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It is significant to note that 50% of patients with sepsis show cardiac insufficiency. Ginsenoside-Rg1 (G-Rg1) has been shown to have a cardiovascular protective effect. However, whether G-Rg1 is involved in the mechanism of action of sepsis-induced myocardial damage (SIMD) is unclear. This study aimed to investigate the protective effect of G-Rg1 on SIMD and to further investigate its mechanism and mechanisms of regulation of downstream pathways. An in vivo model of sepsis was established in mice by cecal ligation and puncture (CLP), and mice was administered intraperitoneally 35 or 70 mg/kg G-Rg1 after surgery. The damage to cardiac tissue was detected by hematoxylin and eosin (HE) staining. Forkhead transcription factor O subfamily member 3a (FOXO3A) in SIMD mice was detected by immunohistochemistry. Apoptosis in mouse myocardial tissue was determined by TUNEL staining. The effect of G-Rg1 on SIMD cardiomyocytes was evaluated by incubating the cells with lipopolysaccharide to induce inflammation as an in vitro model of SIMD. Cardiomyocyte viability and apoptosis were evaluated by cell counting kit-8 (CCK-8) and flow cytometry. Lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and Fe2+ markers of heart damage were detected by the kit. The concentrations of tumor necrosis factor alpha (TNF-a) and interleukin-1beta (IL-1ß) in heart tissue and H9c2 cells were determined by ELISA. The factors related to the focal adhesion kinase (FAK)/protein kinase B (AKT)-FOXO3A signaling pathway were determined by RT-qPCR and Western blot. High-dose G-Rg1 had a significant inhibitory effect on SIMD mouse model and lipopolysaccharide (LPS)-induced H9c2 cardiomyocytes, reducing serum levels of LDH, CK-MB, and cTnI concentrations, which effectively alleviated SIMD. G-Rg1 restored the abnormally elevated levels of TNF-a, IL-1ß, and iron ions and promoted the expression of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) expression, inhibiting apoptosis and inflammatory responses. In addition, G-Rg1 reversed the inhibitory effect of G-Rg1 on LPS-induced H9c2 cardiomyocyte injury through activation of the FAK/AKT signaling pathway and up-regulation of FOXO3A. G-Rg1 promoted the activation of the FAK/AKT signaling pathway and up-regulation of the protein expression levels of pathway-associated proteins, p-FAK and p-AKT. Therefore, G-Rg1 mediated the FAK/AKT-FOXO3A signaling pathway and played a role in the treatment of SIMD. We conclude that G-Rg1 inhibited apoptosis and inflammation of cardiomyocytes induced by sepsis and reduced iron ion levels by regulating FAK/AKT-FOXO3A signaling pathway. [ABSTRACT FROM AUTHOR]

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain and spinal cord. One important aspect of ALS pathogenesis is superoxide dismutase 1 (SOD1) mutant-mediated mitochondrial toxicity, leading to apoptosis in neurons. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on a mutational SOD1 cell model, and to explore the underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were exposed to neuron differentiation reagents for seven days. CM or G-Rg1 decreased the apoptotic rate of SOD1G93A -NSC34 cells to a certain extent, but their combination brought about the least apoptosis, compared with CM or G-Rg1 alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all the treatment groups. Proteins associated with mitochondrial apoptotic pathways, such as Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. Furthermore, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF- κ B) signaling pathway by reducing the phosphorylation of p65 and I κ Bα. CM/G-Rg1 or their combination also reduced the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF- κ B signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1G93A -NSC34 cells through suppressing the NF- κ B/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract). [ABSTRACT FROM AUTHOR]

