Ginsenoside Rd Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Inflammation and Apoptosis through PI3K/Akt Signaling Pathway.

Myocardial ischemia/reperfusion (I/R) injury is the leading cause of death worldwide. Ginsenoside Rd (GRd) has cardioprotective properties but its efficacy and mechanism of action in myocardial I/R injury have not been clarified. This study investigated GRd as a potent therapeutic agent for myocardial I/R injury. Oxygen-glucose deprivation and reperfusion (OGD/R) and left anterior descending (LAD) coronary artery ligation were used to establish a myocardial I/R injury model in vitro and in vivo. In vivo, GRd significantly reduced the myocardial infarct size and markers of myocardial injury and improved the cardiac function in myocardial I/R injury mice. In vitro, GRd enhanced cell viability and protected the H9c2 rat cardiomyoblast cell line from OGD-induced injury GRd. The network pharmacology analysis predicted 48 potential targets of GRd for the treatment of myocardial I/R injury. GO and KEGG enrichment analysis indicated that the cardioprotective effects of GRd were closely related to inflammation and apoptosis mediated by the PI3K/Akt signaling pathway. Furthermore, GRd alleviated inflammation and cardiomyocyte apoptosis in vivo and inhibited OGD/R-induced apoptosis and inflammation in cardiomyocytes. GRd also increased PI3K and Akt phosphorylation, suggesting activation of the PI3K/Akt pathway, whereas LY294002, a PI3K inhibitor, blocked the GRd-induced inhibition of OGD/R-induced apoptosis and inflammation in H9c2 cells. The therapeutic effect of GRd in vivo and in vitro against myocardial I/R injury was primarily dependent on PI3K/Akt pathway activation to inhibit inflammation and cardiomyocyte apoptosis. This study provides new evidence for the use of GRd as a cardiovascular drug.

Ginsenoside Rd: A promising target for ischemia-reperfusion injury therapy (A mini review).

Ischemia-reperfusion injury (IRI) represents a prevalent pathological phenomenon. Traditional treatment approaches primarily aim at restoring blood supply to ischemic organs, disregarding the consequent damage caused by IRI. Belonging to the class of protopanaxadiol ginsenosides that are found in Panax ginseng, ginsenoside Rd (GSRd) demonstrates notable safety alongside a diverse range of biological functions. Its active components exhibit diverse pharmacological effects, encompassing anti-inflammatory, anti-tumor, neuroprotective, cardiovascular-protective, and immune-regulatory properties, making it a promising candidate for addressing multiple medical conditions. GSRd shields against I/R injury by employing crucial cellular mechanisms, including the attenuation of oxidative stress, reduction of inflammation, promotion of cell survival signaling pathways, and inhibition of apoptotic pathways. Additionally, GSRd regulates mitochondrial function, maintains calcium homeostasis, and modulates the expression of genes involved in I/R injury. This review seeks to consolidate the pharmacological mechanism of action of GSRd within the context of IRI. Our objective is to contribute to the advancement of GSRd-related pharmaceuticals and provide novel insights for clinicians involved in developing IRI treatment strategies.

A Cocktail of Natural Compounds Holds Promise for New Immunotherapeutic Potential in Head and Neck Cancer.

OBJECTIVE: To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC). METHODS: Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected. RESULTS: Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production. CONCLUSIONS: This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.

Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3ß Signaling Pathway.

