Journal of Ginseng Research最新文献

Background: Ginsenoside Re (Re) has been shown to activate small-conductance calcium-activated potassium (SK_Ca) current in human coronary artery endothelial cells (HCAECs). We aimed to investigate whether Re increased SK_Ca current via glucocorticoid receptor (GR), its non-genomic pathway phosphoinositide 3-kinase-protein kinase B (PI3K-Akt/PKB), and endothelial nitric oxide synthase (eNOS), and whether SK_Ca mediated Re-induced increase in nitric oxide (NO), prostacyclin (PGI₂), epoxyeicosatrienoic acid (EET), and/or hydrogen peroxide (H₂O₂).

Methods: Whole-cell patch clamp technique was employed to study Re-activated HCAEC currents, using specific inhibitors of the proposed mediating pathway. NO and H₂O₂ were assayed with colorimetric methods; PGI₂ and EET were investigated using ELISA. eNOS phosphorylation was assessed using Western blot analysis.

Results: Re (1 μM) significantly increased HCAEC whole-cell current at +80 mV to 173.73 ± 43.90 % (mean ± SD). Apamin (SK_Ca blocker) could virtually eliminate Re-induced current and apamin-insensitive current could not be increased by Re, while blockers of other endothelial potassium channels did not produce the same effects. Moreover, antagonists of GR, PI3K, Akt/PKB, and eNOS effectively prevented Re's action. Re-induced eNOS phosphorylation and NO production could be prevented by blockers of SK_Ca, GR, or Akt/PKB, but Re-induced PGI₂ production could not be prevented by apamin, while EET and H₂O₂ were not increased by Re.

Conclusion: Re enhances SK_Ca current and NO production via GR-PI3K-Akt/PKB and eNOS activation; in turn, SK_Ca current is essential for Re-increased NO. However, Re-induced PGI₂ release is independent of SK_Ca current. These findings could facilitate further research about ginseng effects on coronary artery and possible use in cardiovascular diseases.

Background: Hepatic fibrosis (HF) continues to be a significant global health concern, substantially contributing to morbidity and mortality due to the absence of effective therapeutic options. This study examines the pharmacological effectiveness and underlying mechanisms of Notoginsenoside R2 (R2) in mitigating HF, aiming to find a new multifunctional candidate for therapeutic application.

Methods: An integrative methodology utilizing network pharmacology, molecular docking, and experimental validation was implemented. In vitro models (HSC-T6), in vivo systems (zebrafish), and microinjection of morpholinos were employed to corroborate the antifibrotic effects of R2 and transcription 3 (STAT3)-dependent processes.

Results: Network pharmacology identified 32 common targets between R2 and HF, with a particular emphasis on pathways critical for the activation of HSCs. Molecular docking confirmed strong interactions between R2 and signal transducer and activator of STAT3. In vitro, R2 inhibited HSCs proliferation and decreased the expression of α-SMA, COL-I, Desimin and TIMP1. In vivo, R2 mitigated thioacetamide-induced fibrosis in zebrafish, leading to decreased collagen deposition and suppression of pro-inflammatory cytokines. Mechanistically, R2 induced senescence in HSCs via the STAT3 pathway, characterized by increased expression of cyclin-dependent kinase inhibitor 2A (CDKN2A/p16) and cyclin-dependent kinase inhibitor 1A (CDKN1A/p21), as well as components of the senescence-associated secretory phenotypes (SASPs).

Conclusion: This study identified R2 as a regulator of STAT3 with dual antifibrotic effects: reduction of the inflammatory microenvironment and induction of senescence. These findings position R2 as a viable treatment candidate for HF, necessitating additional clinical investigation.

Background: Colorectal cancer is the third most common cancer worldwide and the fourth leading cause of cancer death. Protopanaxatriol (PPT), one of the main active metabolic ginsenosides of ginseng, has been found to have neuroprotective and anti-inflammatory effects, but its role in regulating colon cancer development remained unclear.