Objective To explore the role and mechanisms of Sestrin2 in ameliorating hypoxiareoxygenation injury of rat’s cardiomyocytes by ginsenoside-rg1 (G-Rg1). Methods Rat H9c2 cardiomyocytes cultured in vitro were randomly divided into 5 groups according to the experimental requirements：control group, Hypoxia reoxygenation group, G-Rg1 group, hypoxia Inducible Factor-1 (HIF-1, HIF-1α) inhibitor group, and Sestrin2 siRNA interference group. Flow cytometry was used to detect the expression levels of ROS in cardiomyocytes. Western blot was used to detect the protein expression of HIF-1α, Sestrin2, ATF-6, PERK, IRE-1 in cardiomyocytes. Immunofluorescence was used to test the protein expression of Sestrin2, HIF-1α, IRE1. Results Compared with control group, the level of ROS and protein expression of HIF-1α、Sestrin2、ATF6、PERK、IRE-1 of hypoxiareoxygenation group were significantly increased (P < 0.05). Compared with the hypoxiareoxygenation group, the ROS level in G-Rg1 group were significantly reduced and protein expression of HIF-1α、Sestrin2、ATF-6、PERK、IRE-1 in G-Rg1 group were significantly increased (P < 0.05). Compared with G-Rg1 group, the level of ROS were significantly increased and the protein level of Sestrin2 were significantly reduced, in HIF-1α inhibition group (P < 0.05). Compared with G-Rg1 group, the level of ROS were significantly increased and the protein level of IRE-1 were significantly upregulated in Sestrin2 siRNA group (P <0.05). Conclusions　G-Rg1 protects rat cardiomyocytes and maintains endoplasmic reticulum homeostasis in vitro by upregulating expression of Sestrin2. [ABSTRACT FROM AUTHOR]

Ginsenoside‐Rg1 (G‐Rg1), a saponin that is a primary component of ginseng, is effective against inflammatory diseases. The P2X purinoceptor 7 (P2X7) receptor is an ATP‐gated ion channel that is predominantly expressed in immune cells and plays a key role in inflammatory processes. We investigated the role of G‐Rg1 in sepsis‐related cardiac dysfunction and the underlying mechanism involving the regulation of the P2X7 receptor. We detected cell viability, cytotoxicity, cellular reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP) with or without G‐Rg1 in lipopolysaccharide (LPS)‐ or hypoxia/reoxygenation (H/R)‐induced H9c2 cell models of ischemia/reperfusion injury. We applied cecal ligation and puncture (CLP) to induce a mouse model of sepsis and measured the survival duration and cardiac function of CLP mice. Next, we quantified the ROS level, MMP, respiratory chain complex I–IV enzymatic activity, and mitochondrial fusion in CLP mouse heart tissues. We then investigated the role of G‐Rg1 in repairing LPS‐induced cell mitochondrial damage, including mitochondrial superoxidation products. The results showed that G‐Rg1 inhibited LPS‐ or H/R‐induced cardiomyocyte apoptosis, cytotoxicity, ROS levels, and mitochondrial damage. In addition, G‐Rg1 prolonged the survival time of CLP mice. G‐Rg1 attenuated LPS‐induced superoxide production in the mitochondria of cardiomyocytes and the excessive release of cytochrome c from mitochondria into the cytoplasm. Most importantly, G‐Rg1 suppressed LPS‐mediated induction of proapoptotic Bax, activated Akt, induced GSK‐3β phosphorylation, and balanced mitochondrial calcium levels. Overall, G‐Rg1 activates the Akt/GSK‐3β pathway through P2X7 receptors to inhibit sepsis‐induced cardiac dysfunction and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.

Objective: To investigate the promotion effects of Ginsenoside-Rg1 on angiogenesis of rat after acute myocardial infarction. Methods: Myocardial infarction was induced by making a knot to permanently occlude the left anterior descending coronary artery(LAD) of rat. The rats have been divided into two groups: the control and the Rg1. After 3 and 7 days of surgery, we compare the basic life index of the two group rats. Then the hearts of rat have been taken out. We investigate the cells morphological characteristics,myocardial basic institutions and angiogenesis by immunofluorescence staining. Results:(1) We found that body weight(BW), heart weight(HW), HW/BW, Tail-cuff systolic blood pressure(TC-SBP) and heart rate(HR) have no difference between the control group and Rg1 group.(2)Comparing the control group, we found that the heart has higher level of the CD31 expression after 3 days and 7 days in Rg1 group. Conclusion: Ginsenoside-Rg1 can effectively promote angiogenesis of rat after acute myocardial infarction leading to prevent ventricular remodeling. [ABSTRACT FROM AUTHOR]