OBJECTIVE: To investigate the role of ginsenoside Rd (GRd) in acute myeloid leukemia (AML) cell differentiation. METHODS: AML cells were treated with GRd (25, 50, 100 and 200 µg/mL), retinoic acid (RA, 0.1g/L) and PD98059 (20 mg/mL) for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1 (GATA-1), purine rich Box-1 (PU.1), phosphorylated-extracellular signal-related kinase (p-ERK), ERK, phosphorylated-glycogen synthase kinase-3ß (p-GSK3ß), GSK3ß and signal transducer and activator of transcription 1 (STAT1) were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group (non-treated), GRd group [treated with 200 mg/(kg·d) GRd] and homoharringtonine (HTT) group [treated with 1 mg/(kg·d) HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining. RESULTS: The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1 cell arrest (p<0.05). GRd treatment induced leukemia cell differentiation, showing increased expressions of peroxidase and specific proteins concerning erythrogenic or granulocytic differentiation (p<0.05). GRd treatment elicited upregulation of p-ERK, p-GSK-3ß and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1 (P<0.05). After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis (P<0.05). WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor tissues (P<0.05 or P<0.01). CONCLUSION: GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3ß signaling pathway.

Complex components of Shengmai formula interact with organic cation transporter 2 (OCT2) in MDCK cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Shengmai formula (SMF) is a well-known Chinese herbal compound preparation, which is utilized extensively for the treatment of myocardial ischemia, arrhythmia and other life-threatening conditions. Our previous researches have shown that some of the active ingredients in SMF can interact with organic anion transport polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP) and organic anion transporter 1 (OAT1), etc. Organic cation transporter 2 (OCT2) is a highly expressed uptake transporter in the kidney, and its interaction with the major active components in SMF remains unclear. AIM OF THE STUDY: We purposed to explore OCT2-mediated interactions and compatibility mechanisms of the main active compounds in SMF. MATERIALS AND METHODS: Fifteen active ingredients of SMF, including ginsenoside Rb1, Rd, Re, Rg1, Rf, Ro and Rc, methylophiopogonanone A and B, ophiopogonin D and D', schizandrin A and B, schizandrol A and B, were selected to investigate OCT2-mediated interactions in Madin-Darby cacine kidney (MDCK) cells stably expressing OCT2. RESULTS: Among the above 15 main active components, only ginsenosides Rd, Re and schizandrin B could significantly inhibit the uptake of 4-(4-(dimethylamino)styryl)-N-methyl pyridiniumiodide (ASP+), a classical substrate of OCT2. Ginsenoside Rb1 and methylophiopogonanone A can be transported by MDCK-OCT2 cells, and their uptake was significantly reduced when OCT2 inhibitor decynium-22 was added. Ginsenoside Rd could remarkably reduce the uptake of methylophiopogonanone A and ginsenoside Rb1 by OCT2, ginsenoside Re only decreased the uptake of ginsenoside Rb1, while schizandrin B had no effect on the uptake of both. CONCLUSIONS: OCT2 mediates the interaction of the major active components in SMF. Ginsenosides Rd, Re and schizandrin B are the potential inhibitors of OCT2, while ginsenosides Rb1 and methylophiopogonanone A are the potential substrates of OCT2. There is an OCT2-mediated compatibility mechanism among these active ingredients of SMF.

Ginseng Sprouts Attenuate Mortality and Systemic Inflammation by Modulating TLR4/NF-κB Signaling in an LPS-Induced Mouse Model of Sepsis.

Sepsis leads to multi-organ failure due to aggressive systemic inflammation, which is one of the main causes of death clinically. This study aimed to evaluate whether ginseng sprout extracts (GSE) can rescue sepsis and explore its underlying mechanisms. C57BL/6J male mice (n = 15/group) were pre-administered with GSE (25, 50, and 100 mg/kg, p.o) for 5 days, and a single injection of lipopolysaccharide (LPS, 30 mg/kg, i.p) was administered to construct a sepsis model. Additionally, RAW264.7 cells were treated with LPS with/without GSE/its main components (Rd and Re) to explain the mechanisms corresponding to the animal-derived effects. LPS injection led to the death of all mice within 38 h, while GSE pretreatment delayed the time to death. GSE pretreatment also notably ameliorated LPS-induced systemic inflammation such as histological destruction in both the lung and liver, along with reductions in inflammatory cytokines, such as TNF-α, IL-6, and IL-1ß, in both tissues and serum. Additionally, GSE markedly diminished the drastic secretion of nitric oxide (NO) by suppressing the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) in both tissues. Similar changes in TNF-α, IL-1ß, NO, iNOS, and COX2 were observed in LPS-stimulated RAW264.7 cells, and protein expression data and nuclear translocation assays suggested GSE could modulate LPS-binding protein (LBP), Toll-like receptor 4 (TLR4), and NF-κB. Ginsenoside Rd could be a major active component in GSE that produces the anti-sepsis effects. Our data support that ginseng sprouts could be used as an herbal resource to reduce the risk of sepsis. The corresponding mechanisms may involve TLR4/NF-κB signaling and a potentially active component.