Purpose: We sought to confirm the inhibitory effect of PPT on colon cancer cells and elucidate its target and mechanism.

Methods: MTT assay, colony formation, invasion, migration assays, cell apoptosis, and cell-cycle analysis were performed. Quantitative real-time PCR, Western blotting, bioinformatic analysis using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, and cellular thermal shift assay experiments were also employed.

Results: PPT can inhibit the cloning, migration, invasion, and proliferation of colon cancer cells. PPT can increase the number of apoptotic bodies, promote the expression of the apoptotic proteins caspase-9 and caspase-3, induce apoptosis, and inhibit cell proliferation. In addition, by regulating cyclin, PPT can increase the expression of p21 and p27 proteins and inhibit the expression of the cyclin D1 protein, thereby inhibiting the G1/S transformation in the cell cycle. We further demonstrated that PPT can target AKT, reduce its protein expression, and reduce tumor progression and the expression of inflammatory factors caused by AKT high expression (TNF-α, IL-1β, and IL-6), thereby playing a role in inhibiting colon cancer progression.

Conclusion: We are the first to demonstrate that the ginsenoside PPT can inhibit the activity of colon cancer cells by directly binding AKT.

Background: Mitochondrial function is essential for immune cell regulation, and its decline is linked to aging and chronic diseases. Impaired activity contributes to inflammation and reduced immunity. This study explores Red ginseng extract (RGE)'s potential in enhancing mitochondrial function and immune cell viability, offering benefits in mitigating immunosenescence.

Methods: T cells and macrophages from young (12-week-old) and aged (20-month-old) mice were treated with RGE to assess mitochondrial function and cell viability. Flow cytometry evaluated immune cell populations and cytokine expression in splenocytes, while single cell transcriptomics analyzed RGE-induced transcriptional changes in T cells and macrophages.

Results: RGE treatment improved mitochondrial oxygen consumption rate and glycolytic function in CD4⁺ and CD8⁺ T cells from both young and old mice, though effects were more pronounced in young cells. In aged mice, RGE administration resulted in higher proportions of naive T cells and reduced expression of senescence and exhaustion markers. Flow cytometry analysis indicated a decrease in pro-inflammatory cytokines IFN-γ and TNF-α in T cells, along with a reduction in IL-17-producing T cells. Single cell transcriptome analysis revealed downregulation of aging markers (Cd28 and Cd27) and increased expression of mitochondrial complex genes, supporting RGE's role in enhancing mitochondrial function.

Conclusion: RGE treatment enhances mitochondrial function and attenuates T cell senescence and exhaustion in aged immune cells, likely contributing to immune resilience against age-associated inflammation. This study highlights the potential of RGE as a therapeutic intervention for improving immune function and reducing the effects of immunosenescence, offering valuable insights into mitigating age-related immune decline.

Background: Imbalances in nicotinamide adenine dinucleotide (NAD⁺) homeostasis accelerate aging, and targeting NAD⁺ metabolism is a potential strategy for delaying aging. Ginsenoside, as the main active ingredient of Panax ginseng Meyer, exert age-delaying effects. However, the potential molecular mechanism by which total ginsenosides (GS) affect NAD⁺ metabolism remains unclear.

Methods: The ability of GS to improve the health status of aging mice was evaluated by water maze, new object recognition, cardiac ultrasound, biochemical analysis, and H&E staining. LC-MS was used to detect NAD⁺ metabolites. Senescence-associated secretory phenotypes (SASPs), NAD⁺ level and mitochondrial function were used to assess cellular senescence status. Screening of active components of GS in mouse hepatocytes (AML12) based on serum metabolites of GS. Targeted knockdown of IDO2 further validated the molecular mechanism.

Results: GS administration significantly improved the health status of aging mice, as evidenced by improvements in body weight maintenance, skeletal muscle function, neurological performance, and hepatic/cardiac function. Furthermore, GS treatment effectively ameliorated age-associated pathological alterations in multiple organs, including the liver, lung, heart, and brain. In addition, GS affects mainly the de novo biosynthesis pathway in the liver. After performing a phenotype screen, ginsenoside Rb2 (Rb2) was found to promote NAD⁺ metabolism, improve mitochondrial function and relieve AML12 cell senescence. The results attributed to IDO2 knockdown were reversed by GS and Rb2.