Abstract Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes. The liver is an important organ responsible for the development of insulin resistance, and exploring liver glucose metabolism is important to study insulin resistance. We first established the model of insulin resistance in HepG2 cells and then treated them with different concentrations of ginsenoside-Rg1. The results showed that ginsenoside-Rg1 is not toxic to HepG2 cells. In addition, ginsenoside-Rg1 relieved the insulin-induced insulin resistance in HepG2 cells. Furthermore, ginsenoside-Rg1 increased the uptake of glucose by reducing reactive oxygen species and down-regulating the phosphorylation level of p38 MAPK. In addition, ginsenoside-Rg1 also decreased the output of glucose by increasing Akt phosphorylation and reducing GSK3β expression. In conclusion, ginsenoside-Rg1 can alleviate the insulin resistance through increasing the uptake of glucose and decreasing the output of glucose. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Ginsenoside-Rg1, the main active component of Panax notoginseng, exhibits a number of pharmacological functions, including promoting protein synthesis in the brain, increasing the number of synapses, improving memory and promoting recovery of brain function following injury. The effect of ginsenoside-Rg1 on proliferation and glial-like-directed differentiation in the cortical neural stem cells (NSCs) of embryonic rat brain was investigated. The present study used MTS assays to identify the optimum dose and window time of ginsenoside-Rg1 administration to stimulate the proliferation of cortical NSCs in the rat embryonic tissue. The oxygen glucose deprivation (OGD) set-up was used as a cell injury model. Immunofluorescent staining was used for identification of NSCs and subsequent observation of their proliferation and glial-like directed differentiation. Nestin expression was the marker for the presence of NSCs among the cortical cells of embryonic rat brain. The optimum dose of ginsenoside-Rg1 for proliferation of NSCs was 0.32 µg/ml. The optimum window time of 0.32 µg/ml ginsenoside-Rg1 administration on proliferation of NSCs was 6 h. Ginsenoside-Rg1 at 0.32 µg/ml concentration promoted incorporation of bromo-2-deoxyuridine, and expression of nestin and vimentin in primary and passaged NSCs, and NSCs following OGD. Ginsenoside-Rg1 had a role in promoting proliferation and glial-like-directed differentiation of cortical NSCs. The plausible explanation for these responses is that ginsenoside-Rg1 acts similarly to the growth factors to promote the proliferation and differentiation of NSCs. [ABSTRACT FROM AUTHOR]

This study aimed to assess whether Ginsenoside Rg1 (Rg1) inhibits inflammatory responses in human chondrocytes and reduces articular cartilage damage in a rat model of osteoarthritis (OA). Gene expression and protein levels of type II collagen, aggrecan, matrix metalloproteinase (MMP)-13 and cyclooxygenase-2 (COX-2) were determined in vitro by quantitative real-time-polymerase chain reaction and Western blotting. Prostaglandin E2 (PGE2) amounts in the culture medium were determined by enzyme-linked immunosorbent assay (ELISA). For in vivo assessment, a rat model of OA was generated by anterior cruciate ligament transection (ACLT). Four weeks after ACLT, Rg1 (30 or 60 mg/kg) or saline was administered by gavage once a day for eight consecutive weeks. Joint damage was analyzed by histology and immunohistochemistry. Ginsenoside Rg1 inhibited Interleukin (IL)-1β-induced chondrocyte gene and protein expressions of MMP-13, COX-2 and PGE2, and prevented type II collagen and aggrecan degradation, in a dose-dependent manner. Administration of Ginsenoside Rg1 to OA rats attenuated cartilage degeneration, and reduced type II collagen loss and MMP-13 levels. These findings demonstrated that Ginsenoside Rg1 can inhibit inflammatory responses in human chondrocytes in vitro and reduce articular cartilage damage in vivo, confirming the potential therapeutic value of Ginsenoside Rg1 in OA. [ABSTRACT FROM AUTHOR]

Ginsenoside-Rg1 can effectively ameliorate mental disorders, but whether ginsenoside-Rg1 plays a neuroprotective role in cardiac arrest and cardiopulmonary resuscitation (CA/CPR)-induced cognitive impairment remains unclear. In this study, a 5-min asphyxia-based CA/CPR rat model was established to explore the mechanisms underlying the effects of ginsenoside-Rg1 (40 mg·kg-1·d-1, ip, 14 days) on its cognitive alterations. These CA/CPR rats displayed spatial learning and memory impairment in the Morris water maze, as reflected in the compromised basal synaptic transmission and long-term potentiation (LTP) at the Schaffer collateral of hippocampal CA1 area in vivo electrophysiology, whereas the ginsenoside-Rg1 remarkably mitigated these alterations. Next, we found that ginsenoside-Rg1 inhibited hippocampal neuroinflammation by alleviating the CA/CPR-induced hippocampal activation of microglia and astrocytes and the overexpression of related proinflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). In addition, ginsenoside-Rg1 improved CA/CPR-induced hippocampal neuronal apoptosis, dendritic spines and synaptic ultrastructure defects as associated with the upregulation of the key synaptic regulatory proteins. Furthermore, ginsenoside-Rg1 could ameliorate CA/CPR-induced aberrant expression of the key regulators of hippocampal glutamate signaling pathways, excitatory amino acid transporter 2 (EAAT2), excitatory amino acid transporter 1 (EAAT1), Glutamine Synthetase (GS), GluN2B, and glutamate. In conclusion, ginsenoside-Rg1 exerts its neuroprotective effects by ameliorating hippocampus-dependent neuroglia activation-mediated neuroinflammation and neuroplasticity deficits, shedding new light on the therapeutic intervention of CA/CPR-related cognitive disorders. [ABSTRACT FROM AUTHOR]

