Effect of saponins in Panax notoginseng (Burkill) F. H. Chen on the steroid hormone levels in the chronic unpredictable mild stress model of depression in rats.

Recent research has indicated that Panax notoginseng saponins (PNS) extracted from the radix of Panax notoginseng (Burkill) F. H. Chen exert antidepressant effects. This study aimed to assess the antidepressive effects of ginsenoside Rg1 and PNS in a depression model induced by chronic unpredictable mild stress (CUMS). Over a period of three weeks, rats were administered ginsenoside Rg1 at a dose of 30 mg/kg and PNS at dosages ranging from 100 to 200 mg/kg body weight per day. To assess how ginsenoside Rg1 and PNS influence depression-like behaviours in rats, various assessments were conducted, including coat state evaluation, forced swim test, and elevated plus maze test. The levels of cortisol and testosterone in serum samples were analysed using the liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) method. LC-ESI-MS/MS method provides precise and accurate results. The lower limit of quantification values for cortisol and testosterone were determined as 100 and 2 pg/mL, respectively. Our data demonstrated that both ginsenoside Rg1 and PNS significantly reversed depression-like behaviour in rats by improving coat condition, reducing immobility time in the forced swim test, and increasing time spent in the open arms of the elevated plus maze test. Furthermore, ginsenoside Rg1 and PNS exhibited a regulatory effect on cortisol and testosterone levels in plasma. These findings suggest that ginsenoside Rg1 and PNS may be potential antidepressants in clinical treatment.

Ginsenoside Rh4 inhibits colorectal cancer via the modulation of gut microbiota-mediated bile acid metabolism.

INTRODUCTION: Dysbiosis of the gut microbiota is emerging as a pivotal factor in the pathogenesis of colorectal cancer (CRC). Ginsenoside Rh4 (Rh4) is an active compound isolated from ginseng with beneficial effects in modulating intestinal inflammation and gut microbiota dysbiosis, but how Rh4 regulates the gut microbiota to alleviate CRC remains underexplored. OBJECTIVES: We investigated the impact of Rh4 on CRC and the mechanism of its action in inhibiting CRC via modulation of gut microbiota. METHODS: We used the AOM/DSS model and employed transcriptomics, genomics and metabolomics techniques to explore the inhibitory impact of Rh4 on CRC. Furthermore, we employed experiments involving antibiotic treatment and fecal microbiota transplantation (FMT) to investigate the role of the gut microbiota. Finally, we elucidated the pivotal role of key functional bacteria and metabolites regulated by Rh4 in CRC. RESULTS: Our research findings indicated that Rh4 repaired intestinal barrier damage caused by CRC, alleviated intestinal inflammation, and inhibited the development of CRC. Additionally, Rh4 inhibited CRC in a gut microbiota-dependent manner. Rh4 increased the diversity of gut microbiota, enriched the probiotic Akkermansia muciniphila (A. muciniphila), and alleviated gut microbiota dysbiosis caused by CRC. Subsequently, Rh4 regulated A. muciniphila-mediated bile acid metabolism. A. muciniphila promoted the production of UDCA by enhancing the activity of 7α-hydroxysteroid dehydrogenase (7α-HSDH). UDCA further activated FXR, modulated the TLR4-NF-κB signaling pathway, thus inhibiting the development of CRC. CONCLUSION: Our results confirm that Rh4 inhibits CRC in a gut microbiota-dependent manner by modulating gut microbiota-mediated bile acid metabolism and promoting the production of UDCA, which further activates the FXR receptor and regulates the TLR4-NF-κB signaling pathway. Our results confirm that Rh4 has the potential to be used as a modulator of gut microbiota for preventing and treatment of CRC.

Overview of Panax ginseng and its active ingredients protective mechanism on cardiovascular diseases.

