID: 

J Cell Biochem. 2019 Nov 11. Epub 2019 Nov 11. PMID: 31709615

Abstract Title: 

Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF-kB/NLRP3 pathway.

Abstract: 

Sepsis-induced myocardial dysfunction (SIMD) causes high mortality in seriously ill patients. Ginsenoside Rg1 has been proven to have effective anti-inflammatory and antiapoptotic properties. However, the specific role of Rg1 in SIMD and the molecular mechanism remain unclear. Hence, we aimed to investigate the latent effects of ginsenoside Rg1 against SIMD and explore its underlying mechanisms. Male C57BL/6J mice and neonatal rat cardiomyocytes (NRCMs) were used as in vivo and in vitro models, respectively. Western blot analysis was used to detect the level of protein expression, and reverse transcription polymerase chain reaction was conducted todetermine the messenger RNA expression of inflammatory factors. The terminal deoxynucleotidyl transferase-mediated nick end labeling assay and flow cytometry were used to determine the apoptosis rate. Echocardiography was performed to assess cardiac function. The results showed that Rg1 improved cardiac function and attenuated lipopolysaccharide (LPS)-induced apoptosis and inflammation in mice. In addition, in NRCMs, Rg1 downregulated the expression of LPS-induced inflammatory cytokines and reversed the increased expression of Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), and NOD-like receptor 3 (NLRP3). In addition, treatment with TLR4 small interfering RNA (siRNA), a p-NF-κB inhibitor, or NLRP3 siRNA suppressed LPS-induced apoptosis and inflammation. In conclusion, Rg1 can attenuate LPS-induced inflammation and apoptosis both in NRCMs and septic mice and restore impairedcardiac function. Moreover, Rg1 may exert its effect via blocking the TLR4/NF-κB/NLRP3 pathway.

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PMID: 

J Toxicol Environ Health A. 2019 ;82(19):1027-1035. Epub 2019 Nov 18. PMID: 31739751

Abstract Title: 

The protective mechanisms underlying Ginsenoside Rg1 effects on rat sciatic nerve injury.

Abstract: 

Ginsenoside Rg1 (GsRg1), derived from the herb Ginseng, was found to exert protective effects in nerve injury; however, the mechanisms underlying these effects remain to be determined. Oxidant stress and apoptosis are known to be involved in sciatic nerve injury. Thus, the aim of this study was to examine whether GsRg1 was able to modify sciatic nerve injury in a rat model. The following parameters were measured: (1) number of spinal cord motoneurons by Nissl staining, (2) oxidation parameters including spinal cord malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as (3) involvement of apoptosis by determining caspase-3 and X-linked inhibitor of apoptosis protein (XIAP) by immunohistochemistry and Western blot. The number of spinal cord motoneurons was significantly reduced after sciatic nerve injury, while treatment with GsRg1 markedly elevated cell number. Sciatic nerve injury markedly increased spinal cord MDA content concomitant with reduced activities of SOD and GSH-Px. GsRg1 significantly decreased MDA content accompanied by elevated activities of SOD and GSH-Px. Further nerve injury significantly diminished protein expression levels of XIAP accompanied by elevated protein expression levels of caspase-3 in the spinal cord. GsRg1 markedly increased protein expression levels of XIAP, but significantly reduced protein expression levels of caspase-3. Data suggest that the protective effects of GsRg1 in sciatic nerve injury may be associated with reduced oxidative stress involving anti-apoptotic pathways.

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PMID: 

Eur J Pharmacol. 2020 Jan 5 ;866:172801. Epub 2019 Nov 16. PMID: 31738935

Abstract Title: 

Ginsenoside Rg1 protects mice against streptozotocin-induced type 1 diabetic by modulating the NLRP3 and Keap1/Nrf2/HO-1 pathways.