Ginsenoside Rd Inhibited Ferroptosis to Alleviate CCl4-Induced Acute Liver Injury in Mice via cGAS/STING Pathway.

Carbon tetrachloride (CCl4)-induced lipid peroxidation associated with hepatic oxidative stress and cell death is an important mechanism of acute liver injury (ALI). Ginsenoside Rd is considered an active ingredient of ginseng. Evidence suggests that ginsenoside Rd may improve ischaemic stroke, nerve damage, cancer and other diseases involving apoptosis, inflammation, oxidative stress, mitochondrial injury and autophagy. However, the effects of ginsenoside Rd on CCl4-induced ALI and its underlying mechanisms are still unclear. In this study, 0.25% CCl4 was injected intraperitoneally in mice to establish a CCl4-induced ALI model. In the Rd treatment group, Rd (10, 20[Formula: see text]mg/kg) doses were injected intraperitoneally 1[Formula: see text]h before and 23[Formula: see text]h after CCl4 administration. Ferroptosis inducer imidazole ketone erastin (IKE) was injected intraperitoneally 4[Formula: see text]h before CCl4 administration to explore the mechanism. The blood and liver were collected 24[Formula: see text]h after CCl4 administration to investigate the effect and mechanism of ginsenoside Rd on CCl4-induced ALI. Our results showed that ginsenoside Rd inhibited CCl4-induced ALI in mice. Ginsenoside Rd also downregulated CCl4-induced serum and liver iron, 4-hydroxynonenal, and 8-hydroxy-2 deoxyguanosine levels. Furthermore, it upregulated glutathione and glutathione peroxidase 4 levels. In addition, ginsenoside Rd downregulated the expression of cGAS and STING. Subsequently, the ferroptosis inducer imidazole ketone erastin significantly reversed the hepatoprotective effect and influence of ginsenoside Rd with regard to the indicators mentioned above. Our study confirmed that ginsenoside Rd ameliorated CCl4-induced ALI in mice, which was related to the reduction of ferroptosis. Simultaneously, the ginsenoside Rd-mediated inhibition of the cGAS/STING pathway contributed to its antiferroptosis effect. In conclusion, our results suggested that ginsenoside Rd inhibited ferroptosis via the cGAS/STING pathway, thereby protecting mice from CCl4-induced ALI. These results suggested ginsenoside Rd may be used as a potential intervention treatment against CCl4-induced ALI.

Interaction of the main active components in Shengmai formula mediated by organic anion transporter 1 (OAT1).

