Search

Ginsenoside Re was the major bioactive component found rich in Panax ginseng C. A. Meyer, which exerted excellent cardiovascular protection, anti-inflammatory, and anti-oxidation effects. The generation of unexpected degradation products (DPs) may influence the therapeutic effect of Re, or even bring toxic effects to patients. However, to date, only a few reports were available about the stability of Re. The present study aims to systematically investigate the degradation behaviors of Re under different stress conditions, including hydrolysis (acidic, basic, and neutral), oxidation, humidity, thermal, and photolytic (ultraviolet and visible light) conditions. A total of thirteen DPs were putatively identified, and among them, nine were discovered for the first time in our study. The results showed that Re was sensitive to exposure to acidic, basic, and oxidation conditions. It underwent a series of chemical degradation reactions, including deglycosylation, dehydration, addition, oxidation at the double bond, and isomerization under various stress conditions. Structural characterization of these DPs was carried out by UHPLC-DAD-CAD and LC-LTQ/Orbitrap. A plausible mechanism of their formation was proposed to support the structures of all DPs of Re. In silico toxicity prediction and metabolism behavior assessment were done by Derek Nexus and Meteor Nexus software. Re and DP-1 to DP-6 were predicted to possess potential skin irritation/corrosion toxicity. DP-11 and DP-12 bear the potential for carcinogenicity, mutagenicity, irritation, hepatotoxicity, and skin sensitization. The observation of these DPs updates our knowledge regarding the stability of Re, which provides valuable information for quality control and to choose suitable storage conditions. [ABSTRACT FROM AUTHOR]

Despite the rapid advancement of glycosidase biotechnology, ginsenoside-transforming rhamnosidases remain underexplored due to a lack of research. In this study, we aimed to bridge this gap by evaluating eight putative rhamnosidases for their ability to transform ginsenosides. Among them, a novel rhamnosidase (C118) from Bifidobacterium was identified as being efficient at hydrolyzing ginsenoside Re. This enzyme was expressed well in Escherichia coli and exhibited optimal activity at pH of 6.0 and 45 °C. Protein structural predictions revealed that the potential active hydrophobic area near an active pocket may influence the ginsenoside-transforming activities compared to non-active screened rhamnosidases. This enzyme's thermal stability exceeded that of the only previously known ginsenoside-transforming rhamnosidase, BD890. Additionally, the kcat/Km value of C118 was 1.45 times higher than that of BD890. Using recombinant C118 from E. coli, all ginsenoside Re in a PPT-type ginsenoside mixture (2.25 mg/mL) was converted after 12 h of reaction. To the best of our knowledge, this is the most efficient ginsenoside Re-transforming α-L-rhamnosidase reported to date, enhancing our understanding of rhamnosidase–substrate interactions and potentially improving the efficiency and specificity of the conversion process. These findings offer promising implications for the production of pharmacologically active ginsenosides in the pharmaceutical, cosmetic, and functional food industries. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) in non‐small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT‐PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2‐like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2‐like MΦ and consequently inhibiting the epithelial‐mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2‐type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC. [ABSTRACT FROM AUTHOR]

While Ginsenoside Re has been shown to protect the central nervous system, reports of its effects on memory in the model of scopolamine-induced memory impairment are rare. The aim of this study was to investigate the effects of Ginsenoside Re on scopolamine (SCOP)-induced memory damage and the mechanism of action. Male ICR mice were treated with SCOP (3 mg/kg) for 7 days and with or without Ginsenoside Re for 14 days. As evidenced by behavioral studies (escape latency and cross platform position), brain tissue morphology, and oxidative stress indicators after Ginsenoside Re treatment, the memory damage caused by SCOP was significantly ameliorated. Further mechanism research indicated that Ginsenoside Re inhibited cell apoptosis by regulating the PI3K/Akt/Nrf2 pathway, thereby exerting a cognitive impairment improvement effect. This research suggests that Ginsenoside Re could protect against SCOP-induced memory defects possibly through inhibiting oxidative stress and cell apoptosis.

Ginsenoside Re (GS-Re) is a major saponin monomer found in Panax ginseng Meyer. It has been shown to exhibit a wide range of biological and pharmacological activities. This study aimed to investigate the effect of GS-Re on the proliferation of murine bone marrow–derived MSCs in vitro and to assess whether its effect is dependent on the estrogen receptor–mediated signal transduction. CFU colony formation assay, cell counting, and colorimetric MTT test were employed to examine effects of GS-Re on the in vitro proliferation of MSCs and the mechanisms of the underlying effect were detected by flow cytometric analysis, immunofluorescence staining for BrdU, and Western blotting. GS-Re dose-dependently promoted the in vitro proliferation of murine bone marrow–derived MSCs over a range of concentrations of 0.5 ~ 20 µmol/L, and this effect approached the maximal level at 10 µmol/L. Increases in the expression level of phosphorylated extracellular signal–regulated kinases 1/2 (p-ERK1/2) were observed in the passaged MSCs treated with 10 µmol/L of GS-Re. These effects of GS-Re on the MSCs were significantly counteracted by the addition of ICI 182, 780 (an estrogen receptor antagonist) to the culture media. We concluded that GS-Re is able to exert a proliferation-promoting effect on murine bone marrow–derived mesenchymal stem cells in vitro, and its action is involved in the estrogen receptor–mediated signaling. [ABSTRACT FROM AUTHOR]

Hyperglycaemia-induced retinal microvascular endothelial cell apoptosis is a critical and principle event in diabetic retinopathy (DR), which involves a series of complex processes such as mitochondrial dysfunction and oxidative stress. Ginsenoside Re (Re), a key ingredients of ginseng, is considered to have various pharmacologic functions, such as antioxidative, inhibition of inflammation and anti-apoptotic properties. However, the effects of Re in DR and the related mechanisms of endothelial cell injury induced by high glucose (HG) exposure remain unclear. The present study was designed to investigate and evaluate the ability of Re to ameliorate HG-induced retinal endothelial RF/6A cell injury and the potential mechanisms involved in the hypoxia-inducible factor-1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling regulated by phosphoinositide 3-kinase (PI3K)/AKT pathway. Our results showed that preincubation with Re exerted cytoprotective effects by reversing the HG-induced decrease in RF/6A cell viability, downregulation of apoptosis rate and inhibition of oxidative-related enzymes, thereby reducing the excess intracellular reactive oxygen species (ROS) and HG-triggered RF/6A cell injury. In addition, Western blot analysis results showed ginsenoside Re significantly increased HIF-1α expression in the cytoplasm but decreased its expression in the nucleus, suggesting that it reduced the translocation of HIF-1α from the cytoplasm to the nucleus, and downregulated VEGF level. Moreover, this effect is involved in the activation of the PI3K/Akt pathway. LY294002, a PI3K inhibitor, was used to block the Akt pathway. Afterwards, the effects of Re on the regulation of apoptotic related proteins, VEGF and HIF-1α nuclear transcription was partially reversed. These findings suggested the exerting protective effects of ginsenoside Re were associated with regulating of PI3K/AKT and HIF-1α/VEGF signaling pathway, which indicates that ginsenoside Re may ameliorates HG-induced retinal angiogenesis and suggests the potential for the development of Re as a therapeutic for DR. [ABSTRACT FROM AUTHOR]

We previously demonstrated that ginsenoside Re (G-Re) has protective effects on acute kidney injury. However, the underlying mechanism is still unclear. In this study, we conducted a meta-analysis and pathway enrichment analysis of all published transcriptome data to identify differentially expressed genes (DEGs) and pathways of G-Re treatment. We then performed in vitro studies to measure the identified autophagy and fibrosis markers in HK2 cells. In vivo studies were conducted using ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) models to evaluate the effects of G-Re on autophagy and kidney fibrosis. Our informatics analysis identified autophagy-related pathways enriched for G-Re treatment. Treatment with G-Re in HK2 cells reduced autophagy and mRNA levels of profibrosis markers with TGF-β stimulation. In addition, induction of autophagy with PP242 neutralized the anti-fibrotic effects of G-Re. In murine models with UUO and AAN, treatment with G-Re significantly improved renal function and reduced the upregulation of autophagy and profibrotic markers. A combination of informatics analysis and biological experiments confirmed that ginsenoside Re could improve renal fibrosis and kidney function through the regulation of autophagy. These findings provide important insights into the mechanisms of G-Re's protective effects in kidney injuries. [ABSTRACT FROM AUTHOR]

This study investigated the effects of ginseng berry extract (GBE) and its major ginsenoside Re (GinRe) on skeletal muscle atrophy and exercise performance. GBE and GinRe upregulated the mRNA expression of sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) in C2C12 myotubes. Administration of GBE and GinRe in high-fat diet-induced muscle atrophy mice enhanced endurance exercise performance and increased skeletal muscle weight with a significant downregulation of skeletal muscle atrophy genes and upregulation of oxidative myosin heavy chain subtypes, mitochondrial biogenesis, and oxidative phosphorylation regulatory genes in skeletal muscle tissue. Oral administration of GBE and GinRe enhanced the protein expression of SIRT1, phosphorylation of adenosine monophosphate-activated protein kinase (AMPK)/PGC-1α/peroxisome proliferator-activated receptor-δ (PPARδ) signaling axis in skeletal muscle tissue, acting as an exercise metabolism regulator. These results suggest that GBE and GinRe have the potential to enhance exercise performance through mitochondrial biogenesis.