Aim: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are implicated in many fibrotic diseases, including renal fibrosis. Whether Ginsenoside-Rg1 (G-Rg1) could attenuate renal fibrosisviasuppression of ER stress and UPR has not been reported. The aim of this study was to explore the effect of G-Rg1 on ER stress and UPR-induced apoptosis in kidneys with unilateral ureteral obstruction (UUO) rat model.Methods: Twenty-four male Sprague–Dawley rats were randomly divided into control group, model group and G-Rg1 treatment group. G-Rg1 was administered to rats by intraperitoneal injection. Renal interstitial fibrosis in the model group was developed by UUO in rats. Renal function was estimated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathological damage was evaluated by hematoxylin and eosin (HE) and Masson’s trichrome staining. The ER stress was assessed with glucose-regulated protein (GRP) 78 expression, and the proapoptotic response was detected with CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase-12 expressions by Western Blot. The number of apoptotic cells was determined by Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) analysis.Results: UUO for 14 days aggravated renal function, renal damage and renal interstitial fibrosis, activated ER stress response (induction of GRP78 protein), enhanced the proapoptotic response (increase in CHOP and caspase-12 proteins) and increased the number of apoptotic cells (shown by the TUNEL assay). Treatment with G-Rg1 significantly ameliorates the renal pathological lesions and decreases expressions of ER stress-associated proteins and the level of apoptotic cells in kidneys.Conclusion: G-Rg1 suppresses renal cell apoptotic and fibrotic process partly through inhibition of ERS- and UPR-related apoptotic pathway in the kidneys after UUO. [ABSTRACT FROM AUTHOR]

Aims Ginsenoside-Rg1 (G-Rg1), a saponin that is a primary component of ginseng, is very useful and important in traditional Chinese medicine for stroke. The objective of this study was to explore the mechanisms underlying the neuroprotective effect of G-Rg1 on focal cerebral ischemia/reperfusion. Main methods Focal cerebral ischemia was induced by middle cerebral artery occlusion. Neurological examinations were performed by using Longa's 5-point scale. The brain infarct volume was determined by the 2,3,5-triphenyltetrazolium chloride staining. The permeability of the blood–brain barrier (BBB) was evaluated by Evans blue dye. Western blot and quantitative RT-PCR were used to assess protease-activated receptor-1 (PAR-1) expression. Key findings After G-Rg1 treatment, there was a significant decrease in the neurobehavioral function score compared with normal saline (NS) treatment after ischemia/reperfusion (P < 0.05). G-Rg1 significantly reduced the infarct volume compared with NS treatment after ischemia/reperfusion (P < 0.001). The permeability of the BBB was significantly decreased in the G-Rg1 group compared with the NS group (P < 0.05 or P < 0.01). Western blot and quantitative real time RT-PCR indicated that G-Rg1 administration down-regulated the expression of PAR-1 in the ischemic hemisphere compared with NS administration (P < 0.01 and P < 0.05, respectively). The level of PAR-1 expression strongly correlated with BBB permeability in both the G-Rg1- and NS-treated rats (r = 0.856 and r = 0.908, respectively, P < 0.01). Significance G-Rg1 may ameliorate the neurological injury, the brain infarct volume and the BBB permeability induced by focal cerebral ischemia in rats and its neuroprotective mechanism is related to the down-regulation of PAR-1 expression. [ABSTRACT FROM AUTHOR]