ETHNOPHARMACOLOGICAL RELEVANCE: Shengmai formula (SMF) is a classical traditional Chinese medicine prescription, which is widely used in the treatment of cardiovascular and cerebrovascular diseases. Our previous studies have demonstrated that some components in SMF can interact with each other through breast cancer resistance protein, sodium taurocholate co-transporting polypeptide, organic anion transporting polypeptide 1B1 and 1B3. Organic anion transporter 1 (OAT1) is highly expressed in kidney, mediating the elimination of many endogenous and exogenous substances. However, the interaction between the main active components in SMF and OAT1 is not clear. AIM OF THE STUDY: This study aimed to investigate the interactions of the major bioactive components in SMF mediated by OAT1. MATERIALS AND METHODS: Four main fractions, namely, ginseng total saponins (GTS), ophiopogon total saponins (OTS), ophiopogon total flavonoids (OTF), fructus schisandrae total lignans (STL), and 12 active components, namely, ginsenoside Rg1, Re, Rd and Rb1, ophiopogonin D and D', methylophiopogonanone A and B, schizandrol A and B, schizandrin A and B, were selected to explore the interactions of SMF with OAT1 using cell and rat models. RESULTS: The above four main fractions in SMF all exhibited inhibitory effects on the uptake of 6-carboxyfluorescein (6-CF), a classic substrate of OAT1. Among the 12 main effective components, only ginsenoside Re, Rd, and methylophiopogonanone A showed inhibition of 6-CF uptake. Additionally, we found that schizandrin B was transported by HEK293-OAT1 cells, and schizandrin B uptake was markedly inhibited by GTS, OTS, OTF, ginsenoside Re, Rd, and methylophiopogonanone A. In rats, ginsenoside Re, Rd, and methylophiopogonanone A jointly increased the AUC(0-t), AUC(0-∞), and Cmax of schizandrin B, but they decreased its clearance in plasma and excretion in urine. CONCLUSIONS: Ginsenoside Re, Rd, and methylophiopogonanone A were the potential inhibitors of OAT1, and may interact with some drugs serving as OAT1 substrates clinically. Schizandrin B was a potential OAT1 substrate, and its OAT1-mediated transport was inhibited by ginsenoside Re, Rd, and methylophiopogonanone A. OAT1-mediated interactions of the main active components in SMF can be regarded as one of the important compatibility mechanisms of traditional Chinese medicine preparations.

Insights into Recent Studies on Biotransformation and Pharmacological Activities of Ginsenoside Rd.

It is well known that ginsenosides-major bioactive constituents of Panax ginseng-are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities of Rd-as a potential treatment for a variety of diseases-have been published. However, no specific, comprehensive reviews have been documented to date. The present review not only summarizes the in vitro and in vivo studies on the health benefits of Rd, including anti-cancer, anti-diabetic, anti-inflammatory, neuroprotective, cardioprotective, ischemic stroke, immunoregulation, and other pharmacological effects, it also delves into the inclusion of potential molecular mechanisms, providing an overview of future prospects for the use of Rd in the treatment of chronic metabolic diseases and neurodegenerative disorders. Although biotransformation, pharmacokinetics, and clinical studies of Rd have also been reviewed, clinical trial data of Rd are limited; the only data available are for its treatment of acute ischemic stroke. Therefore, clinical evidence of Rd should be considered in future studies.

[Quality evaluation of ginsenoside reference substances based on qNMR spectroscopy].

The present study established a quality evaluation method for ginsenoside reference substances based on quantitative nuclear magnetic resonance(qNMR) spectroscopy. ~1H-NMR spectra were collected on Bruker Avance Ⅲ 500 MHz NMR spectrometer equipped with a 5 mm BBO probe. The acquire parameters were set up as follows: pulse sequence of 30°, D_1=20 s, probe temperature= 303 K, and the scan number = 32. Dimethyl terephthalate, a high-quality ~1H-qNMR standard, was used as the internal standard and measured by the absolute quantitative method. Methyl peaks of comparatively good sensitivity were selected for quantification, and linear fitting deconvolution was adopted to improve the accuracy of integration results. The qNMR spectroscopy-based method was established and validated, which was then used for the quality evaluation of ginsenoside Rg_1, ginsenoside Re, ginsenoside Rb_1, ginsenoside Rd, and notoginsenoside R_1. The results suggested that the content of these ginsenoside reference standards obtained from the qNMR spectroscopy-based method was lower than that detected by the normalization method in HPLC provided by the manufacturers. In conclusion, the qNMR spectroscopy-based method can ensure the quality of ginsenoside reference substances and provide powerful support for the accurate quality evaluation of Chinese medicine and its preparations. The qNMR spectroscopy-based method is simple, rapid, and accurate, which can be developed for the quantitative assay of Chinese medicine standard references.