ETHNIC PHARMACOLOGICAL RELEVANCE: Panax ginseng is a traditional Chinese herbal medicine used to treat cardiovascular diseases (CVDs), and it is still widely used to improve the clinical symptoms of various CVDs. However, there is currently a lack of summary and analysis on the mechanism of Panax ginseng exerts its cardiovascular protective effects. This article provides a review of in vivo and in vitro pharmacological studies on Panax ginseng and its active ingredients in reducing CVDs damage. AIM OF THIS REVIEW: This review summarized the latest literature on Panax ginseng and its active ingredients in CVDs research, aiming to have a comprehensive and in-depth understanding of the cardiovascular protection mechanism of Panax ginseng, and to provide new ideas for the treatment of CVDs, as well as to optimize the clinical application of Panax ginseng. METHODS: Enrichment of pathways and biological terms using the traditional Chinese medicine molecular mechanism bioinformatics analysis tool (BATMAN-TCM). The literature search is based on electronic databases such as PubMed, ScienceDirect, Scopus, CNKI, with a search period of 2002-2023. The search terms include Panax ginseng, Panax ginseng ingredients, ginsenosides, ginseng polysaccharides, ginseng glycoproteins, ginseng volatile oil, CVDs, heart, and cardiac. RESULTS: 132 articles were ultimately included in the review. The ingredients in Panax ginseng that manifested cardiovascular protective effects are mainly ginsenosides (especially ginsenoside Rb1). Ginsenosides protected against CVDs such as ischemic reperfusion injury, atherosclerosis and heart failure mainly through improving energy metabolism, inhibiting hyper-autophagy, antioxidant, anti-inflammatory and promoting secretion of exosomes. CONCLUSION: Panax ginseng and its active ingredients have a particularly prominent effect on improving myocardial energy metabolism remodeling in protecting against CVDs. The AMPK and PPAR signaling pathways are the key targets through which Panax ginseng produces multiple mechanisms of cardiovascular protection. Extracellular vesicles and nanoparticles as carriers are potential delivery ways for optimizing the bioavailability of Panax ginseng and its active ingredients.

Ginsenoside Rg1 regulates astrocytes to promote angiogenesis in spinal cord injury via the JAK2/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Mey) is a common traditional Chinese medicine used for anti-inflammation, anti-apoptosis, anti-oxidative stress, and neuroprotection. Ginsenosides Rg1, the main active components isolated from ginseng, may be a feasible therapy for spinal cord injury (SCI). AIMS OF THE STUDY: SCI causes endothelial cell death and blood vessel rupture, ultimately resulting in long-term neurological impairment. As a result, encouraging spinal angiogenesis may be a feasible therapy for SCI. This investigation aimed to validate the capacity of ginsenoside Rg1 in stimulating angiogenesis within the spinal cord. MATERIALS AND METHODS: Rats with SCI were injected intraperitoneally with ginsenoside Rg1. The effectiveness of ginsenoside Rg1 was assessed using the motor function score and the motor-evoked potential (MEP). Immunofluorescence techniques were applied to identify the spinal cord's angiogenesis. Angiogenic factors were examined through Western Blot (WB) and Immunohistochemistry. Oxygen-glucose deprivation (OGD) was employed to establish the hypoxia-ischemia model in vitro, and astrocytes (As) were given ginsenoside Rg1 and co-cultured with spinal cord microvascular endothelial cells (SCMECs). Immunofluorescence, wound healing test, and tube formation assay were used to identify the co-cultured SCMECs' activity. Finally, network pharmacology analysis and siRNA transfection were applied to verify the mechanism of ginsenoside Rg1 promoting angiogenesis. RESULTS: The rats with SCI treated with ginsenoside Rg1 indicated more significant functional recovery, more pronounced angiogenesis, and higher levels of angiogenic factor expression. In vitro, the co-culture system with ginsenoside Rg1 intervention improved SCMECs' capacity for proliferating, migrating, and forming tubes, possibly by promoting the expression of vascular endothelial growth factor (VEGF) in As via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. CONCLUSION: Ginsenoside Rg1 can regulate As to promote angiogenesis, which may help to understand the mechanism of promoting SCI recovery.

Ginsenosides in cancer: Proliferation, metastasis, and drug resistance.

Ginseng, the dried root of Panax ginseng C.A. Mey., is widely used in Chinese herbal medicine. Ginsenosides, the primary active components of ginseng, exhibit diverse anticancer functions through various mechanisms, such as inhibiting tumor cell proliferation, promoting apoptosis, and suppressing cell invasion and migration. In this article, the mechanism of action of 20 ginsenoside subtypes in tumor therapy and the research progress of multifunctional nanosystems are reviewed, in order to provide reference for clinical prevention and treatment of cancer.

Ginsenoside Rg3 attenuates myocardial ischemia/reperfusion-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway.