Abstract: Ginsenoside-Rg1 (Rg1) has been identified as potent proangiogenic agent, which plays an important role in wound healing promotion or treatment of ischemic injury. We previously reported that miR-214/eNOS pathway was involved in Rg1-induced angiogenesis. Following the same microRNA microarray profiling data, we proposed miR-15b would be another microRNA candidate involved in Rg1-induced angiogenesis. Using human umbilical vein endothelial cells (HUVECs), it was showed that Rg1 could reduce miR-15b expression rapidly and steadily, leading to a temporal induction of vascular endothelial growth factor receptor-2 (VEGFR-2). The in vitro motility and tubulogenesis via VEGFR-2 in Rg1-treated HUVECs were also demonstrated. Besides, the reduction of VEGFR-2 3′-UTR reporter activity by miR-15b in the luciferase reporter gene assay clearly indicated that miR-15b could affect the VEGFR-2 transcript through targeting its 3′-UTR region. Diminishing expression of endogenous miR-15b could increase VEGFR-2 expression and HUVECs migration and tubulogenesis; while over-expression of miR-15b was found to associate with the reduction of VEGFR-2 expression as well as cellular migration and tubulogenesis. In vivo, artificial increment of miR-15b by injecting Pre-miR-15b precursor into zebrafish embryos was also found to significantly suppress the subintestinal vessels formation. In conclusion, our results further demonstrated the involvement of microRNAs in Rg1-induced angiogenesis. [Copyright &y& Elsevier]

Abstract: Biotransformation of ginsenoside-Rg1 (1) by the fungus Absidia coerulea AS 3.2462 yielded five metabolites (2− 6). On the basis of spectroscopic data analyses, the metabolites were identified as ginsenoside-F1 (2), 6α,12β-dihydroxydammar-3-one-20(S)-O-β-D-glucopyranoside (3), 3-oxo-20(S)-protopanaxatriol (4), 3-oxo-7β-hydroxy-20(S)-protopanaxatriol (5), and 3-oxo-7β,15α-dihydroxy-20(S)-protopanaxatriol (6), respectively. Among them, 5 and 6 are new compounds. These results indicated that Absidia coerulea AS 3.2462 could catalyze the specific C-3 dehydrogenation of derivatives of ginsenoside-Rg1, as well as hydroxylation at the 7β and 15α positions. Metabolites 2, 4 and 5 exhibited moderate reversal activity towards A549/taxol MDR tumor cells in vitro. [Copyright &y& Elsevier]

Abstract: Aim of the study: Podocytes injury mediated by complement complex C5b-9 is the main feature of membranous nephropathy (MN). Little work has been done to prove that ginsenoside-Rg1 could inhibit this process. Our study aims to investigate the efficacy of ginsenoside-Rg1 in protecting the podocyte from complement mediated injury. Materials and methods: We chose sublethal C5b-9 induced podocyte injury as the model of MN in vitro. Ginsenoside-Rg1 was given as an intervention. Morphological changes were observed by electron microscope and fluorescence microscope. The production of reactive oxygen species (ROS) was detected by flow cytometry. The expression of the mitogen activated protein kinase (MAPK) including JNK, ERK and P38 was detected by western-blot technique. Results: Ginsenoside-Rg1 could protect foot processes of podocytes, suppress the damage of F-actin, decrease the production of ROS, and inhibit the activation of P38 kinase pathway. Conclusion: These results suggest that ginsenoside-Rg1 could protect podocyte from sMAC-induced injury partly because of its antioxidant property and inhibit the activation of P38 kinase pathway. [Copyright &y& Elsevier]

Bone marrow-derived mesenchymal stem cells (MSCs) possess a multi-lineage differentiation potential and have the ability to repair and rebuild injured vessels. The autologous differentiated MSC transplantation also makes possible the tissue-engineered grafts. Therefore, the efficient endothelial differentiation of MSCs could be beneficial in the successful injured vessel repair and engraftment. Ginsenoside-Rg1, the most prevalent active constituent of ginseng, is a potent proangiogenic factor of vascular endothelial cells and also has the ability to enhance the proliferation of bone marrow cells. The aim of this study is to investigate the role of ginsenoside-Rg1 in the microenvironment-dependent endothelial differentiation of human MSCs (hMSCs) in vitro. The endothelial differentiation environment was established by co-culturing hMSCs with mature endothelial cells (human umbilical vein endothelial cells) indirectly in vitro. Reverse transcriptase-polymerase chain reaction analysis and fluorescence immunocytochemistry showed a strong expression of endothelial-specific markers such as CD31, Von Willebrand factor, and VE-cadherin. Electron microscopy showed the endothelial characteristic Weibel-Palade bodies of differentiated hMSCs. The increased expression of CD31 demonstrated that Rg1 promoted the endothelial differentiation of hMSCs. The findings here show the differentiation of hMSCs into cells with phenotypic features of endothelial cells using indirect co-culture with mature endothelial cells and provide the evidence that ginsenoside-Rg1 can promote the milieu-dependent endothelial differentiation of hMSCs in vitro. [ABSTRACT FROM AUTHOR]