Ginsenoside Rd: A promising natural neuroprotective agent.

BACKGROUND: Neurological diseases seriously affect human health, which are arousing wider attention, and it is a great challenge to discover neuroprotective drugs with minimal side-effects and better efficacies. Natural agents derived from herbs or plants have become unparalleled resources for the discovery of novel drug candidates. Panax ginseng C. A. Meyer, a well-known herbal medicine in China, occupies a very important position in traditional Chinese medicines (TCMs) with a long history of clinical application. Ginsenoside Rd is the active compound in P. ginseng known to have broad-spectrum pharmacological effects to reduce neurological damage that can lead to neurological diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, cognitive impairment, and cerebral ischemia. PURPOSE: To review and discuss the effects and mechanisms of ginsenoside Rd in the treatment of neurological diseases. STUDY DESIGN & METHODS: The related information was compiled by the major scientific databases, such as Chinese National Knowledge Infrastructure (CNKI), Elsevier, ScienceDirect, PubMed, SpringerLink, Web of Science, and GeenMedical. Using 'Ginsenoside Rd', 'Ginsenosides', 'Anti-inflammation', 'Antioxidant', 'Apoptosis' and 'Neuroprotection' as keywords, the correlated literature was extracted and conducted from the databases mentioned above. RESULTS: Through summarizing the existing research progress, we found that the general effects of ginsenoside Rd are anti-inflammatory, antioxidant, anti-apoptosis, inhibition of Ca2+ influx and protection of mitochondria, and through these pathways, the compound can inhibit excitatory toxicity, regulate nerve growth factor, and promote nerve regeneration. CONCLUSION: Ginsenoside Rd is a promising natural neuroprotective agent. This review would contribute to the future development of ginsenoside Rd as a novel clinical candidate drug for treating neurological diseases.

Effect of steam-processing of the Panax ginseng root on its inducible activity on granulocyte-colony stimulating factor secretion in intestinal epithelial cells in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng root has been used as tonic in traditional Chinese medicine (TCM) and traditional Japanese Kampo medicine. Steam processing of Panax ginseng root is carried out to enhance its nourishing effects on qi. AIM OF THE STUDY: In order to explore the mechanism of these beneficial effects behind the steam processing of the P. ginseng root, we evaluated effectiveness of processing on the granulocyte-colony stimulating factor (G-CSF) secretion in intestinal epithelial cell-like MCE301 cells. MATERIALS AND METHODS: We collected P. ginseng root samples in the markets of China and Japan. Fresh or dried samples were steamed for different time lengths and subsequently dried and extracted. MCE301 cells were incubated with the medium containing various P. ginseng root extracts, while the concentration of G-CSF in the medium was measured. We also investigated the active ingredients by size exclusion HPLC. RESULTS: The extracts of fresh P. ginseng hairy root samples steamed for more than 6 h significantly induced G-CSF secretion, and the maximum activity was recorded at a 9-h steaming. The same activity was noted when already dried P. ginseng hairy root samples were steamed. The extracts of fresh P. ginseng hairy root without steam processing and those of fresh P. ginseng root body samples with steam processing exhibited no activities. The active ingredients of steamed P. ginseng hairy root samples were high-molecular-weight compounds with an average molecular weight of 758 kDa, and the activity was mediated by the toll-like receptor (TLR) 9. CONCLUSIONS: Our results shed on more light on the mechanism underlying the appearance of immunostimulatory activity of the P. ginseng hairy root induced by steam processing.

Ginsenoside Rd protects transgenic Caenorhabditis elegans from ß-amyloid toxicity by activating oxidative resistant.