Objective To determine the effects of main components (Rg1, Re and R1) of Panax notoginseng saponins on platelet activation and aggregation induced by shear stress. Methods A narrow microfluidic chip model was established, and used to evaluate the effects of Rg1, Re and R1 at different concentrations (0.05, 0.1, 0.25 and 0.5 mg/mL) on shear-induced platelet aggregation under different shear rates (1 500, 4 500 and 9 000 s-1). Flow cytometry was used to quantitatively detect the shear-induced platelet activation (P-selectin and PAC-1) after the treatment of Rg1, Re and R1. PL-12 analyzer was performed to measure the effects of Rg1, Re and R1 on platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP). Results Rg1, Re and R1 inhibited platelet aggregation induced by high shear stress in a concentration-dependent manner (P < 0.01), but had no such inhibitory effect under lower shear stress. Among the 3 components, Re had the strongest inhibitory effect, and their IC50 value was 0.1, 0.07, and 0.2 mg/mL, respectively. No synergistic effect was observed when the 3 components were used together at the same dose. Rg1, Re and R1 inhibited the expression of P-selectin and PAC-1 (P < 0.01), which was consistent with the results of the aggregation experiment. In addition, the 3 components also could inhibit platelet aggregation induced by AA and ADP. Conclusion The main components of Panax notoginseng saponins exert their antiplatelet activity by inhibiting shear-induced platelet aggregation.

Background: The human hair follicle undergoes cyclic phases—anagen, catagen, and telogen—throughout its lifetime. This cyclic transition has been studied as a target for treating hair loss. Recently, correlation between the inhibition of autophagy and acceleration of the catagen phase in human hair follicles was investigated. However, the role of autophagy in human dermal papilla cells (hDPCs), which is involved in the development and growth of hair follicles, is not known. We hypothesized that acceleration of hair catagen phase upon inhibition of autophagy is due to the downregulation of Wnt/β-catenin signaling in hDPCs, and that components of Panax ginseng extract can increase the autophagic flux in hDPCs. Methods: We generated an autophagy-inhibited condition using 3-methyladenine (3-MA), a specific autophagy inhibitor, and investigated the regulation of Wnt/β-catenin signaling using the luciferase reporter assay, qRT-PCR, and western blot analysis. In addition, cells were cotreated with ginsenoside Re and 3-MA and their roles in inhibiting autophagosome formation were investigated. Results: We found that the unstimulated anagen phase dermal papilla region expressed the autophagy marker, LC3. Transcription of Wnt-related genes and nuclear translocation of β-catenin were reduced after treatment of hDPCs with 3-MA. In addition, treatment with the combination of ginsenoside Re and 3-MA changed the Wnt activity and hair cycle by restoring autophagy. Conclusions: Our results suggest that autophagy inhibition in hDPCs accelerates the catagen phase by downregulating Wnt/β-catenin signaling. Furthermore, ginsenoside Re, which increased autophagy in hDPCs, could be useful for reducing hair loss caused by abnormal inhibition of autophagy.

Loss of photoreceptors is the central pathology accountable for irreversible vision impairment in patients with photoreceptor degenerative disorders. Currently, mechanisms-based pharmacological therapies protecting photoreceptors from degenerative progression remain clinically unavailable. Photooxidative stress plays a pivotal role in initiating the degenerative cascade in photoreceptors. Meanwhile, photoreceptor degeneration interacts closely with neurotoxic inflammatory responses primarily mediated by aberrantly activated microglia in the retina. Thus, therapies with anti-oxidant and anti-inflammatory properties have been actively investigated for their pharmacological value in controlling photoreceptor degeneration. In the current study, we examined the pharmacological potentials of ginsenoside Re (Re), a naturally occurring antioxidant with anti-inflammatory activities, in photooxidative stress-mediated photoreceptor degeneration. Our results demonstrate that Re attenuates photooxidative stress and associated lipid peroxidation in the retina. Furthermore, Re treatment preserves the morphological and functional integrity of the retina, counteracts photooxidative stress-induced perturbation of the retinal gene expression profiles and mitigates photoreceptor degeneration-associated neuroinflammatory responses and microglia activation in the retina. Lastly, Re partially antagonizes the deleterious effects of photooxidative stress on müller cells, verifying its beneficial impact on retina homeostasis. In conclusion, the work here provides experimental evidence supporting novel pharmacological implications of Re in attenuating photooxidative stress-mediated photoreceptor degeneration and ensuing neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Myocardial fibrosis (MF) is an advanced pathological manifestation of many cardiovascular diseases, which can induce heart failure and malignant arrhythmias. However, the current treatment of MF lacks specific drugs. Ginsenoside Re has anti-MF effect in rat, but its mechanism is still not clear. Therefore, we investigated the anti-MF effect of ginsenoside Re by constructing mouse acute myocardial infarction (AMI) model and AngⅡ induced cardiac fibroblasts (CFs) model. Methods: The anti-MF effect of miR-489 was investigated by transfection of miR-489 mimic and inhibitor in CFs. Effect of ginsenoside Re on MF and its related mechanisms were investigated by ultrasonographic, ELISA, histopathologic staining, transwell test, immunofluorescence, Western blot and qPCR in the mouse model of AMI and the AngⅡ-induced CFs model. Results: MiR-489 decreased the expression of α-SMA, collagenⅠ, collagen Ⅲ and myd88, and inhibited the phosphorylation of NF-κB p65 in normal CFs and CFs treated with AngⅡ. Ginsenoside Re could improve cardiac function, inhibit collagen deposition and CFs migration, promote the transcription of miR-489, and reduce the expression of myd88 and the phosphorylation of NF-κB p65. Conclusion: MiR-489 can effectively inhibit the pathological process of MF, and the mechanism is at least partly related to the regulation of myd88/NF-κB pathway. Ginsenoside Re can ameliorate AMI and AngⅡ induced MF, and the mechanism is at least partially related to the regulation of miR-489/myd88/NF-κB signaling pathway. Therefore, miR-489 may be a potential target of anti-MF and ginsenoside Re may be an effective drug for the treatment of MF.

It has been recognized that serotonergic blocker showed serious side effects, and that ginsenoside modulated serotonergic system with the safety. However, the effects of ginsenoside on serotonergic impairments remain to be clarified. Thus, we investigated ginsenoside Re (GRe), a major bioactive component in the mountain-cultivated ginseng on (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist. In the present study, we observed that the treatment with GRe resulted in significant inhibition of protein kinase C δ (PKCδ) phosphorylation induced by the 5-HT1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) in the hypothalamus of the wild-type (WT) mice. The inhibition of GRe was comparable with that of the PKCδ inhibitor rottlerin or the 5-HT1A receptor antagonist WAY100635 (WAY). 8-OH-DPAT-induced significant reduction in nuclear factor erythroid-2-related factor 2 (Nrf2)-related system (i.e., Nrf2 DNA binding activity, γ-glutamylcysteine ligase modifier (GCLm) and γ-glutamylcysteine ligase catalytic (GCLc) mRNA expression, and glutathione (GSH)/oxidized glutathione (GSSG) ratio) was significantly attenuated by GRe, rottlerin, or WAY in WT mice. However, PKCδ gene knockout significantly protected the Nrf2-dependent system from 8-OH-DPAT insult in mice. Increases in 5-hydroxytryptophan (5-HT) turnover rate, overall serotonergic behavioral score, and hypothermia induced by 8-OH-DPAT were significantly attenuated by GRe, rottlerin, or WAY in WT mice. Consistently, PKCδ gene knockout significantly attenuated these parameters in mice. However, GRe or WAY did not provide any additional positive effects on the serotonergic protective potential mediated by PKCδ gene knockout in mice. Therefore, our results suggest that PKCδ is an important mediator for GRe-mediated protective activity against serotonergic impairments/oxidative burden caused by the 5-HT1A receptor. [ABSTRACT FROM AUTHOR]