BACKGROUND: Ginsenoside Rg3 is a component of ginseng that protects against myocardial ischemia/reperfusion (MI/R) injury. Ferroptosis is a new form of cell death characterized by oxidative damage to phospholipids. The purpose of this study was to examine the role and of ginsenoside Rg3 in MI/R and the mechanism. METHODS: A mouse model of left anterior descending (LAD) ligation-induced myocardial ischemia/reperfusion (MI/R) injury and oxygen-glucose deprivation/reperfusion (OGD/R) were used as in vitro and in vivo models, respectively. Echocardiographic analysis, 2,3,5-triphenyltetrazolium chloride (TTC) staining and hematoxylin-eosin (H&E) staining were used to assess the cardioprotective effects of ginsenoside Rg3. Western blotting, biochemical analysis, small interfering RNA analysis and molecular docking were performed to examine the underlying mechanism. RESULTS: Ginsenoside Rg3 improved cardiac function and infarct size in mice with MI/R injury. Moreover, ginsenoside Rg3 increased the expression of the ferroptosis-related protein GPX4 and inhibited iron deposition in mice with MI/R injury. Ginsenoside Rg3 also activated the Nrf2 signaling pathway. Ginsenoside Rg3 attenuated myocardial ischemia/reperfusion-induced ferroptosis via the Nrf2 signaling pathway. Notably, ginsenoside Rg3 regulated the keap1/Nrf2 signaling pathway to attenuate OGD/R-induced ferroptosis in H9C2 cells. Taken together, ginsenoside Rg3 attenuated myocardial ischemia/reperfusion-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway. CONCLUSIONS: Our findings demonstrated that ginsenoside Rg3 ameliorate MI/R-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway.

Functional Validation of the Cytochrome P450 Family PgCYP309 Gene in Panax ginseng.

Ginseng (Panax ginseng C. A. Meyer) is an ancient and valuable Chinese herbal medicine, and ginsenoside, as the main active ingredient of ginseng, has received wide attention because of its various pharmacological active effects. Cytochrome P450 is the largest family of enzymes in plant metabolism and is involved in the biosynthesis of terpenoids, alkaloids, lipids, and other primary and secondary plant metabolites. It is significant to explore more PgCYP450 genes with unknown functions and reveal their roles in ginsenoside synthesis. In this study, based on the five PgCYP450 genes screened in the pre-laboratory, through the correlation analysis with the content of ginsenosides and the analysis of the interactions network of the key enzyme genes for ginsenoside synthesis, we screened out those highly correlated with ginsenosides, PgCYP309, as the target gene from among the five PgCYP450 genes. Methyl jasmonate-induced treatment of ginseng adventitious roots showed that the PgCYP309 gene responded to methyl jasmonate induction and was involved in the synthesis of ginsenosides. The PgCYP309 gene was cloned and the overexpression vector pBI121-PgCYP309 and the interference vector pART27-PgCYP309 were constructed. Transformation of ginseng adventitious roots by the Agrobacterium fermentum-mediated method and successful induction of transgenic ginseng hairy roots were achieved. The transformation rate of ginseng hairy roots with overexpression of the PgCYP309 gene was 22.7%, and the transformation rate of ginseng hairy roots with interference of the PgCYP309 gene was 40%. Analysis of ginseng saponin content and relative gene expression levels in positive ginseng hairy root asexual lines revealed a significant increase in PPD, PPT, and PPT-type monomeric saponins Re and Rg2. The relative expression levels of PgCYP309 and PgCYP716A53v2 genes were also significantly increased. PgCYP309 gene promotes the synthesis of ginsenosides, and it was preliminarily verified that PgCYP309 gene can promote the synthesis of dammarane-type ginsenosides.

Self-Assembled Micelles Based on Ginsenoside Rg5 for the Targeted Treatment of PTX-Resistant Tumors.

Paclitaxel (PTX) is one of the first-line drugs for prostate cancer (PC) treatment. However, the poor water solubility, inadequate specific targeting ability, multidrug resistance, and severe neurotoxicity are far from being fully resolved, despite diverse PTX formulations in the market, such as the gold-standard PTX albumin nanoparticle (Abraxane) and polymer micelles (Genexol-PM). Some studies attempting to solve the multiple problems of chemotherapy delivery fall into the trap of an extremely complicated formulation design and sacrifice druggability. To better address these issues, this study designed an efficient, toxicity-reduced paclitaxel-ginsenoside polymeric micelle (RPM). With the aid of the inherent amphiphilic molecular structure and pharmacological effects of ginsenoside Rg5, the prepared RPM enhances the water solubility and active targeting of PTX, inhibiting chemotherapy resistance in cancer cells. Moreover, the polymeric micelles demonstrated favorable anti-inflammatory and neuroprotective effects, providing ideas for the development of new clinical anti-PC preparations.