Abstract: 

Ginseng has been traditionally used to treat diabetes mellitus (DM) in China. Ginsenoside Rg1 is a major active ingredient in processed ginseng, which elicits proven biological and pharmacological effects. Although a correlation between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and predisposition to type 1 diabetes mellitus (T1DM) has been identified, the mechanism underlying the potential function and activation of NLRP3 inflammasome in DM have not been elucidated to date. The present study aimed to elucidate the effects and underlying mechanism of Rg1 on streptozotocin (STZ)-induced T1DM in mice through short or long-term observation. Concurrently, we intended to explore the relationships between inflammasome, pyroptosis and oxidative stress and the role of NLRP3 and Keap1/Nrf2/HO-1 pathways in the development and progression of DM. Using ELISA and Western blot analysis, we found that Rg1 attenuated abnormally elevated blood glucose, reduced inflammatory factors IL-1β and IL-18 in the blood, decreased ALT and AST levels, promoted insulin secretion, and weakened the function of NLRP3 in mouse liver and pancreas. In addition, Rg1 protected against STZ-induced reactive oxygen species-mediated inflammation by upregulating Nrf2/ARE pathway, which further activatedantioxidant enzymes. Interestingly, Rg1 also regulated H3K9 methylation in liver and pancreas, as detected by immunohistochemistry. In summary, these data provide new understanding about the mechanism of Rg1 action, suggesting that it is a potential drug applied for preventing the occurrence and development of T1DM.

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PMID: 

Front Neurosci. 2019 ;13:1168. Epub 2019 Nov 7. PMID: 31787867

Abstract Title: 

Ginsenoside Rg1 Exerts Anti-inflammatory Effects via G Protein-Coupled Estrogen Receptor in Lipopolysaccharide-Induced Microglia Activation.

Abstract: 

Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease. Ginsenoside Rg1, the most active ingredient of ginseng, has been reported to exert neuroprotective effects via estrogen and glucocorticoid receptors. The present study evaluated the involvement of the G protein-coupled estrogen receptor (GPER) in the anti-inflammatory effects of ginsenoside Rg1 against lipopolysaccharide (LPS)-induced microglia activation in the BV2 microglial cell line and ventral mesencephalic primary microglial culture. The pharmacological blockade and lentivirus-mediated small interfering RNA (siRNA) knockdown of GPER were used to study the underlying mechanism. Rg1 attenuated LPS-induced upregulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA and protein levels. The GPER antagonist G15 blocked the inhibitory effects of Rg1 and the GPER-specific agonist G1 on LPS-induced microglia activation. Rg1 mimicked the effects of G1 by inhibiting the LPS-induced activation of nuclear transcription factor-kappa B (NF-κB) and mitogen activated protein kinase signaling pathways, which was also blocked by G15. Moreover, lentivirus-mediated siRNA knockdown of GPER inhibited the anti-inflammatory effects of Rg1. Taken together, our results indicate that GPER is involved in the anti-inflammatory effects of Rg1 against LPS-induced microglia activation. These findings provide a new biological target of Rg1 for the treatment of neuroinflammatory disorders.

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PMID: 

J Ginseng Res. 2019 Jul ;43(3):394-401. Epub 2018 Jun 2. PMID: 31308811

Abstract Title: 

Ginsenoside Rb1 increases macrophage phagocytosis through p38 mitogen-activated protein kinase/Akt pathway.

Abstract: 

Background: Ginsenoside Rb1, a triterpene saponin, is derived from theroot and has potent antiinflammatory activity. In this study, we determined if Rb1 can increase macrophage phagocytosis and elucidated the underlying mechanisms.Methods: To measure macrophage phagocytosis, mouse peritoneal macrophages or RAW 264.7 cells were cultured with fluorescein isothiocyanate-conjugated, and the phagocytic index was determined by flow cytometry. Western blot analyses were performed.Results: Ginsenoside Rb1 increased macrophage phagocytosis and phosphorylation of p38 mitogen-activated protein kinase (MAPK), but inhibition of p38 MAPK activity with SB203580 decreased the phagocytic ability of macrophages. Rb1 also increased Akt phosphorylation, which was suppressed by LY294002, a phosphoinositide 3-kinase inhibitor. Rb1-induced Akt phosphorylation was inhibited by SB203580, (5Z)-7-oxozeaenol, and small-interfering RNA (siRNA)-mediated knockdown of p38α MAPK in macrophages. However, Rb1-induced p38 MAPK phosphorylation was not blocked by LY294002 or siRNA-mediated knockdown of Akt. The inhibition of Akt activation with siRNA or LY294002 also inhibited the Rb1-induced increase in phagocytosis. Rb1 increased macrophage phagocytosis of IgG-opsonized beads but not unopsonized beads. The phosphorylation of p21 activated kinase 1/2 and actin polymerization induced by IgG-opsonized beads and Rb1 were inhibited by SB203580 and LY294002. Intraperitoneal injection of Rb1 increased phosphorylation of p38 MAPK and Akt and the phagocytosis of bacteriain bronchoalveolar cells.Conclusion: These results suggest that ginsenoside Rb1 enhances the phagocytic capacity of macrophages for bacteria via activation of the p38/Akt pathway. Rb1 may be a useful pharmacological adjuvant for the treatment of bacterial infections in clinically relevant conditions.