Conclusion: GS and Rb2 enhance mitochondrial function and delay hepatocyte senescence by modulating the IDO2/QPRT-mediated NAD ⁺ de novo biosynthesis pathway. This discovery provides new insights into the role of ginsenosides in antiaging.

Background: Aging is a complex and inevitable biological process that involves the decline of function in multiple systems and organs, and it is possible to delay aging process and improve health conditions through diet. Ginsenosides, the major active compounds in Panax ginseng Meyer, exhibit anti-oxidant, anti-cancer, and anti-aging properties. However, the relationship between bioactivities and structures of ginsenoside derivatives with same molecular formula remain unclear.

Methods: Using Caenorhabditis elegans (C. elegans) model, we evaluated the anti-aging activities of 4 ginsenoside derivatives (Rg5, Rg6, Rk1, and F4), which differ in glycoside composition and double bond position. Their effects on lifespan, physiological functions, locomotion ability, lipofuscin accumulation, stress resistance, and acetylcholinesterase (AChE) activity were assessed.

Results: Four ginsenoside derivatives showed different activities of delaying aging by improving muscle function, enhancing anti-oxidant stress, and reducing AChE activity in C. elegans. Particularly, Rg5 and Rk1, which contain two glucose residues, demonstrated superior activity compared to Rg6 and F4, which possess glucose-(2-1)-rhamnose residues. Meanwhile, Rg5 and F4, with a double bond at Δ²⁰⁽²²⁾ had better effects than Rk1 and Rg6 with a double bond at Δ²⁰⁽²¹⁾. Molecular docking analysis showed that Rg5 and Rk1 formed more hydrogen bonds and hydrophobic interactions with amino acid residues at the AChE active site compared to Rg6 and F4, Rg5 exhibited the most favorable binding energy, while Rg6 formed only a hydrogen bond and F4 showed no hydrogen bonding; both had the same binding energy.

Conclusion: These findings suggest that glycoside types and double bond position are key structural determinants of the anti-aging activities of ginsenoside derivatives. This provides a theoretical foundation for the development of ginsenoside-based therapeutics for aging and aging-related chronic diseases.

Background: The development of resistance to CDK4/6 inhibitors is a significant challenge in treating estrogen receptor-positive (ER+) breast cancer. This study aimed to explore the regulatory mechanisms of ginsenoside Rg5 in enhancing Abemaciclib sensitivity in ER+breast cancer.

Materials and methods: Abemaciclib-resistant ER + breast cancer cell lines were established. Cell viability, colony formation, cell cycle progression, and apoptosis were evaluated following treatment with ginsenoside Rg5 and/or Abemaciclib. Molecular mechanisms were investigated using Western blot analysis, qRT-PCR, co-immunoprecipitation, and cycloheximide chase assays. The therapeutic efficacy of ginsenoside Rg5 was further validated in xenograft models.

Results: Ginsenoside Rg5 significantly enhanced Abemaciclib sensitivity in both parental and resistant ER+breast cancer cells. The combination treatment induced G1 arrest and apoptosis more effectively than either agent alone. Mechanistically, Rg5 suppressed the PI3K/Akt signaling pathway, downregulated CDK4 and CDK6 mRNA expression, and disrupted the HSP90-CDC37 chaperone complex. This disruption promoted proteasomal degradation of CDK2, CDK4, and CDK6 proteins. Introduction of an HSP90α-Y61A mutant, which resists Rg5 binding, abrogated these effects both in vitro and in vivo.

Conclusions: Ginsenoside Rg5 increases the sensitivity of ER+breast cancer cells by modulating cell cycle proteins via transcriptional and post-translational levels. These findings provide insights into novel combination therapies to circumvent CDK4/6 inhibitor resistance in ER+breast cancer.