Alzheimer's disease (AD) is a serious public health issue but few drugs are currently available for the disease, and these only target the symptoms. It is well established that oxidative stress plays a crucial role in AD, and there is compelling evidence linking oxidative stress to ß-amyloid (Aß). An exciting source of potential new AD therapeutic medication possibilities is medicinal plants. Ginsenoside Rd (GS-Rd) is one of the main bioactive substances in ginseng extracts. In our study, we used a network pharmacology analysis to identify overlapping GS-Rd (therapeutic) and AD (disease)-relevant protein targets, gene ontology (GO) and bio-process annotation, and the KEGG pathway analysis data predicted that GS-Rd impacts multiple targets and pathways, such as the MAPK signal pathway and the JAT-STAT3 signaling pathway. We then assessed the role of GS-Rd in C. elegans and found that GS-Rd prolongs lifespan, improves resistance to heat stress, delays physical paralysis and increases oxidative stress responses. Overall, these results suggest that GS-Rd protects against the toxicity of Aß. The RNA-seq analysis revealed that GS-Rd achieves its effects by regulating gene expressions like daf-16 and skn-1, as well as by participating in many AD-related pathways like the MAPK signaling pathway. In addition, in CL4176 worms, GS-Rd decreased reactive oxygen species (ROS) levels and increased SOD activity. Additional research with transgenic worms showed that GS-Rd aided in the movement of DAF-16 from the cytoplasm to the nucleus. Taken together, the results indicate that GS-Rd significantly reduces Aß aggregation by targeting the MAPK signal pathway, induces nuclear translocation of DAF-16 to activate downstream signaling pathways and increases resistance to oxidative stress in C. elegans to protect against Aß-induced toxicity.

Chinese patent medicine Aidi injection for cancer care: An overview of systematic reviews and meta-analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Aidi injection is one of the China Food and Drug Administration approved Chinese herbal injections and the most competitive product in cancer care in China. It is composed of the extracts from Mylabris Phalerata, Astragalus Membranaceus, Panax Ginseng, and Acanthopanax Senticosus. AIM OF THE STUDY: This overview aims to map systematic reviews (SRs) of Aidi injection for cancer and provide a summarized evidence for clinical practice and decision making. MATERIALS AND METHODS: Seven databases were searched for SRs and/or meta-analyses of randomized controlled trials on Aidi injection for cancer care until December 2020. Six authors worked in pairs independently identified studies, collected data, and assessed the quality of included studies according to the revised Assessment of Multiple Systematic Reviews (AMSTAR 2) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A narrative synthesis was used for the evidence mapping. RESULTS: Fifty-two SRs on Aidi injection as adjuvant therapy were included, involving lung cancer (20 SRs), liver cancer (10), colorectal cancer (7), gastric cancer (6), lymphoma (2), breast cancer (2), esophageal cancer (1), ovary cancer (1), and a mix of different cancers (4). Except for one SR focusing on Aidi injection used alone, other SRs evaluated Aidi injection in combination with chemotherapy (43), radiotherapy (4), or chemo/radiology/targeting therapy (4). Aidi injection showed additional beneficial effects on survival (9), objective response rate (44), quality of life (42), and the reduction of side-effects from chemo/radiotherapy (48). Using AMSTAR 2 tool, two reviews were assessed as low and the rest as critically low methodological quality mainly due to the lack of prospective registration. The reporting quality was insufficient assessed with PRISMA in the reporting of search strategy (26, 50.0%), additional analysis (19, 36.5%), and the summary of evidence (2, 3.8%). CONCLUSION: Aidi injection has been evaluated for its adjuvant beneficial effects on cancer survival, tumor responses, quality of life, and reducing the side effects of chemo/radiotherapy, mainly focusing on lung, liver and colorectal cancer. The methodological and reporting quality are weak and need to be improved in the future.

Ginsenosides in vascular remodeling: Cellular and molecular mechanisms of their therapeutic action.