Crosstalk among Oxidative Stress, Autophagy, and Apoptosis in the Protective Effects of Ginsenoside Rb1 on Brain Microvascular Endothelial Cells: A Mixed Computational and Experimental Study.

OBJECTIVE: Brain microvascular endothelial cells (BMECs) were found to shift from their usually inactive state to an active state in ischemic stroke (IS) and cause neuronal damage. Ginsenoside Rb1 (GRb1), a component derived from medicinal plants, is known for its pharmacological benefits in IS, but its protective effects on BMECs have yet to be explored. This study aimed to investigate the potential protective effects of GRb1 on BMECs. METHODS: An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established to mimic ischemia-reperfusion (I/R) injury. Bulk RNA-sequencing data were analyzed by using the Human Autophagy Database and various bioinformatic tools, including gene set enrichment analysis (GSEA), Gene Ontology (GO) classification and enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction network analysis, and molecular docking. Experimental validation was also performed to ensure the reliability of our findings. RESULTS: Rb1 had a protective effect on BMECs subjected to OGD/R injury. Specifically, GRb1 was found to modulate the interplay between oxidative stress, apoptosis, and autophagy in BMECs. Key targets such as sequestosome 1 (SQSTM1/p62), autophagy related 5 (ATG5), and hypoxia-inducible factor 1-alpha (HIF-1α) were identified, highlighting their potential roles in mediating the protective effects of GRb1 against IS-induced damage. CONCLUSION: GRbl protects BMECs against OGD/R injury by influencing oxidative stress, apoptosis, and autophagy. The identification of SQSTM1/p62, ATG5, and HIF-1α as promising targets further supports the potential of GRb1 as a therapeutic agent for IS, providing a foundation for future research into its mechanisms and applications in IS treatment.

Computer-driven formulation development of Ginsenoside Rh2 ternary solid dispersion.

(20 S)-Ginsenoside Rh2 is a natural saponin derived from Panax ginseng Meyer (P. ginseng), which showed significantly potent anticancer properties. However, its low water solubility and bioavailability strongly restrict its pharmaceutical applications. The aim of current research is to develop a modified (20 S)-Ginsenoside Rh2 formulation with high solubility, dissolution rate and bioavailability by combined computational and experimental methodology. The "PharmSD" model was employed to predict the optimal polymer for (20 S)-Ginsenoside Rh2 solid dispersion formulations. The solubility of (20 S)-Ginsenoside Rh2 in various polymers was assessed, and the optimal ternary solid dispersion was evaluated across different dissolution mediums. Characterization techniques included the Powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). Molecular dynamics simulations were employed to elucidate the formation mechanism of the solid dispersion and the interactions among active pharmaceutical ingredient (API) and excipient molecules. Cell and animal experiments were conducted to evaluate the in vivo performance of the modified formulation. The "PharmSD" solid dispersion model identified Gelucire 44/14 as the most effective polymer for enhancing the dissolution rate of Rh2. Subsequent experiment also confirmed that Gelucire 44/14 outperformed the other selected polymers. Moreover, the addition of the third component, sodium dodecyl sulfate (SDS), in the ternary solid dispersion formulation significantly amplified dissolution rates than the binary systems. Characterization experiments revealed that the API existed in an amorphous state and interacted via hydrogen bonding with SDS and Gelucire. Moreover, molecular modeling results provided additional evidence of hydrogen bonding interactions between the API and excipient molecules within the optimal ternary solid dispersion. Cell experiments demonstrated efflux ratio (EfR) of Rh2 ternary solid dispersion was lower than that of pure Rh2. In vivo experiments revealed that the modified formulation substantially improved the absorption of Rh2 in rats. Our research successfully developed an optimal ternary solid dispersion for Rh2 with high solubility, dissolution rate and bioavailability by integrated computational and experimental tools. The combination of Artificial Intelligence (AI) technology and molecular dynamics simulation is a wise way to support the future formulation development.

Four-Dimensional Label-Free Quantitative Proteomics of Ginsenoside Rg2 Ameliorated Scopolamine-Induced Memory Impairment in Mice through the Lysosomal Pathway.