Abstract: Panax notoginseng saponins have recently been reported to suppress liver fibrosis. Since ginsenoside-Rg1 is the most abundant component of P. notoginseng saponins, we investigated the effect of ginsenoside-Rg1 on experimental liver fibrosis in rats. Histological analysis revealed that ginsenoside-Rg1 significantly improved the extent of liver fibrosis in rats induced by thioacetamide. Ginsenoside-Rg1 markedly suppressed the serum levels of fibrotic markers and hepatic hydroxyproline content in rats treated with thioacetamide. Ginsenoside-Rg1 also reduced the serum levels of alanine transaminase, aspartate transaminase and alkaline phosphatase. Finally, ginsenoside-Rg1 attenuated the levels of thiobarbituric acid reactive substances in livers of rats treated by thioacetamide. In cultured hepatic stellate cells, ginsenoside-Rg1 markedly inhibited cell proliferation, activation and formation of reactive oxygen species stimulated by platelet-derived growth factor-BB (PDGF-BB). Additionally, ginsenoside-Rg1 down-regulated the expression of PDGF receptor-β by reducing the nuclear factor-κB activity, which was required for the gene expression. These results suggest that ginsenoside-Rg1, which exhibits its antioxidant and antifibrotic properties, may be of potential therapeutic value in protecting the liver fibrosis. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional gene modulators. Ginsenoside-Rg1, one of the active components of ginseng, has been confirmed as an angiogenesis inducer. Using miRNA microarray analysis, a total of 17 (including miR-214) and 5 miRNAs were found to be down- or up-regulated by Rg1 in human umbilical vein endothelial cells (HUVECs), respectively. Since miR-214 is closely related to endothelial nitric oxide synthase (eNOS) and hence angiogenesis, its expression was further validated by qRT-PCR. We also investigated the role of miR-214 on eNOS expression and in tubulogenesis and motility of HUVEC by transfection of specific miRNA inhibitor or precursor. Our results suggested that Rg1 can down-regulate miR-214 expression in HUVEC, leading to an increase in eNOS expression, and in vitro cell migration and tube formation which can possibly promote angiogenesis. These results signify a new understanding towards how a simple natural compound can affect physiological changes through modulation of miRNA expression. [Copyright &y& Elsevier]

Abstract: Ginsenoside-Rg1, the pharmacologically active component isolated from ginseng, demonstrated neuroprotective effects on primary cultured rat nigral neurons against rotenone toxicity. Rotenone, a common household pesticide known for its specific and irreversible mitochondria complex I inhibition, has been suggested to be the causal agent of Parkinson''s disease (PD) by inducing degeneration of cells in the substantial nigra. The present study demonstrated that co-treatment of rotenone and Rg1 could reduce rotenone-induced cell death by 58% (SEM=±5.60; N =3). Rotenone-induced mitochondria membrane potential (MMP, ΔΨm) depletion was restored and elevated by at least 38% (SEM=±2.15; N =3) by Rg1. In addition, Rg1 prevented cytochrome c release from the mitochrondrial membrane and increased the phosphorylation inhibition of the pro-apoptotic protein Bad through activation of the PI3K/Akt pathway. The protective effects of Rg1 was blocked by glucocorticoid receptor antagonist RU486, indicating that the action of Rg1 is mediated through glucocorticoid receptor (GR). In conclusion, Rg1 inhibits the mitochondrial apoptotic pathway and increases the survival chance of the primary cultured nigral neurons against rotenone toxicity. Thus, Rg1 and its related compounds may be developed as protective agents against neurodegenerative diseases induced by mitochondrial toxins. [Copyright &y& Elsevier]

Abstract: We here provide definitive evidence that ginsenoside-Rg1, the pharmacologically active component of ginseng, is a functional ligand of the glucocorticoid receptor (GR) as determined by fluorescence polarization assay. Rg1 increased the phosphorylation of GR, phosphatidylinositol-3 kinase (PI3K), Akt/PKB and endothelial nitric oxide synthase (eNOS) leading to increase nitric oxide (NO) production in human umbilical vein endothelial cell. Rg1-induced eNOS phosphorylation and NO production were significantly reduced by RU486, LY294,002, or SH-6. Also, knockdown of GR completely eliminated the Rg1-induced NO production. This study revealed that Rg1 can indeed serve as an agonist ligand for GR and the activated GR can induce rapid NO production from eNOS via the non-transcriptional PI3K/Akt pathway. [Copyright &y& Elsevier]