Previous reports have confirmed that crude saponins (ginsenosides) in Panax ginseng have a preventive effect on chemotherapy-induced intestinal injury. However, the protective effects and possible mechanisms of ginsenoside Re (G-Re, a maker saponin in ginseng) against chemotherapy-induced intestinal damage have not been thoroughly studied. In this work, a series of experiments in vivo and in vitro on the intestinal toxicity caused by cisplatin have been designed to verify the improvement effect of G-Re, focusing on the levels of Wnt3a and β -catenin. Mice were intragastric with G-Re for 10 days, and intestinal injury was induced by intraperitoneal administration of cisplatin at a dose of 20 mg/kg. Histopathology, gastrointestinal digestive enzyme activities, inflammatory cytokines, and oxidative status were evaluated to investigate the protective effect. Furthermore, in IEC-6 cells, G-Re statistically reverses cisplatin-induced oxidative damage and cytotoxicity. The TUNEL and Hoechst 33258 staining demonstrated that G-Re possesses protective effects in cisplatin-induced apoptosis. Additionally, pretreatment with G-Re significantly alleviated the apoptosis via inhibition of over-expressions of B-associated X (Bax), as well as the caspase family members, such as caspase 3 and 9, respectively, in vivo and in vitro. Notably, western blotting results showed that G-Re treatment decreased Wnt3a, Glycogen synthase kinase 3 β (GSK- 3 β), and β -catenin expression, suggesting that nuclear accumulation of β -catenin was attenuated, thereby inhibiting the activation of GSK- 3 β -dependent Wnt/ β -catenin signaling, which was consistent with our expected results. Therefore, the above evidence suggested that G-Re may be a candidate drug for the treatment of intestinal injury. [ABSTRACT FROM AUTHOR]

Heat stress (HS) affects the development of porcine gametes and embryos negatively, induces the decrease of reproductive ability significantly, threatens global pig production. Ginsenoside Re (GRe), is a main bioactive component of ginseng, shows very specific anti‐apoptotic, antioxidant and anti‐inflammatory activities. To investigate the alleviating effect of GRe on the in vitro maturation of porcine oocyte under the HS, the polar body extrusion rate, intracellular levels of reactive oxygen species (ROS) and glutathione (GSH), ATP content, mitochondrial membrane potential (MMP) were assessed. For the current study, porcine cumulus‐oocyte complexes (COCs) randomly divided into four groups: the control, GRe, HS and HS + GRe group. The results showed that HS inhibited the cumulus cell expansion and polar body extrusion rate, the levels of GSH and MMP, the ATP content, the gene expression of Nrf2 of porcine oocytes and the parthenogenetic activation (PA) embryo development competence, but GRe treatment could partly neutralize these adverse effects. Furthermore, HS increased the ROS formation and percentage of apoptosis, the gene expression of HSP90, CASP3 and CytoC of porcine oocytes, but GRe could weaken the effect on Cyto C and BAX expression induced by HS. Taken together, these results showed that the presence of GRe during in vitro maturation protects porcine oocytes from HS. These findings lay a foundation for GRe may be used as a potential protective drug to protect porcine oocytes against HS damage. [ABSTRACT FROM AUTHOR]

Ginseng is known to possess anti-aging potential. Klotho mutant mice exhibit phenotypes that resemble the phenotype of the human aging process. Similar to Klotho deficient mice, patients with chronic kidney disease (CKD) suffer vascular damage and cognitive impairment, which might upregulate the angiotensin II AT1 receptor. Since AT1 receptor expression was more pronounced than endothelin ET-1 expression in the hippocampus of aged Klotho deficient (±) mice, we focused on the AT1 receptor in this study. Ginsenoside Re (GRe), but not ginsenoside Rb1 (GRb1), significantly attenuated the increase in AT1 receptor expression in aged Klotho deficient mice. Both GRe and the AT1 receptor antagonist losartan failed to attenuate the decrease in phosphorylation of JAK2/STAT3 in aged Klotho deficient (±) mice but significantly activated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling. Both GRe and losartan attenuated the increased NADPH oxidase (NOX) activity and reactive oxygen species (ROS) in aged Klotho deficient mice. Furthermore, of all the antioxidant enzymes, GRe significantly increased glutathione peroxidase (GPx) activity. GRe significantly attenuated the reduced phosphorylation of ERK and CREB in GPx-1 knockout mice; however, genetic overexpression of GPx-1 did not significantly affect them in aged mice. Klotho -, Nrf2-, and GPx-1-immunoreactivities were co-localized in the same cells of the hippocampus in aged Klotho wild-type mice. Both the GPx inhibitor mercaptosuccinate and Nrf2 inhibitor brusatol counteracted the effects of GRe on all neurobehavioral impairments in aged Klotho deficient (±) mice. Our results suggest that GRe attenuates all alterations, such as AT1 receptor expression, NOX-, ROS-, and GPx-levels, and cognitive dysfunction in aged Klotho deficient (±) mice via upregulation of Nrf2/GPx-1/ERK/CREB signaling. [Display omitted] • Memory declines in aged Klotho (±) mice are more prominent than those in young case. • GRe attenuates changes in the AT1 receptor and redox status in aged Klotho (±) mice. • Induction of GPx-1 by GRe can be prerequisite for the memory potential of Klotho gene. • GRe-mediated activation in Nrf2/GPx-1/ERK/CREB signaling leads to memory enhancement. [ABSTRACT FROM AUTHOR]

• Re protects cardiomyocytes from oxidative stress with low toxicity. • Re regulates ROS level and reduces OGD- induced cardiomyocyte apoptosis. • Re reduces ischemia cardiac fibrosis, and improves myocardial status in mice. • MAPK, AKT and ferroptosis signaling are verified as key targets for Re against MI. Clinically, various diseases cause myocardial ischemia (MI), which further induces severe cardiac injury and leads to high mortality in patients. Ginsenoside Re , one of the major ginsenosides in ginseng, can regulate the level of oxidative stress in the injured myocardium. Thus, it may attenuate MI injury, but the related mechanism has not been comprehensively studied. This study aimed to investigate the anti-MI effect and comprehensively mechanisms of Ginsenoside Re. Oxygen–glucose deprivation (OGD), oxidative-induced cardiomyocyte injury, and isoproterenol-induced MI mice were used to explore their protective effect of Ginsenoside Re. An integrated approach of network pharmacology, molecular docking, and tandem mass tag proteomics was applied to determine the corresponding common potential targets of Ginsenoside Re against MI, such as target proteins and related pathways. The major anti-MI target proteins and related pathways were validated by immunofluorescence (IF) assay and Western blotting (WB). Ginsenoside Re (1.32–168.93 µM) had low toxicity to normal cardiomyocytes, and increased the survival of oxidative stress-injured (OGD-induced injury or H 2 O 2 -induced injury) cardiomyocytes in this concentration range. It regulated the reactive oxygen species (ROS) level in OGD-injured cardiomyocytes; stabilized the nuclear morphology, mitochondrial membrane potential (MMP), and mitochondrial function; and reduced apoptosis. Meanwhile, Ginsenoside Re (5–20 mg/kg) alleviated cardiac injury in MI mice and maintained cardiac function. Through network pharmacology and proteomics, the relevant mechanisms revealed several key pathways of Ginsenoside Re anti-MI, including inhibition of MAPK pathway protein phosphorylation, downregulation of phosphorylated PDPK1, AKT, and STAT3, and upregulation of TGF-β3, ferroptosis pathway (upregulation of GPX4 and downregulation of phosphorylation level of MDM2) and AMPK pathway (regulating the synthesis of cholesterol in the myocardium by downregulation of HMGCR). The key proteins of these target pathways were validated by IF and/or WB. Ginsenoside Re may target MAPK, AKT, ferroptosis pathways and AMPK pathway to prevent and/or treat MI injury and protect cardiomyocytes from oxidative damage. [Display omitted] [ABSTRACT FROM AUTHOR]