Alzheimer's disease (AD) is a neurodegenerative disease. Ginsenoside Rg2 has shown potential in treating AD, but the underlying protein regulatory mechanisms associated with ginsenoside Rg2 treatment for AD remain unclear. This study utilized scopolamine to induce memory impairment in mice, and proteomics methods were employed to investigate the potential molecular mechanism of ginsenoside Rg2 in treating AD model mice. The Morris water maze, hematoxylin and eosin staining, and Nissl staining results indicated that ginsenoside Rg2 enhanced cognitive ability and decreased neuronal damage in AD mice. Proteomics, western blot, and immunofluorescence results showed that ginsenoside Rg2 primarily improved AD mice by downregulating the expression of LGMN, LAMP1, and PSAP proteins through the regulation of the lysosomal pathway. Transmission electron microscopy and network pharmacology prediction results showed a potential connection between the mechanism of ginsenoside Rg2 treatment for AD mice and lysosomes. The comprehensive results indicated that ginsenoside Rg2 may improve AD by downregulating LGMN, LAMP1, and PSAP through the regulation of the lysosomal pathway.

Ginsenoside-Rh2 Promotes Functional Recovery after Spinal Cord Injury by Enhancing TFEB-Mediated Autophagy.

Background: Following spinal cord injury (SCI), autophagy plays a positive role in neuronal protection, whereas pyroptosis triggers an inflammatory response. Ginsenoside-Rh2 (GRh2), known for its neuroprotective effects, is considered a promising drug. However, the exact molecular mechanisms underlying these protective effects remain unclear. Aim of the Study: Explore the therapeutic value of GRh2 in SCI and its potential mechanisms of action. Materials and Methods: An SCI mouse model was established, followed by random grouping and drug treatments under different conditions. Subsequently, the functional recovery of SCI mice after GRh2 treatment was assessed using hematoxylin and eosin, Masson's trichrome, and Nissl staining, footprint analysis, Basso Mouse Scale scoring, and inclined plane tests. The expression levels of relevant indicators in the mice were detected using Western blotting, immunofluorescence, and a quantitative polymerase chain reaction. Network pharmacology analysis was used to identify the relevant signaling pathways through which GRh2 exerts its therapeutic effects. Results: GRh2 promoted functional recovery after SCI. GRh2 significantly inhibits pyroptosis by enhancing autophagy in SCI mice. Simultaneously, the neuroprotective effect of GRh2, achieved through the inhibition of pyroptosis, is partially reversed by 3-methyladenine, an autophagy inhibitor. Additionally, the increase in autophagy induced by GRh2 is mediated by the promotion of transcription factor EB (TFEB) nuclear translocation and dephosphorylation. Partial attenuation of the protective effects of GRh2 was observed after TFEB knockdown. Additionally, GRh2 can modulate the activity of TFEB in mice post-SCI through the EGFR-MAPK signaling pathway, and NSC228155 (an EGFR activator) can partially reverse the effect of GRh2 on the EGFR-MAPK signaling pathway. Conclusions: GRh2 improves functional recovery after SCI by upregulating TFEB-mediated autophagic flux and inhibiting pyroptosis, indicating its potential clinical applicability.

Ginsenoside Rg3 induces mesangial cells proliferation and attenuates apoptosis by miR-216a-5p/MAPK pathway in diabetic kidney disease.

BACKGROUND: Ginsenoside Rg3 is an active saponin isolated from ginseng, which can reduce renal inflammation. However, the role and mechanism of Rg3 in diabetic kidney disease (DKD) are far from being studied. METHODS: The effects of Rg3 and miR-216a-5p on the proliferation, apoptosis, and MAPK pathway in high glucose (HG)-induced SV40 MES 13 were monitored by CCK-8, TUNEL staining, and western blot. RESULTS: Rg3 treatment could accelerate proliferation and suppress apoptosis in HG-induced SV40 MES. Moreover, miR-216a-5p inhibition also could alleviate renal injury, prevent apoptosis, and activate the MAPK pathway in kidney tissues of diabetic model mice. CONCLUSION: Rg3 could attenuate DKD progression by downregulating miR-216a-5p, suggesting Rg3 and miR-216a-5p might be the potential drug and molecular targets for DKD therapy.

Increasing Multienzyme Cascade Efficiency and Stability of MOF via Partitioning Immobilization.