Evidence is mounting that abnormal vascular remodeling (VR) is a vital pathological event that precedes many cardiovascular diseases (CVD). This provides us with a new research perspective that VR can be a pivotal target for CVD treatment and prevention. However, the current drugs for treating CVD do not fundamentally reverse VR and repair vascular function. The reason may be that a complicated regulatory network is formed between the various signaling pathways involved in VR. Recently, ginsenoside, the main active substance of ginseng, has become increasingly the focus of many researchers for its multiple targets, multiple pathways, and few side effects. Several data have revealed that ginsenosides can improve VR caused by vasodilation dysfunction, abnormal vascular structure and blood pressure. This review is intended to discuss the therapeutic effects and mechanisms of ginsenosides in some diseases involved in VR. Besides, we herein also give a new and contradictory insight into intracellular and molecular signaling of ginsenosides in all kinds of vascular cells. Most importantly, we also discuss the feasibility of ginsenosides Rb1/Rg1/Rg3 in drug development by combining the pharmacodynamics and pharmacokinetics of ginsenosides, and provide a pharmacological basis for the development of ginsenosides in clinical applications.

Ginsenoside Rd attenuates mouse experimental autoimmune neuritis by modulating monocyte subsets conversion.

Guillain-Barré Syndrome (GBS), characterized by peripheral nerve demyelination and axonal damage, is initiated and aggravated through various of immunopathogenesis. Ginsenoside Rd, main active components extracted from ginseng saponins, is known to exhibit immune-regulate functions in many immune-mediated diseases. However, the evidence of preventive effect of Ginsenoside Rd on GBS is lacking. Experimental autoimmune neuritis (EAN) mice, classic model of GBS, were established and treated with GSRd or vehicle. Clinical score and nerve tissue histomorphology were evaluated. Monocytes in peripheral blood and tissue were detected by flow cytometry analysis and immunofluorescence staining. For the in vitro study, GSRd and vehicle were added in the culture medium to assess their regulatory function on monocytes phenotype. In vivo data showed a protective role of GSRd on alleviating symptoms and tissue damage on Day 20 and 25. Administration of GSRd increased non-classical Ly6Clo monocytes in both peripheral blood and injured nerve tissue, and also switched tissue macrophages phenotype into resolution-phase. In vitro study indicated similar role of GSRd on monocytes differentiation status. Transcription factors like Nr4a1 were elevated after GSRd treatment. These findings revealed the protective role of GSRd against EAN, and potential preventive function on GBS patients.

Biotransformation of ginsenoside Rc to Rd by endophytic bacterium Bacillus sp. G9y isolated from Panax quinquefolius.

To isolate endophytic bacterium with the ability to specifically convert ginsenoside Rc from Panax quinquefolius. An endophytic bacterium G9y was isolated from Panax quinquefolius and indentified as Bacillus sp. based on 16s rDNA gene sequence. Ginsenoside Rc was effectively converted to Rd by G9y, which was confirmed by thin-layer chromatography and high performance liquid chromatography (HPLC) analysis. The biotransformation conditions were further optimized as follows: inoculum amount 5%, converting temperature 45 °C, medium beef extract peptone broth at pH of 7, and the time of Rc addition was 4 h after bacterium G9y growth, under which ginsenoside Rc was completely converted to Rd by bacterium G9y within 25 h after inoculation. A strain of G9y with the ability to convert ginsenoside Rc into Rd was screened from endophytic bacteria isolated from P. quinquefolius. The results provide a new microbial resource for preparing ginsenoside Rd via biotransformation, and explore a pathway for Rc utilization, which has great potential application value.