Ginsenoside Re, a unique tetracyclic triterpenoid compound found in ginseng, has been suggested in previous reports to improve non-alcoholic fatty liver disease (NAFLD) by modulating lipid imbalance. This study aims to elucidate the potential mechanisms of Ginsenoside Re in treating NAFLD through a combination of bioinformatics analysis and biological experiments. Network pharmacology methods were employed to systematically depict the effective components and mechanisms of Ginsenoside Re in improving NAFLD. Molecular docking was utilized to evaluate the binding affinity of Ginsenoside Re with NAFLD-related targets and identify potential targets. NAFLD-related target genes were obtained from the GEO database for gene enrichment analysis, revealing signaling pathways, biological processes, and gene differential expression. Finally, animal experiments were conducted to verify the mechanism of action of Ginsenoside Re in NAFLD. Network pharmacology analysis revealed that Ginsenoside Re improves NAFLD by modulating targets such as AKT1 and TLR4, findings corroborated by molecular docking, GEO database analysis, and experimental validation. Further investigation found that Ginsenoside Re ameliorates lipid metabolism disorders and inflammatory responses induced by NAFLD by modulating the PI3K/AKT and TLR4/NF-κB signaling pathways. Our study demonstrates the pharmacological effects of Ginsenoside Re in treating NAFLD, implicating multiple components, targets, and pathways. This provides a solid foundation for considering Ginsenoside Re as an alternative therapy for NAFLD, with promising clinical applications. [Display omitted] • Network pharmacology analysis reveals the biological functions and signaling pathways of potential and core targets of Ginsenoside Re for NAFLD. • Molecular docking technology predicts the affinity and binding modes of Ginsenoside Re with key targets of NAFLD. • Based on the GEO database, prediction of the biological functions and signaling pathways of core genes is conducted, along with analysis of gene differential expression. • Further experiments demonstrate that the therapeutic effect of Ginsenoside Re in improving NAFLD is closely associated with the regulation of lipid metabolism and inflammatory responses mediated by the PI3K/AKT and TLR4/NFκB pathways. [ABSTRACT FROM AUTHOR]

Ginsenoside Re is a protopanaxatriol-type saponin extracted from the berry, leaf, stem, flower bud, and root of Panax ginseng. In recent years, ginsenoside Re (Re) has been attracting attention as a dietary phytochemical. In this review, studies on Re were compiled by searching a combination of keywords, namely "pharmacology," "pharmacokinetics," and "toxicology," in the Google Scholar, NCBI, PubMed, and Web of Science databases. The aim of this review was to provide an exhaustive overview of the pharmacological activities, pharmacokinetics, and toxicity of Re, focusing on clinical evidence that has shown effectiveness in specific diseases, such as diabetes mellitus, nervous system diseases, inflammation, cardiovascular disease, and cancer. Re is also known to eliminate virus, enhance the immune response, improve osteoporosis, improve skin barrier function, enhance intracellular anti-oxidant actions, regulate cholesterol metabolism, alleviate allergic responses, increase sperm motility, reduce erectile dysfunction, promote cyclic growth of hair follicles, and reduce gastrointestinal motility dysfunction. Furthermore, this review provides data on pharmacokinetic parameters and toxicological factors to examine the safety profile of Re. Such data will provide a theoretical basis and reference for Re-related studies and future applications. [ABSTRACT FROM AUTHOR]

Ginsenoside Re is a protopanaxatriol-type saponin extracted from the berry, leaf, stem, flower bud, and root of Panax ginseng. In recent years, ginsenoside Re (Re) has been attracting attention as a dietary phytochemical. In this review, studies on Re were compiled by searching a combination of keywords, namely “pharmacology,” “pharmacokinetics,” and “toxicology,” in the Google Scholar, NCBI, PubMed, and Web of Science databases. The aim of this review was to provide an exhaustive overview of the pharmacological activities, pharmacokinetics, and toxicity of Re, focusing on clinical evidence that has shown effectiveness in specific diseases, such as diabetes mellitus, nervous system diseases, inflammation, cardiovascular disease, and cancer. Re is also known to eliminate virus, enhance the immune response, improve osteoporosis, improve skin barrier function, enhance intracellular anti-oxidant actions, regulate cholesterol metabolism, alleviate allergic responses, increase sperm motility, reduce erectile dysfunction, promote cyclic growth of hair follicles, and reduce gastrointestinal motility dysfunction. Furthermore, this review provides data on pharmacokinetic parameters and toxicological factors to examine the safety profile of Re. Such data will provide a theoretical basis and reference for Re-related studies and future applications.

Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H 2 O 2 -induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H 2 O 2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H 2 O 2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.

Panax notoginseng saponins (PNS) have been used to treat cardiovascular diseases for hundreds of years in China. Lysozyme can bind to exogenous compounds and promote their activity. Nevertheless, knowledge of whether there is a synergistic role between lysozyme and PNS is far from sufficient. In this study, we show that the mixture of PNS and lysozyme synergistically inhibited platelet derived growth factor BB (PDGF-BB)-induced vascular smooth muscle cell (VSMC) viability, and in the five main components of PNS, GS-Re, but not GS-Rb1, NG-R1, GS-Rg1, or GS-Rd, reduced VSMC viability by combined application with lysozyme. Next, the supramolecular complexes formed by GS-Re and lysozyme were detected by mass spectrometry, and the binding ability increased with the concentration ratio of GS-Re to lysozyme from 4:1 to 12:1. In the supramolecular complexes, the relative contents of α-helix of lysozyme were increased, which was beneficial for stabilizing the structure of lysozyme. The 12:1 mixture of GS-Re and lysozyme (12.8 μmol/L GS-Re+1.067 μmol/L lysozyme) repressed PDGF-BB-induced VSMC viability, proliferation, and migration, which were associated with the upregulated differentiated markers and downregulated dedifferentiated markers. Finally, in CaCl2-induced rodent abdominal aortic aneurysm (AAA) models, we found that the 12:1 mixture of GS-Re and lysozyme slowed down AAA progression and reversed phenotype transformation of VSMCs. Thus, Gs-Re combined with a small amount of lysozyme may provide a novel therapeutic strategy for vascular remodeling-associated cardiovascular diseases.

[Display omitted] • GBE and ginsenoside Re reduced body weight gain in high-fat diet-fed mice. • GBE and ginsenoside Re induced favorable changes in blood lipid levels and glucose. • GBE and ginsenoside Re improved exercise performance and muscle mass. • GBE and ginsenoside Re activated Sirt1/AMPK/PGC-1α/PPARδ signaling pathway and promoted mitochondrial biogenesis. This study investigated the effects of ginseng berry extract (GBE) and its major ginsenoside Re (GinRe) on skeletal muscle atrophy and exercise performance. GBE and GinRe upregulated the mRNA expression of sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) in C2C12 myotubes. Administration of GBE and GinRe in high-fat diet-induced muscle atrophy mice enhanced endurance exercise performance and increased skeletal muscle weight with a significant downregulation of skeletal muscle atrophy genes and upregulation of oxidative myosin heavy chain subtypes, mitochondrial biogenesis, and oxidative phosphorylation regulatory genes in skeletal muscle tissue. Oral administration of GBE and GinRe enhanced the protein expression of SIRT1, phosphorylation of adenosine monophosphate-activated protein kinase (AMPK)/PGC-1α/peroxisome proliferator-activated receptor-δ (PPARδ) signaling axis in skeletal muscle tissue, acting as an exercise metabolism regulator. These results suggest that GBE and GinRe have the potential to enhance exercise performance through mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Copyright of China Surfactant Detergent & Cosmetics (1001-1803) is the property of China Surfactant Detergent & Cosmetics Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Exposure to chronic stress negatively affects the development of cognition, characterized by learning and memory decline. Ginsenoside Re (GRe), an active compound derived from Panax ginseng, exhibited neuroprotective activity in various neurological diseases. In this study, the protective effect of GRe on chronic restraint stress (CRS)-induced memory deficit was investigated. The mice were experienced 35 days of the CRS induction. The GRe was administered daily orally (10, 20, or 40 mg/kg) during the next 3 weeks stress session and the behavior test period. The CRS-induced memory impairment mice were subjected to behavioral tasks, such as the Y-maze, novel objects recognition, and step-through passive avoidance tests. Nissl staining was used to examine the neuron numbers. The levels of antioxidant enzymes, malondialdehyde, and proinflammatory factor were determined by kits and ELISA assays. The expressions of brain-derived neurotrophic factor (BDNF), NOD-like receptor protein 3 (NLRP3), nuclear factor erythroid-2 related factor 2 (Nrf2) and synapse-associated proteins (synaptophysin, SYP, and postsynaptic density 95, PSD95) were measured by Western blotting. Behavioral assessments indicated that GRe could ameliorate the cognitive impairment of CRS-induced mice, as indicated by increased responses in Y-maze (p < .05), novel objects recognition (p < .01), and step-through passive avoidance tests (p < .01). In addition, GRe treatment significantly decreased the neuronal loss in CRS mice in histological examination. Moreover, chronic GRe treatment significantly ameliorated the down-regulated the expressions of BDNF, Nrf2, heme oxygenase (HO)-1, SYP, and PSD95, as well as up-regulated NLRP3, the adaptor protein ASC, and Caspase-1 protein expression in the hippocampus of CRS-treated mice. Taken together, these findings suggest that GRe has a potential therapeutic effect on memory impairment in C57BL/6J mice exposed to CRS paradigm. [ABSTRACT FROM AUTHOR]

Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving cardiac hypertrophy have not been fully elucidated. This study aimed to investigate the therapeutic effects and underlying mechanism of Re on isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro . Methods Rats were intraperitoneally injected with ISO 30 mg/kg thrice daily for 14 consecutive days to induce cardiac hypertrophy, and these rats were treated with atorvastatin (ATC, 20 mg/kg) or Re (20 mg/kg or 40 mg/kg) once daily for three days in advance until the end of the experiment. Heart weight index, hematoxylin and eosin staining, and hypertrophy-related fetal gene expression were measured to evaluate the effect of Re on cardiac hypertrophy in vivo . Meanwhile, the rat H9c2 cardiomyocyte hypertrophy model was induced by ISO 10 μM for 24 hours. Cell surface area and hypertrophy-related fetal gene expression were determined to assess the effect of Re on ISO-induced cardiomyocyte hypertrophy in vitro . The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and cardiomyocytes were detected by enzymatic colorimetric assays. Furthermore, we chose cholesteryl ester transfer protein (CETP) as a target to explore the influence of Re on CETP expression in vivo and in vitro through real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Results Intraperitoneal administration of ISO into rats resulted in increases in cross-sectional cardiomyocyte area, the ratio of heart weight to body weight, the ratio of left ventricular weight to body weight, and the ratio of right ventricular weight to body weight, as well as reactivation of fetal genes; however, treatment with Re or ATC ameliorated most of these hypertrophic responses. Similarly, Re pronouncedly alleviated ISO-induced cardiomyocyte hypertrophy, as evidenced by a decreased cell surface area and downregulation of fetal genes. Moreover, our in vivo and in vitro data revealed that Re reduced TC, TG, and LDL-C levels, and enhanced HDL-C levels. Re improved cardiac hypertrophy mainly associated with the inhibition of mRNA level and protein expression of CETP, to an extent comparable to that of the classical CETP inhibitor, anacetrapib. Conclusions Our research found that CETP inhibition contributes to the protection of Re against ISO-induced cardiac hypertrophy, which provides evidence for the application of Re for cardiovascular disease treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Qiu et al.)

Previous studies have shown an attenuating effect of ginsenoside Re on myocardial injury induced by hypoxia/reoxygenation (H/R). However, the underlying mechanism remains unclear. This study was designed to determine the underlying mechanism by which ginsenoside Re protects from myocardial injury induced by H/R. HL-1 cells derived from AT-1 mouse atrial cardiomyocyte tumor line were divided into control, H/R, and H/R + ginsenoside Re groups. Cell viability was measured by CCK-8 assay. ATP levels were quantified by enzymatic assays. Signaling pathway was predicted by network pharmacology analyses and verified by luciferase assay and gene-silencing experiment. The relationship between ginsenoside Re and its target genes and proteins was analyzed by docking experiments, allosteric site analysis, real-time PCR, and ubiquitination and immunoprecipitation assays. Our results showed that ginsenoside Re treatment consistently increased HL-1 cell viability and significantly up-regulated ATP levels after H/R-induced injury. Network pharmacology analysis suggested that the effect of ginsenoside Re was associated with the regulation of the Hypoxia-inducing factor 1 (HIF-1) signaling pathway. Silencing of HIF-1α abrogated the effect of ginsenoside Re on HL-1 cell viability, which was restored by transfection with an HIF-1α-expressing plasmid. Results of the bioinformatics analysis suggested that ginsenoside Re docked at the binding interface between HIF-1α and the von Hippel-Lindau (VHL) E3 ubiquitin ligase, preventing VHL from binding HIF-1α, thereby inhibiting the ubiquitination of HIF-1α. To validate the results of the bioinformatics analysis, real-time PCR, ubiquitination and immunoprecipitation assays were performed. Compared with the mRNA expression levels of the H/R group, ginsenoside Re did not change expression of HIF-1α mRNA, while protein level of HIF-1α increased and that of HIF-1α[Ub]n decreased following ginsenoside Re treatment. Immunoprecipitation results showed that the amount of HIF-1α bound to VHL substantially decreased following ginsenoside Re treatment. In addition, ginsenoside Re treatment increased the expression of GLUT1 (glucose transporter 1) and REDD1 (regulated in development and DNA damage response 1), which are targets of HIF-1α and are critical for cell metabolism and viability. These results suggested that Ginsenoside Re treatment attenuated the myocardial injury induced by H/R, and the possible mechanism was associated with the inhibition of HIF-1α ubiquitination.

Hyperglycaemia-induced retinal microvascular endothelial cell apoptosis is a critical and principle event in diabetic retinopathy (DR), which involves a series of complex processes such as mitochondrial dysfunction and oxidative stress. Ginsenoside Re (Re), a key ingredients of ginseng, is considered to have various pharmacologic functions, such as antioxidative, inhibition of inflammation and anti-apoptotic properties. However, the effects of Re in DR and the related mechanisms of endothelial cell injury induced by high glucose (HG) exposure remain unclear. The present study was designed to investigate and evaluate the ability of Re to ameliorate HG-induced retinal endothelial RF/6A cell injury and the potential mechanisms involved in the hypoxia-inducible factor-1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling regulated by phosphoinositide 3-kinase (PI3K)/AKT pathway. Our results showed that preincubation with Re exerted cytoprotective effects by reversing the HG-induced decrease in RF/6A cell viability, downregulation of apoptosis rate and inhibition of oxidative-related enzymes, thereby reducing the excess intracellular reactive oxygen species (ROS) and HG-triggered RF/6A cell injury. In addition, Western blot analysis results showed ginsenoside Re significantly increased HIF-1α expression in the cytoplasm but decreased its expression in the nucleus, suggesting that it reduced the translocation of HIF-1α from the cytoplasm to the nucleus, and downregulated VEGF level. Moreover, this effect is involved in the activation of the PI3K/Akt pathway. LY294002, a PI3K inhibitor, was used to block the Akt pathway. Afterwards, the effects of Re on the regulation of apoptotic related proteins, VEGF and HIF-1α nuclear transcription was partially reversed. These findings suggested the exerting protective effects of ginsenoside Re were associated with regulating of PI3K/AKT and HIF-1α/VEGF signaling pathway, which indicates that ginsenoside Re may ameliorates HG-induced retinal angiogenesis and suggests the potential for the development of Re as a therapeutic for DR.

Hua Yao,1,* Jing Li,1,* Yubin Song,2 Hong Zhao,1 Zhenhong Wei,1 Xiuying Li,1 Yongri Jin,3 Bai Yang,2 Jinlan Jiang1 1Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, P. R. China; 2State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, Jilin, P. R. China; 3College of Chemistry, Jilin University, Changchun, Jilin, P. R. China *These authors contributed equally to this work Background: Fluorescent carbon-based nanomaterials have promising properties such as biosensing, cell imaging, tracing and drug delivery. However, carbon dots (CDs) with specific inherent biological functions have not been investigated. Ginsenosides are the components with multiple bioactivities found in plants of the genus Panax, which have attracted a lot of attention for their anticancer effect.Materials and methods: In this study, we prepared a kind of novel photoluminescent CDs from ginsenoside Re by one-step hydrothermal synthesis method. The conventional methods including transmission electron microscopy, Fourier transform infrared spectroscopy, HPLC and fluorescence spectrum were used for characterization of CDs. In vitro anticancer effect was investigated by cytotoxicity assay, flow cytometry and Western blot analysis.Results: The as-prepared Re-CDs had an average diameter of 4.6±0.6 nm and excellent luminescent properties. Cellular uptake of Re-CDs was facilitated by their tiny nanosize, with evidence of their bright excitation-dependent fluorescent images. Compared with ginsenoside Re, the Re-CDs showed greater inhibition efficiency of cancer cell proliferation, with lower toxicity to the normal cells. The anticancer activity of Re-CDs was suggested to be associated with the generation of large amount of ROS and the caspase-3 related cell apoptosis.Conclusion: Hopefully, the dual functional Re-CDs, which could both exhibit bioimaging and anticancer effect, are expected to have great potential in future clinical applications. Keywords: carbon dots, ginsenoside Re, excitation-dependent fluorescence, cell imaging, anticancer activity

Background/Aims: Cisplatin (CDDP) was the first platinum-containing anti-cancer drug. However, CDDP causes nephrotoxicity as a side effect, which limits its clinic application. The aim of this study was to investigate the renoprotective effect of ginsenoside Re (G-Re) in a murine model of CDDP-induced acute kidney injury. Methods: Male ICR mice were divided into 4 groups. G-Re was administered to the mice by oral gavage once a day at a dose of 25 mg/kg for 10 days. On the 7th day, a single injection of CDDP (25 mg/kg) was given at 1 h after G-Re treatment. Results: CDDP administration resulted in renal dysfunction, as evidenced by an increase in the serum levels of creatinine and urea nitrogen. Oxidative stress in the CDDP group was reflected by an increase of malondialdehyde and a depletion of reduced glutathione and catalase in renal tissue. These findings were supported by increased 4-hydroxynonenal expression, which was significantly reduced by G-Re. Simultaneously, the overexpression of cytochrome P450 E1 was inhibited. G-Re inhibited the inflammatory response by the reduction of the protein expression of cyclooxygenase-2 and inducible nitric oxide synthase. Furthermore, CDDP increased the expression of Bax and decreased Bcl-2 expression in renal tissue. Hematoxylin and eosin, Hoechst 33258, and TUNEL staining also confirmed the presence of acute tubular necrosis and apoptosis. G-Re significantly decreased the levels of indicators of renal dysfunction, inflammatory cytokines, apoptosis, and malondialdehyde in the kidney and also significantly attenuated the histopathological changes associated with acute renal failure. Conclusions: Collectively, the results of this study suggest that the nephroprotective potential of G-Re may, in part, be related to its anti-oxidant, anti-inflammatory, and anti-apoptotic effects.