Enhancing the stability of multienzyme cascade reactions in metal-organic frameworks (MOFs) is a challenging task in the fields of biotechnology and chemistry. However, addressing this challenge could yield far-reaching benefits across the application range in the biomedical, food, and environmental sectors. In this study, multienzyme partitioning immobilization that sequentially immobilizes cascade enzymes with hierarchical MOFs is proposed to reduce substrate diffusion resistance. Conversion results of ginsenosides indicate that this strategy improves the cascade efficiency up to 1.26 times. The substrate diffusion model is used to investigate the dual-interenzyme mass transfer behavior of substrates in the restricted domain space and evaluate the substrate channeling effect under partitioning immobilization. Molecular docking and kinetic simulations reveal that the MOFs effectively limit the conformational changes of cascade enzymes at high temperatures and in organic solvents while maintaining a large pocket of active centers. This phenomenon increased efficient substrate docking to the enzyme molecules, further optimizing cascade efficiency. The results of the immobilization of GOX and horseradish peroxidase as model enzymes indicate that the partitioned MOF immobilization strategy could be used for universal adaptation of cascade enzymes.

Ginsenoside Rg1 Regulates Immune Microenvironment and Neurological Recovery After Spinal Cord Injury Through MYCBP2 Delivery via Neuronal Cell-Derived Extracellular Vesicles.

Spinal cord injury (SCI) is a severe neurological condition that frequently leads to significant sensory, motor, and autonomic dysfunction. This study sought to delineate the potential mechanistic underpinnings of extracellular vesicles (EVs) derived from ginsenoside Rg1-pretreated neuronal cells (Rg1-EVs) in ameliorating SCI. These results demonstrated that treatment with Rg1-EVs substantially improved motor function in spinal cord-injured mice. Rg1-EVs enhance microglial polarization toward the M2 phenotype and repressed oxidative stress, thereby altering immune responses and decreasing inflammatory cytokine secretion. Moreover, Rg1-EVs substantially diminish reactive oxygen species accumulation and enhanced neural tissue repair by regulating mitochondrial function. Proteomic profiling highlighted a significant enrichment of MYCBP2 in Rg1-EVs, and functional assays confirmed that MYCBP2 knockdown counteracted the beneficial effects of Rg1-EVs in vitro and in vivo. Mechanistically, MYCBP2 is implicated in the ubiquitination and degradation of S100A9, thereby promoting microglial M2-phenotype polarization and reducing oxidative stress. Overall, these findings substantiated the pivotal role of Rg1-EVs in neuronal protection and functional recovery following SCI through MYCBP2-mediated ubiquitination of S100A9. This research offers novel mechanistic insights into therapeutic strategies against SCI and supports the clinical potential of Rg1-EVs.

Regulation of Autophagy Signaling Pathways by Ginseng Saponins: A Review.

Ginseng saponins ( ginsenosides), bioactive compounds derived from ginseng, are widely used natural products with potent therapeutic properties in the management of various ailments, particularly tumors, cardiovascular and cerebrovascular diseases, and immune system disorders. Autophagy, a highly regulated and multistep process involving the breakdown of impaired organelles and macromolecules by autophagolysosomes and autophagy-related genes (ATGs), has gained increasing attention as a potential target for ginsenoside-mediated disease treatment. This review aims to provide a comprehensive overview of recent research advances in the understanding of autophagy-related signaling pathways and the role of ginsenoside-mediated autophagy regulation. By delving into the intricate autophagy signaling pathways underpinning the pharmacological properties of ginsenosides, we highlight their therapeutic potential in addressing various conditions. Our findings serve as a comprehensive reference for further investigation into the medicinal properties of ginseng or ginseng-related products.

Therapeutic Potential of Ginsenosides on Bone Metabolism: A Review of Osteoporosis, Periodontal Disease and Osteoarthritis.