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PMID: 

Pediatr Res. 2019 Dec 18. Epub 2019 Dec 18. PMID: 31852009

Abstract Title: 

Association between maternal acetaminophen use and adverse birth outcomes in a pregnancy and birth cohort.

Abstract: 

INTRODUCTION: Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes-preterm birth, low birthweight, and small for gestational age-are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use.METHODS: Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age.RESULTS: Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen use

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PMID: 

J Ginseng Res. 2018 Oct ;42(4):524-531. Epub 2017 Jul 25. PMID: 30337813

Abstract Title: 

Effects of fermented black ginseng on wound healing mediated by angiogenesis through the mitogen-activated protein kinase pathway in human umbilical vein endothelial cells.

Abstract: 

Background: Fermented black ginseng (FBG) is produced through several cycles of steam treatment of raw ginseng, at which point its color turns black. During this process, the original ginsenoside components of raw ginseng (e.g., Re, Rg1, Rb1, Rc, and Rb2) are altered, and less-polar ginsenosides are generated (e.g., Rg3, Rg5, Rk1, and Rh4). The aim of this study was to determine the effect of FBG on wound healing.Methods: The effects of FBG on tube formation and on scratch wound healing were measured using human umbilical vein endothelial cells (HUVECs) and HaCaT cells, respectively. Protein phosphorylation of mitogen-activated protein kinase was evaluated via Western blotting. Finally, the wound-healing effects of FBG were assessed using an experimental cutaneous wounds model in mice.Results and Conclusion: The results showed that FBG enhanced the tube formation in HUVECs and migration in HaCaT cells. Western blot analysis revealed that FBG stimulated the phosphorylation of p38 and extracellular signal-regulated kinase in HaCaT cells. Moreover, mice treated with 25 μg/mL of FBG exhibited faster wound closure than the control mice did in the experimental cutaneous wounds model in mice.

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PMID: 

Nutrients. 2019 Aug 13 ;11(8). Epub 2019 Aug 13. PMID: 31412594

Abstract Title: 

Greater Efficacy of Black Ginseng (CJ EnerG) over Red Ginseng against Lethal Influenza A Virus Infection.

Abstract: 

Black ginseng (BG, CJ EnerG), prepared via nine repeated cycles of steaming and drying of fresh ginseng, contains more accessible acid polysaccharides and smaller and less polar ginsenosides than red ginseng (RG) processed only once. Because RG exhibits the ability to increase host protection against viral respiratory infections, we investigated the antiviral effects of BG. Mice were orally administered either BG or RG extract at 10 mg/kg bw daily for two weeks. Mice were then infected with a A(H1N1) pdm09 (A/California/04/2009) virus and fed extracts for an additional week. Untreated, infected mice were assigned to either the negative control, without treatments, or the positive control, treated with Tamiflu. Infected mice were monitored for 14 days to determine the survival rate. Lung tissues were evaluated for virus titer and by histological analyses. Cytokine levels were measured in bronchoalveolar lavage fluid. Mice treated with BG displayed a 100% survival rate against infection, while mice treated with RG had a 50% survival rate. Further, mice treated with BG had fewer accumulated inflammatory cells in bronchioles following viral infection than did mice treated with RG. BG also enhanced the levels of GM-CSF and IL-10 during the early and late stages of infection, respectively, compared to RG. Thus, BG may be useful as an alternative antiviral adjuvant to modulate immune responses to influenza A virus.

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