Objective · To clarify the therapeutic effect of ginsenoside Re on intervertebral disc degeneration (IDD) and the potential underlying mechanism. Methods · 10 ng/mL tumor necrosis factor-α (TNF-α) was used to stimulate nucleus pulposus (NP) cells. The expression of inflammation and cartilage-related genes, including matrix metalloproteinase 3 (Mmp 3), a disintegrin and metalloproteinase with thrombospondin 5 (Adamts 5), aggrecan and collagen typeⅡa1 (Col2a1), were measured and compared by real-time quantitative polymerase chain reaction with ginsenoside Re concentration varying from 12.5-50 μmol/L. After stimulation of NP cells with 10 ng/mL TNF-α, the amounts of nuclear factor-κB (NF-κB) pathway-related proteins were measured by using Western blotting with or without 50 μmol/L ginsenoside Re. Twelve 8-week-old rats were used to make coccyx degeneration models (coccygeal vertebrae 6/7 as sham, coccygeal vertebrae 7/8 as puncture), intraperitoneal injection of 50 μmol/L ginsenoside Re as treatment group (n=6) and phosphate buffered saline solution (PBS) as control group (n=6). One month later, the heights of the intervertebral discs were detected by X-ray. The rats' intervertebral disc NP tissues were observed by safranin O-fast green staining and hematoxylin-eosin staining, and histological grade was evaluated. By immunofluorescence, the expressions of TNF-α, MMP 3, aggrecan and COL2A1 were observed. Results · The expressions of inflammatory factors in the NP cells including Mmp 3 and Adamts 5 decreased and the expressions of aggrecan and Col2a1 increased under the treatment of 50 μmol/L ginsenoside Re (all P=0.000). Western blotting showed that compared with the NP cells only stimulated by TNF-α, the amounts of protein p-p65 and p-IκBα decreased significantly under the treatment of ginsenoside Re (both P=0.000). X-ray showed that compared with the puncture segment of PBS injection group, the puncture segment of ginsenoside Re injection group had better disc height indices (P=0.004) and degeneration grades (P=0.000). Immunofluorescence showed ginsenoside Re injection group expressed more aggrecan and COL2A1 (P=0.000), and less TNF-α and MMP 3 (P=0.000). Conclusion · Ginsenoside Re can reduce the expressions of inflammatory factors by inhibiting NF-κB pathway in NP cells as well as maintain the disc heights and effectively alleviate the IDD level of rats. [ABSTRACT FROM AUTHOR]

Previous studies have shown an attenuating effect of ginsenoside Re on myocardial injury induced by hypoxia/reoxygenation (H/R). However, the underlying mechanism remains unclear. This study was designed to determine the underlying mechanism by which ginsenoside Re protects from myocardial injury induced by H/R. HL-1 cells derived from AT-1 mouse atrial cardiomyocyte tumor line were divided into control, H/R, and H/R + ginsenoside Re groups. Cell viability was measured by CCK-8 assay. ATP levels were quantified by enzymatic assays. Signaling pathway was predicted by network pharmacology analyses and verified by luciferase assay and gene-silencing experiment. The relationship between ginsenoside Re and its target genes and proteins was analyzed by docking experiments, allosteric site analysis, real-time PCR, and ubiquitination and immunoprecipitation assays. Our results showed that ginsenoside Re treatment consistently increased HL-1 cell viability and significantly up-regulated ATP levels after H/R-induced injury. Network pharmacology analysis suggested that the effect of ginsenoside Re was associated with the regulation of the Hypoxia-inducing factor 1 (HIF-1) signaling pathway. Silencing of HIF-1α abrogated the effect of ginsenoside Re on HL-1 cell viability, which was restored by transfection with an HIF-1α-expressing plasmid. Results of the bioinformatics analysis suggested that ginsenoside Re docked at the binding interface between HIF-1α and the von Hippel-Lindau (VHL) E3 ubiquitin ligase, preventing VHL from binding HIF-1α, thereby inhibiting the ubiquitination of HIF-1α. To validate the results of the bioinformatics analysis, real-time PCR, ubiquitination and immunoprecipitation assays were performed. Compared with the mRNA expression levels of the H/R group, ginsenoside Re did not change expression of HIF-1α mRNA, while protein level of HIF-1α increased and that of HIF-1α[Ub]n decreased following ginsenoside Re treatment. Immunoprecipitation results showed that the amount of HIF-1α bound to VHL substantially decreased following ginsenoside Re treatment. In addition, ginsenoside Re treatment increased the expression of GLUT1 (glucose transporter 1) and REDD1 (regulated in development and DNA damage response 1), which are targets of HIF-1α and are critical for cell metabolism and viability. These results suggested that Ginsenoside Re treatment attenuated the myocardial injury induced by H/R, and the possible mechanism was associated with the inhibition of HIF-1α ubiquitination. [ABSTRACT FROM AUTHOR]

We examined the effect of ginsenoside Re (G-Re) on autophagy in H9c2 cardiomyocytes cultured in glucose deprivation (GD). Levels of the membrane-bound autophagy-related microtubule-associated protein 1A/1B-light chain 3 (LC3) B-2 were measured via immunoblotting and immunofluorescence was conducted to assess autophagosome formation. GD H9c2 cells were treated with 100 μmol/l G-Re. Cell viability was determined in culture medium. Phosphorylated 5′ AMP-activated protein kinase (AMPK)-α and mammalian target of rapamycin (mTOR) levels were measured to explore the mechanisms underlying the effects of G-Re on autophagy in GD cells. G-Re treatment inhibited autophagosome formation and may be beneficial to GD cardiomyocytes. [ABSTRACT FROM AUTHOR]

In order to study the effect ofSS(squalene synthase) and SE (squalene epoxidase) genes co-over-expression in hairy roots of Panax japonicus on ginsenoside Resynthesis, the callus of P· japonicus was used as receptor material. The double expression vector of SS and SE genes were constructed respectively and transformed the P· japonicus callus by Agrobacterium LBA4404. Finally, C58Cl was used to induce hairy roots from Callus of transgenic P· japonicus. The results of PCR showed that SS and SE genes could be integrated into hairy roots of P· japonicus individually or jointly. RP-HPLC indicated that Re content in transgenic P·japonicus hairy roots was 2.4 times and 2.3 times of that in non-transgenic ones (CK) when SS and SE geneswere transferred alone. The Re content in transgenic P· japonicus hairy roots was 5.3 times that of the non-transgenic ones when SS and SE genes co-over-expression. It can be seen that the SS and SE genes has a positive regulatory effect on Re synthesis in P· japonicus hairy roots and the co-over-expression of SS and SE genes canincrease Re content. [ABSTRACT FROM AUTHOR]