Ginsenosides, bioactive compounds from the genus Panax, have potential therapeutic effects on diverse ailments, including diabetes. Emerging evidence suggests their involvement in bone metabolism. The present review summarizes the current understanding of the effects of ginsenosides on osteoporosis, periodontal disease, and osteoarthritis. Their mechanisms of action include effects on osteoblasts, osteoclasts, periodontal ligament fibroblasts (PDLFs), and chondrocytes, which are pivotal in maintaining bone, periodontal tissue, and cartilage homeostasis. Ginsenosides may exert their beneficial effects by enhancing PDLF and osteoblast activity, suppressing osteoclast function, augmenting chondrocyte synthesis in the cartilage matrix, and mitigating connective tissue degradation. Moreover, they possess antioxidant, anti-inflammatory, antimicrobial, and anti-pyroptotic properties. Their efficacy in increasing bone density, ameliorating periodontitis, and alleviating osteoarthritis symptoms has been demonstrated in preclinical studies using animal models. In terms of their mechanism of action, ginsenosides modulate cellular differentiation, activity, and key signaling pathway molecules, such as mitogen-activated protein kinases (MAPKs), while also regulating various mediators. Furthermore, the symptomatic relief observed in animal models lends further credence to their therapeutic utility. However, to translate these preclinical findings into clinical practice, rigorous animal and clinical investigations are imperative to ascertain the safety, efficacy, and optimal dosing regimens in human subjects.

Ginsenoside Rb2 Inhibits the Pyroptosis in Myocardial Ischemia Progression Through Regulating the SIRT1 Mediated Deacetylation of ASC.

Myocardial ischemic (MI) injury is a common cardiovascular disease, and the potential therapeutic effects of ginsenoside Rb2 (Rb2) have been lately the focus of interest. Therefore, this study aimed to investigate the effects of Rb2 on pyroptosis of cardiomyocytes in MI progression. An in vitro MI model was developed by subjecting rat's cardiomyocytes (H9c2) to hypoxia/reoxygenation (H/R). The cell viability was determined by CCK-8 assay, while cell death was analyzed by propidium iodide staining. Similarly, pyroptosis-related protein levels and acetylation levels of apoptosis-associated speck-like protein containing a CARD (ASC) were detected by western blotting, and the relationship between Sirtuin 1 (SIRT1) and ASC was confirmed by co-immunoprecipitation (Co-IP) assay. Moreover, hematoxylin-eosin (H&E) and triphenyl tetrazolium chloride staining were used to study pathological structure and infarct size. It was found that post-Rb2 treatment significantly increased the cell viability and decreased the cell death and lactic dehydrogenase release, while the increased gasdermin D-N, NOD-like receptor thermal protein domain-associated protein 3, ASC, and cleaved-caspase-1 protein levels were significantly decreased in H/R-stimulated H9c2 cells. Moreover, the acetylation levels of H92c cells were decreased post-Rb2 treatment via increasing SIRT1 levels, while knocking down SIRT1, translated into an increase in ASC acetylation levels, leading to the increase in ASC protein stability and expressions. Additionally, the Rb2 effects on pyroptosis in H/R-stimulated H92c cells were reversed by overexpressing ASC, while reduced myocardial tissue damage was observed in MI rats following in vivo Rb2 treatment. Rb2 treatment inhibited pyroptosis in MI progression by decreasing the ASC levels. Mechanistically, Rb2 treatment increased the SIRT1 levels, further increasing the acetylation levels of ASC and decreasing the protein stability of ASC.

Inhibition of Cholesteryl Ester Transfer Protein Contributes to the Protection of Ginsenoside Re Against Isoproterenol-Induced Cardiac Hypertrophy.

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.

Protective effects of Panax ginseng as a medical food against chemical toxic agents: molecular and cellular mechanisms.

Humans are exposed to different types of toxic agents, which may directly induce organ malfunction or indirectly alter gene expression, leading to carcinogenic and teratogenic effects, and eventually death. Ginseng (Panax ginseng) is the most valuable of all medicinal herbs. Nevertheless, specific data on the antidotal mechanisms of this golden herb are currently unavailable. Based on the findings of in vitro, in vivo, and clinical studies, this review focused on the probable protective mechanisms of ginseng and its major components, such as protopanaxadiols, protopanaxatriols, and pentacyclic ginsenosides against various chemical toxic agents. Relevant articles from 2000 to 2023 were gathered from PubMed/Medline, Scopus, and Google Scholar. This literature review shows that P. ginseng and its main components have protective and antidotal effects against the deteriorative effects of pesticides, pharmaceutical agents, including acetaminophen, doxorubicin, isoproterenol, cyclosporine A, tacrolimus, and gentamicin, ethanol, and some chemical agents. These improvements occur through multi-functional mechanisms. They exhibit antioxidant activity, induce anti-inflammatory action, and block intrinsic and extrinsic apoptotic pathways. However, relevant clinical trials are necessary to validate the mentioned effects and translate the knowledge from basic science to human benefit, fulfilling the fundamental goal of all toxicologists.