In the present paper, we overview the discovery of new biological activities induced by ginsenoside Rg1 and Rb1 and discuss possible mechanisms of action. Both compounds could increase neural plasticity in efficacy and structure; especially Rg1, as one small molecular drug, can increase proliferation and differentiation of neural progenitor cells in dentate gyrus of hippocampus of normal adult mice and global ischemia model in gerbils. This finding has great value for treatment of Alzheimer's disease and other neurodegenerative disorders which is characterized by neurons loss. Increase of expression of brain derived neurotrophic factor, Bcl-2 and antioxidant enzyme, enhanced new synapse formation, inhibition of apoptosis and calcium overload are also important neuron protective factors. Rg1 and Rb1 have common effects, but there are some differences in pharmacology and mechanism. These differences may attribute to their different chemical structure. Rg1 is panaxtriol with two sugars, while Rb1 is panaxtriol with four sugars. [ABSTRACT FROM AUTHOR]

Previous studies have reported that ginsenoside-Rg1 (G-Rg1) was able to mitigate the loss of dopaminergic neurons in animal models of Parkinson's disease (PD). The present study provided a systematic review and meta-analysis of preclinical studies to pool current evidence on the effect of G-Rg1 on neurogenesis in the treatment of PD. Eligible studies were identified through a search from six databases: PubMed, EMBASE, Web of Science, VIP, Chinese National Knowledge Infrastructure and the Wanfang database. Primary outcomes were tyrosine hydroxylase (TH)-positive cells in the nigra, Nissl staining-positive cells in the nigra, pole test time and dopamine (DA) levels in the striatum. A total of 18 eligible studies were identified, involving 343 animals. Of these, 13 reported a significant relationship between G-Rg1 and improved TH-positive cells in the nigra compared with the control group (P<0.00001). Furthermore, 3 studies reported a significant relationship between G-Rg1 and improved Nissl-positive cells in the nigra compared with the control group (P<0.00001). In addition, 4 studies reported a significant effect of G-Rg1 to reduce the total pole test time compared with that in the control group (P=0.001). A total of 3 studies indicated a significant association between G-Rg1 and improved DA levels in the striatum compared with the control group (P<0.00001). These results suggested that G-Rg1 has positive effects in attenuating damage in models of PD, and thus, it is a potential candidate neuroprotective drug for human PD. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease and lacks for safe and effective drug to therapy completely. Ginsenoside-Rg1 is one of the main components of ginseng and has been proved to counteract a variety of diseases. However, there is currently a lack of sufficient evidence to support the efficacy of ginsenoside-Rg1 in the treatment of NAFLD. Our aim was to investigate whether Ginsenoside-Rg1 is a potential drug for NAFLD. NAFLD model in rats was established by giving a high-fat diet (HFD), ginsenoside-Rg1 was intragastrically administered 100 mg/kg/d for 8 weeks in NAFLD rat. Serum biochemical indices were measured. Liver tissues were stained with hematoxylin and eosin (HE) and oil red O. Total RNA was extracted from liver and was used for high throughput sequencing to identify the changes of transcriptome. The relevant hub genes were verified by quantitative real-time PCR and western blot. Serum biochemical analysis indicated that ginsenoside-Rg1 improved liver function. Additionally, the staining of HE and oil red O indicated ginsenoside-Rg1 could remit pathology process of NAFLD. The transcriptome changes also support this result and reveals Atf3 and Acox2 were key genes. Taken together, these results suggest that the efficiency of ginsenoside-Rg1 against NAFLD and confirmed that ginsenoside-Rg1 is a potential effective drug in treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Background: Severe hepatitis is a common cause of chronic or acute liver disease and autophagy might play an important role in cellular response to inflammation and injury. It has been reported that Ginsenoside-Rg1 (G-Rg1) has strong hepatoprotective effects for acute liver injury, but its protective mechanisms have not yet been elucidated. This study aims to explore the detailed molecular mechanisms of G-Rg1 on acute liver injury via autophagy. Methods: The role of G-Rg1 by autophagic induction was studied in the mouse model of acute liver injury which induced by carbon tetrachloride (CCl4). Liver function, inflammatory reaction and apoptosis were detected when autophagy has been inhibited by 3-MA or stimulated by RPA. MCC950 and ATP were applied to investigate the role of NLRP3 inflammasome in acute liver injury. The differential expression of NF-κB, NLRP3 inflammasome, caspase 1, caspase 3, IL-1β, IL-18, LC3-I, LC3-II, Beclin-1, PINK1 and Parkin have been detected by the quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Results: G-Rg1 could decrease ALT, AST, TNF-α, IL-1β and IL-6 in mice with CCl4-induced acute liver injury. The change of autophagy and apoptosis after the treatment of 3-MA or RPA demonstrated that the autophagy played a key role in the protective effect of G-Rg1 in acute liver injury. The enhancement of G-Rg1 promoted-autophagy resulted in the significant decrease in NF-κB, NLRP3 inflammasome, caspase 1, caspase 3, IL-1β and IL-18, which suggesting that NF-κB/NLRP3 inflammasome signaling pathway was associated with the autophagy induced by G-Rg1 in acute liver injury. Conclusion: G-Rg1 ameliorated acute liver injury via the autophagy, which may be related to NF-κB/NLRP3 inflammasome signaling pathway., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.