Hyperglycaemia-induced retinal microvascular endothelial cell apoptosis is a critical and principle event in diabetic retinopathy (DR), which involves a series of complex processes such as mitochondrial dysfunction and oxidative stress. Ginsenoside Re (Re), a key ingredients of ginseng, is considered to have various pharmacologic functions, such as antioxidative, inhibition of inflammation and anti-apoptotic properties. However, the effects of Re in DR and the related mechanisms of endothelial cell injury induced by high glucose (HG) exposure remain unclear. The present study was designed to investigate and evaluate the ability of Re to ameliorate HG-induced retinal endothelial RF/6A cell injury and the potential mechanisms involved in the hypoxia-inducible factor-1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling regulated by phosphoinositide 3-kinase (PI3K)/AKT pathway. Our results showed that preincubation with Re exerted cytoprotective effects by reversing the HG-induced decrease in RF/6A cell viability, downregulation of apoptosis rate and inhibition of oxidative-related enzymes, thereby reducing the excess intracellular reactive oxygen species (ROS) and HG-triggered RF/6A cell injury. In addition, Western blot analysis results showed ginsenoside Re significantly increased HIF-1α expression in the cytoplasm but decreased its expression in the nucleus, suggesting that it reduced the translocation of HIF-1α from the cytoplasm to the nucleus, and downregulated VEGF level. Moreover, this effect is involved in the activation of the PI3K/Akt pathway. LY294002, a PI3K inhibitor, was used to block the Akt pathway. Afterwards, the effects of Re on the regulation of apoptotic related proteins, VEGF and HIF-1α nuclear transcription was partially reversed. These findings suggested the exerting protective effects of ginsenoside Re were associated with regulating of PI3K/AKT and HIF-1α/VEGF signaling pathway, which indicates that ginsenoside Re may ameliorates HG-induced retinal angiogenesis and suggests the potential for the development of Re as a therapeutic for DR. [ABSTRACT FROM AUTHOR]

Panax ginseng was employed in the treatment of “Xiao-Ke” symptom, which nowadays known as diabetes mellitus, in traditional Chinese medicine for more than a thousand years. Ginsenoside Re was the major pharmacologic ingredient found abundantly in ginseng. However, the anti-diabetic of Ginsenoside Re and its underlying mechanism in metabolic level are still unclear. Serum and urine metabolomic method was carried out to investigate the anti-diabetic pharmacological effects and the potential mechanism of Ginsenoside Re on high-fat diet combined streptozotocin-induced type 2 diabetes mellitus (T2DM) rats based on ultra-high-performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). Serum and urine samples were collected from the control group (CON), T2DM group, metformin (MET) treatment group, and ginsenoside Re treatment group after intervention. The biochemical parameters of serum were firstly analyzed. The endogenous metabolites in serum and urine were detected by UHPLC-MS. The potential metabolites were screened by multivariate statistical analysis and identified by accurate mass measurement, MS/MS, and metabolite databases. The anti-diabetic-related metabolites were analyzed by KEGG metabolic pathway, and its potential mechanism was discussed. The treatment of ginsenoside Re significantly reduced the blood glucose and serum lipid level improved the oxidative stress caused by T2DM. Biochemical parameters (urea nitrogen, uric acid) showed that ginsenoside Re could improve renal function in T2DM rats. Respective 2 and 6 differential metabolites were found and identified in serum and urine of ginsenoside Re compared with T2DM group and enriched in KEGG pathway. Metabolic pathways analysis indicated that the differential metabolites related to T2DM were mainly involved in arachidonic acid metabolism, Vitamin B6, steroid hormone biosynthesis, and bile secretion metabolic pathways. This study verified the anti-diabetic and anti-oxidation effects of ginsenoside Re, elaborated that ginsenoside Re has a good regulation of the metabolic disorder in T2DM rats, which could promote insulin secretion, stimulated cannabinoid type 1 receptor (CB1), and CaMKK β to activate AMPK signaling pathway, inhibited insulin resistance, and improved blood glucose uptake and diabetic nephropathy, so as to play the role of anti-diabetic.

This work aimed at improving the water solubility of Ginsenoside (G)-Re by forming an inclusion complex. The solubility parameters of G-Re in alpha (α), beta (β), and gamma (γ) cyclodextrin (CD) were investigated. The phase solubility profiles were all classified as AL-type that indicated the 1:1 stoichiometric relationship with the stability constants Ks which were 22 M−1 (α-CD), 612 M−1 (β-CD), and 14,410 M−1 (γ-CD), respectively. Molecular docking studies confirmed the results of phase solubility with the binding energy of −4.7 (α-CD), −5.10 (β-CD), and −6.70 (γ-CD) kcal/mol, respectively. The inclusion complex (IC) of G-Re was prepared with γ-CD via the water-stirring method followed by freeze-drying. The successful preparation of IC was confirmed by powder X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In-vivo absorption studies were carried out by LC-MS/MS. Dissolution rate of G-Re was increased 9.27 times after inclusion, and the peak blood concentration was 2.7-fold higher than that of pure G-Re powder. The relative bioavailability calculated from the ratio of Area under the curve AUC0–∞ of the inclusion to pure G-Re powder was 171%. This study offers the first report that describes G-Re’s inclusion into γ-CD, and explored the inclusion complex’s mechanism at the molecular level. The results indicated that the solubility could be significantly improved as well as the bioavailability, implying γ-CD was a very suitable inclusion host for complex preparation of G-Re.

Background: Both ginsenoside Re and B-complex vitamins are widely used as nutritional supplements. They are often taken together so as to fully utilize their antifatigue and refreshing effects, respectively. Whether actually a drug–nutrient interaction exists between ginsenoside Re and B-complex vitamins is still unknown. The objective of this study was to simultaneously investigate the effect of B-complex vitamins on the antifatigue activity and bioavailability of ginsenoside Re after their oral administration. The study results will provide valuable theoretical guidance for the combined utilization of ginseng and B-complex vitamins. Methods: Ginsenoside Re with or without B-complex vitamins was orally administered to mice to evaluate its antifatigue effects and to rats to evaluate its bioavailability. The antifatigue activity was evaluated by the weight-loaded swimming test and biochemical parameters, including hepatic glycogen, plasma urea nitrogen, and blood lactic acid. The concentration of ginsenoside Re in plasma was determined by liquid chromatography–tandem mass spectrometry. Results: No antifatigue effect of ginsenoside Re was noted when ginsenoside Re in combination with B-complex vitamins was orally administered to mice. B-complex vitamins caused to a reduction in the bioavailability of ginsenoside Re with the area under the concentration–time curve from zero to infinity markedly decreasing from 11,830.85 ± 2,366.47 h·ng/mL to 890.55 ± 372.94 h·ng/mL. Conclusion: The results suggested that there were pharmacokinetic and pharmacodynamic drug–nutrient interactions between ginsenoside Re and B-complex vitamins. B-complex vitamins can significantly weaken the antifatigue effect and decrease the bioavailability of ginsenoside Re when simultaneously administered orally.

Yao H, Li J, Song Y, et al. Int J Nanomedicine. 2018;13:6249–6264. The authors have advised due to an error at the time of figure assembly, the β-actin of Figure 8D on page 6261 is incorrect and is a duplication of Figure 8C. The correct Figure 8 is shown below. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

This article explored the mechanism by which ginsenoside Re reduces hypoxia/reoxygenation(H/R) injury in H9c2 cells by regulating mitochondrial biogenesis through nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/peroxisome prolife-rator-activated receptor gamma coactivator-1α(PGC-1α) pathway. In this study, H9c2 cells were cultured in hypoxia for 4 hours and then reoxygenated for 2 hours to construct a cardiomyocyte H/R injury model. After ginsenoside Re pre-administration intervention, cell activity, superoxide dismutase(SOD) activity, malondialdehyde(MDA) content, intracellular reactive oxygen species(Cyto-ROS), and intramitochondrial reactive oxygen species(Mito-ROS) levels were detected to evaluate the protective effect of ginsenoside Re on H/R injury of H9c2 cells by resisting oxidative stress. Secondly, fluorescent probes were used to detect changes in mitochondrial membrane potential(ΔΨ&#95;m) and mitochondrial membrane permeability open pore(mPTP), and immunofluorescence was used to detect the expression level of TOM20 to study the protective effect of ginsenoside Re on mitochondria. Western blot was further used to detect the protein expression levels of caspase-3, cleaved caspase-3, Cyto C, Nrf2, HO-1, and PGC-1α to explore the specific mechanism by which ginsenoside Re protected mitochondria against oxidative stress and reduced H/R injury. Compared with the model group, ginse-noside Re effectively reduced the H/R injury oxidative stress response of H9c2 cells, increased SOD activity, reduced MDA content, and decreased Cyto-ROS and Mito-ROS levels in cells. Ginsenoside Re showed a good protective effect on mitochondria by increasing ΔΨ&#95;m, reducing mPTP, and increasing TOM20 expression. Further studies showed that ginsenoside Re promoted the expression of Nrf2, HO-1, and PGC-1α proteins, and reduced the activation of the apoptosis-related regulatory factor caspase-3 to cleaved caspase-3 and the expression of Cyto C protein. In summary, ginsenoside Re can significantly reduce I/R injury in H9c2 cells. The specific mechanism is related to the promotion of mitochondrial biogenesis through the Nrf2/HO-1/PGC-1α pathway, thereby increasing the number of mitochondria, improving mitochondrial function, enhancing the ability of cells to resist oxidative stress, and alleviating cell apoptosis.