The dual roles of ginsenosides in improving the anti-tumor efficiency of cyclophosphamide in mammary carcinoma mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyclophosphamide (CTX) is a first line chemotherapeutic agent, but often limited for its unstable therapeutic effect and serious side effects. Ginsenosides could facilitate the anti-tumor efficiency of CTX, including benefiting therapeutic effect and decreasing side effects. AIM OF THE STUDY: To investigate the potential mechanism of ginsenosides on benefiting the anti-tumor efficiency of CTX. MATERIALS AND METHODS: Mammary carcinoma mice were applied to investigate the anti-tumor efficiency and potential mechanism of combinational treatment of ginsenosides and CTX. Therapeutic effect was evaluated based on survival rate, tumor burden, tumor growth inhibition rate, and apoptosis and histological changes of tumor tissues. Anti-tumor immunity was studied by measuring serum level of anti-tumor cytokines. Gut mucositis, one of lethal side effects of CTX, was evaluated by diarrhea degree, gut permeability and tight junction proteins expressions. Gut microbial diversity was analyzed by 16S rRNA gene sequencing, and fecal transplant and antibiotics sterilized animals were performed to evaluate the therapeutic effect of gut microbiota on tumor suppression. RESULTS: Ginsenosides facilitated the therapeutic effect of CTX in mice, which manifested as prolonged survival rate, decreased tumor burden, as well as enhanced tumor growth inhibition rate and apoptosis. The favoring effect was related to elevation of anti-tumor immunity which manifested as the increased anti-tumor cytokines (INF-γ, IL-17, IL-2 and IL-6). Further studies indicated the elevation was ascribed to ginsenosides promoted reproduction of gut probiotics including Akkermansia, Bifidobacterium and Lactobacillus. Moreover, co-administration of ginsenosides in mice alleviated CTX-induced gut mucositis, including lower gut permeability, less diarrhea, less epithelium damage and higher tight junction proteins. Further researches suggested the alleviation was related to ginsenosides activated Nrf2 and inhibited NFκB pathways. CONCLUSION: Ginsenosides show dual roles to facilitate the anti-tumor efficiency of CTX, namely promote the anti-tumor immunity through maintaining gut microflora and ameliorate gut mucositis by modulating Nrf2 and NFκB pathways.

Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: Pharmacology and mechanisms.

Epidemiological studies showed that the metabolic syndromes (MetS) and cardiovascular diseases (CVDs) are responsible for a serious threat to human health worldwide. MetS is a syndromes characterized by fat metabolism disorder, obesity, diabetes, insulin resistance and other risk factors, which increases the risk of CVDs initiation and development. Although certain drugs play a role in lowering blood sugar and lipid, some side effects also occur. Considering the multiple pathogenesis, a great deal of natural products have been attempted to treat metabolic syndromes. Ginsenosides, as the active components isolated from Panax ginseng C.A.Mey, have been reported to have therapeutic effects on MetS and CVDs, of which pharmacological mechanisms were further studied as well. This review aims to systematically summarize current pharmacological effects of ginsenosides on MetS and CVDs, potential mechanisms and clinic trials, which will greatly contribute to the development of potential agents for related disease treatment.

Chemical constituents of Panax ginseng and Panax notoginseng explain why they differ in therapeutic efficacy.

Panax ginseng (Meyer) and Panax notoginseng (Burkill), belonging to the family Araliaceae, are used worldwide as medicinal and functional herbs. Numerous publications over the past decades have revealed that both P. notoginseng and P. ginseng contain important bioactive ingredients such as ginsenosides and exert multiple pharmacological effects on nervous system and immune diseases. However, based on traditional Chinese medicine (TCM) theory, their applications clearly differ as ginseng reinforces vital energy and notoginseng promotes blood circulation. In this article, we review the similarities and differences between ginseng and notoginseng in terms of their chemical composition and pharmacological effects. Their chemical comparisons indicate that ginseng contains more polysaccharides and amino acids, while notoginseng has more saponins, volatile oil, and polyacetylenes. Regarding pharmacological effects, ginseng exhibits better protective effects on cardiovascular disease, nerve disease, cancer, and diabetes mellitus, whereas notoginseng displays a superior protective effect on cerebrovascular disease. The evidence presented in this review facilitates further research and clinical applications of these two herbs, and exploration of the relationship between the chemical components and disease efficacy may be the critical next step.