Ginsenoside-Rg1 (G-Rg1) is an agent isolated from Panax ginseng that exerts anti-fibrotic effects; however, the mechanism is still unclear. Herein, we investigated whether G-Rg1 administration can mitigate or reverse unilateral ureteral obstruction (UUO)-induced renal fibrosis by regulating the Klotho/transforming growth factor (TGF)-β1/Smad signaling pathway in rats. Sprague-Dawley male rats were subjected to UUO, and rats in the treatment group were administered G-Rg1 or G-Rg1 plus Klotho short hairpin RNA interference (shRNA), while rats in the control and model groups were administered vehicle for 14 d. Epithelial-mesenchymal transition (EMT) biomarkers and Klotho/TGF-β1 signaling molecules were examined by immunohistochemistry, quantitative real-time PCR and Western blotting. Immunohistochemistry showed that UUO induced increased pro-fibrotic TGF-β1 expression, overexpression of the mesenchymal marker, α-smooth muscle actin (α-SMA), and suppression of the epithelial marker, E-cadherin. Moreover, Western blotting analysis indicated that UUO promoted TGF-β1 and phosphorylated Smad3 (p-Smad3) expression (p<0.01), but blocked Klotho and Smad7 expression (p<0.01). After G-Rg1 administration, the UUO-induced TGF-β1 and p-Smad3 expression was suppressed (p<0.01), whereas the reduced Klotho and Smad7 expression was reversed (p<0.05), followed by amelioration of the EMT process. Intriguingly, the G-Rg1 effects were largely abrogated by Klotho knockdown. Furthermore, Klotho expression was upregulated by G-Rg1 treatment at the mRNA and protein levels. Our results suggest that G-Rg1 may be beneficial for ameliorating renal fibrosis by targeting Klotho/TGF-β1/Smad signaling in UUO rats.

This study aimed to assess whether Ginsenoside Rg1 (Rg1) inhibits inflammatory responses in human chondrocytes and reduces articular cartilage damage in a rat model of osteoarthritis (OA). Gene expression and protein levels of type II collagen, aggrecan, matrix metalloproteinase (MMP)-13 and cyclooxygenase-2 (COX-2) were determined in vitro by quantitative real-time-polymerase chain reaction and Western blotting. Prostaglandin E2 (PGE2) amounts in the culture medium were determined by enzyme-linked immunosorbent assay (ELISA). For in vivo assessment, a rat model of OA was generated by anterior cruciate ligament transection (ACLT). Four weeks after ACLT, Rg1 (30 or 60 mg/kg) or saline was administered by gavage once a day for eight consecutive weeks. Joint damage was analyzed by histology and immunohistochemistry. Ginsenoside Rg1 inhibited Interleukin (IL)-1β-induced chondrocyte gene and protein expressions of MMP-13, COX-2 and PGE2, and prevented type II collagen and aggrecan degradation, in a dose-dependent manner. Administration of Ginsenoside Rg1 to OA rats attenuated cartilage degeneration, and reduced type II collagen loss and MMP-13 levels. These findings demonstrated that Ginsenoside Rg1 can inhibit inflammatory responses in human chondrocytes in vitro and reduce articular cartilage damage in vivo, confirming the potential therapeutic value of Ginsenoside Rg1 in OA.