Graphical abstract Highlights • C. cellulans sp. 21 transformed ginsenoside Rb1 into Rg3, and Re into Rg2. • Re impacts on biotransformation products of Rb1and Rd. • Re and its product Rg2 inhibited the activity of β-1,2-glucosidase. • Sugar chains play key roles in the inhibition on the β-1,2 glucosidase activity. Abstract Ginsenoside Rg3, a known anti-cancer agent, is usually prepared by enzyme-mediated and acid hydrolysis of ginsenoside Rb1 and Rd. In this study, we used the bacterium Cellulosimicrobium cellulans sp. 21 to transform Rb1 into Rg3. When Rb1 was used as the sole substrate, the transformation products included Rg3, Rh2, C-K and PPD. However, when Rb1 and Re were mixed, the yield of Rg3 was significantly higher, indicating that Re attenuates the activity of β-1,2-glucosidase secreted by C. cellulans sp. 21. β-1,2-glucosidase hydrolyzes the β-1,2-glucose moiety at the C-3 position of Rb1, but Re dose not modify enzymes that produce Rg3 by hydrolyzing glucose at the C-20 position in aglycon. We also tested the inhibitory effects from various ginsenosides on β-1,2-glucosidase, and discovered that sugar chains played key roles in inhibiting β-1,2 glucosidase activity, whereas aglycones of protopanaxadiol and protopanaxatriol had little inhibitory effects. Some sugar chains with different linkages, such as C-20, C-3 and C-6, exhibited different inhibitory effects. Overall, our findings demonstrate that a combination of substrates, in addition to microorganism-secreted enzymes, can be used for selective biotransformation. This approach provides a novel strategy for natural product preparations via microbial transformation. [ABSTRACT FROM AUTHOR]

Targeting neuronal functional restoration can be an efficacious regimen for treating neurological diseases, including cerebral ischemia-reperfusion injury (CIRI). Then, there is great significance for screening natural ingredient-played neuroprotection with therapeutical safety. Ginsenoside Re (Re), a nutraceutical molecule isolated from Panax ginseng , is previously proven to possess the neuroprotective benefit against CIRI. However, anti-CIRI regulatory mechanisms of Re action have not been totally explicated. In present study, we performed a network pharmacology approach accompanied with molecular docking analysis to illustrate the neuroprotective activity and biological mechanism of Re in the treatment of CIRI, characterized with bioinformatics findings by using gene ontology (GO) functional assay, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Data from integrated bioinformatics analysis exhibited that 60 candidate genes were identified as the therapeutic potentials of Re against CIRI related to autophagy. Most of these genes were found to be regulated functionally for CIRI after Re treatment. According to topological parameter analysis, total 30 core targets in Re against CIRI relating autophagy were discovered. The molecular pathways enriched from core targets might be implicated in neural regeneration, neural restoration and immunoregulation. Further computational assay identified 3 key proteins including protein kinase B (AKT1), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and heat shock protein 90 AA1 (HSP90AA1), in which these proteins' functions were related to the actions and pathways of autophagy. Current findings from this study combine network pharmacology approach and molecular docking analysis to uncover the core targets and molecular mechanisms of Re in the treatment of CIRI related to autophagy, and then we extrapolate that Ginsenoside Re may be used for the potential application for treating CIRI. [Display omitted] • All 60 candidate genes were identified as potential anti-CIRI targets of Re related to autophagy. • All core targets of Re against CIRI related to autophagy were identified. • Molecular mechanisms in Re against CIRI linked to neural regeneration, neural restoration and immunoregulation. • Computational assay identified key proteins including AKT1, PIK3CA and HSP90AA1. • These bioinformatics findings showed Re may be clinical application for treating CIRI. [ABSTRACT FROM AUTHOR]

Salvianolic acid B (SalB) and ginsenoside Re (Re) protect endotheliocytes against apoptosis through different mechanisms. However, whether both compounds could synergistically protect endothelial cells against oxidized low-density lipoprotein (Ox-LDL)-induced apoptosis is unclear. This study aimed to assess the protective effect of combined SalB and Re (SR) treatment on Ox-LDL-induced endothelial apoptosis and to explore the mechanism underlying this effect. Results showed that SalB, Re, or SR could protect against Ox-LDL-induced endothelial apoptosis. Furthermore, the composition of SR was optimized through central composite design with response surface methodology. SR with a composition of 60 μg/mL of SalB and 120 μg/mL of Re exerted the optimal protective effect. Network pharmacology research revealed that SalB and Re in SR synergistically protect against Ox-LDL-induced endothelial apoptosis by regulating oxidative stress and phlogistic pathways. In vitro experiments confirmed these results. Compared with the same dose of SalB or Re alone, SR significantly decreased the contents of inflammatory mediators and increased the activities of antioxidant enzymes. SR could synergistically restore the balanced redox state of the cells and inhibit the activation of nuclear transcription factor kappa B and the caspase cascade by activating the phosphatidylinositol 3 kinase/protein kinase B pathway and inhibiting the phosphorylation of p38 mitogen-activated protein kinase. These pathways are regulated by down-regulating the expression of lectin-like Ox-LDL receptor-1 and NADPH oxidase and up-regulating the expression of estrogen receptor alpha. Therefore, SR effectively prevents Ox-LDL-induced endothelial apoptosis through antioxidative and antiinflammatory mechanisms.

Background: Ginseng belongs to the genus Panax. Its main active ingredients are the ginsenosides. Interstitial cells of Cajal (ICCs) are the pacemaker cells of the gastrointestinal (GI) tract. To understand the effects of ginsenoside Re (GRe) on GI motility, the authors investigated its effects on the pacemaker activity of ICCs of the murine small intestine. Methods: Interstitial cells of Cajal were dissociated from mouse small intestines by enzymatic digestion. The whole-cell patch clamp configuration was used to record pacemaker potentials in cultured ICCs. Changes in cyclic guanosine monophosphate (cGMP) content induced by GRe were investigated. Results: Ginsenoside Re (20–40μM) decreased the amplitude and frequency of ICC pacemaker activity in a concentration-dependent manner. This action was blocked by guanosine 5′-[β-thio]diphosphate [a guanosine-5'-triphosphate (GTP)-binding protein inhibitor] and by glibenclamide [an adenosine triphosphate (ATP)-sensitive K+ channel blocker]. To study the GRe-induced signaling pathway in ICCs, the effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) and RP-8-CPT-cGMPS (a protein kinase G inhibitor) were examined. Both inhibitors blocked the inhibitory effect of GRe on ICC pacemaker activity. L-NG-nitroarginine methyl ester (100μM), which is a nonselective nitric oxide synthase (NOS) inhibitor, blocked the effects of GRe on ICC pacemaker activity and GRe-stimulated cGMP production in ICCs. Conclusion: In cultured murine ICCs, GRe inhibits the pacemaker activity of ICCs via the ATP-sensitive potassium (K+) channel and the cGMP/NO-dependent pathway. Ginsenoside Re may be a basis for developing novel spasmolytic agents to prevent or alleviate GI motility dysfunction.

Ginsenoside Re (GS-Re) is one of the main ingredients of ginseng, a widely known Chinese traditional medicine, and has a variety of beneficial effects, including vasorelaxation, antioxidative, anti-inflammatory, and anticancer properties. The aims of the present study were to observe the effect of GS-Re on balloon injury-induced neointimal hyperplasia in the arteries and to investigate the mechanisms underlying this effect. A rat vascular neointimal hyperplasia model was generated by rubbing the endothelium of the common carotid artery (CCA) with a balloon, and GS-Re (12.5, 25 or 50 mg/kg/d) were subsequently continuously administered to the rats by gavage for 14 days. After GS-Re treatment, the vessel lumen of injured vessels showed significant increases in the GS-Re 25.0 and 50.0 mg/kg/d (intermediate- and high-dose) groups according to H.E. staining. Additionally, a reduced percentage of proliferating cell nuclear antigen (PCNA)-positive cells and an increased number of SM α-actin-positive cells were detected, and the levels of NO, cyclic guanosine monophosphate (cGMP), and eNOS mRNA as well as the phos-eNOS ser1177 /eNOS protein ratio were obviously upregulated in the intermediate- and high-dose groups. Moreover, the promotive effects of GS-Re on NO and eNOS expression were blocked by L-NAME treatment to different degrees. These results suggested that GS-Re can suppress balloon injury-induced vascular neointimal hyperplasia by inhibiting VSMC proliferation, which is closely related to the activation of the eNOS/NO/cGMP pathway. [ABSTRACT FROM AUTHOR]