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ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng flowers, which are the buds of the traditional Chinese medicinal herb Sanqi, are widely used in China for their cough-ameliorating properties, with demonstrated therapeutic effects in the treatment of both acute and chronic coughs. However, both the antitussive mechanism and active compound basis of P. notoginseng flowers remain poorly understood. AIM OF THE STUDY: We investigated the antitussive effects of P. notoginseng flowers, identified the bioactive constituents responsible for alleviating cough symptoms, and elucidated the underlying pharmacological mechanisms. MATERIALS AND METHODS: We analyzed the major chemical constituents of aqueous extracts of P. notoginseng flowers using liquid chromatography-mass spectrometry and quantitatively analyzed the key component, 20S-ginsenoside Rh2, using high-performance liquid chromatography. Using a cough reflex model in healthy mice and an ovalbumin-induced, highly sensitive guinea pig cough model, we verified the suppressive effects of P. notoginseng flowers and their saponin constituents on coughing. Furthermore, we explored the mechanisms of action of the key ion channels, NaV1.7 and TRPV1, using whole-cell patch-clamp techniques and molecular docking. Finally, the therapeutic mechanisms of P. notoginseng flowers on pathological cough were revealed using hematoxylin and eosin staining, immunohistochemistry, and western blotting. RESULTS: The active components of P. notoginseng flowers were primarily protopanaxadiol-type saponins, among which 20S-ginsenoside Rh2 had the highest content (51.46 mg/g). In the mouse model, P. notoginseng flowers exhibited antitussive effects comparable to those of pentoxyverine citrate. Although its main saponin component, 20S-ginsenoside Rh2, showed slightly weaker effects, it still demonstrated concentration-dependent inhibition of channel activity. The whole-cell patch-clamp technique and virtual molecular docking showed that Rh2 might exert its effects by directly binding to the NaV1.7 and TRPV1 channels. In the guinea pig model, P. notoginseng flowers and their saponin components not only reduced cough frequency and prolonged the latency period before cough onset, but also significantly inhibited tracheal and pulmonary inflammation and the overexpression of TRPV1. CONCLUSIONS: 20S-Ginsenoside Rh2, the major bioactive saponin in P. notoginseng flowers, exhibits potent antitussive effects. The potential mechanism of action of 20S-Ginsenoside Rh2 in the treatment of cough may involve inhibiting NaV1.7 and TRPV1 channel currents through direct binding to core protein active sites and downregulating TRPV1 expression.
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Antitusígenos , Tos , Regulación hacia Abajo , Flores , Ginsenósidos , Canal de Sodio Activado por Voltaje NAV1.7 , Panax notoginseng , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Cobayas , Flores/química , Tos/tratamiento farmacológico , Ginsenósidos/farmacología , Antitusígenos/farmacología , Masculino , Ratones , Panax notoginseng/química , Regulación hacia Abajo/efectos de los fármacos , Humanos , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Células HEK293 , Simulación del Acoplamiento Molecular , Cricetulus , Modelos Animales de Enfermedad , Células CHO , Saponinas/farmacología , OvalbúminaRESUMEN
BACKGROUND: Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. METHODS: A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. RESULTS: DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). CONCLUSIONS: Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.
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Colitis Ulcerosa , Ferroptosis , Ginsenósidos , MicroARNs , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Ginsenósidos/farmacología , MicroARNs/genética , Ratones , Ferroptosis/efectos de los fármacos , Humanos , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Regulación hacia Arriba/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Sulfato de Dextran/toxicidad , Apoptosis/efectos de los fármacosRESUMEN
Background: Reactivate the T cell immunity by PD-1/PD-L1 checkpoint blockade is widely used in non-small cell lung cancer (NSCLC) patients, while the post-translational modification of Programmed death ligand-1 (PD-L1) is commonly existed in various cancer cells, thus increases the complexity and difficulty in therapy development. Ginsenoside Rg3 is an active component of traditional Chinese herb Ginseng with multiple pharmacological effects including immune regulation. However, the effect on the glycosylation of PD-L1 is unknown. Methods: NSCLC cell lines were tested for glycosylation of PD-L1, and the potential mechanisms were investigated. Tumor cell-T cell coculture experiment was conducted and the activation of T cells and cytotoxicity were measured by flow cytometry. In vivo xenograft mouse tumor model was used to investigate the effects of Rg3 on PD-L1-mediated immunosuppression and tumor growth. Results: Here, we identified PD-L1 is widely N-linked glycosylated in NSCLC cell lines, while Rg3 could inhibit the glycosylation of PD-L1 by downregulating the EGFR signaling and further activate GSK3b-mediated degradation, thus resulted in reduced PD-L1 expression. Moreover, the inhibition of PD-L1 glycosylation promoted the activation and cytotoxicity of T cells under coculture condition. In addition, Rg3 could decrease the tumor volume and enhance anti-tumor T cell immunity as evidence by the upregulated expression of Granzyme B and perforin in CD8+T cells, along with elevated serum IL-2, IFN-g and TNF-a level in Rg3-treated mice. Conclusions: These results suggest that Rg3 inhibits PD-L1 glycosylation and thus enhance anti-tumor immunity, which provide new therapeutic insight into drug discovery.
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Ginsenósidos , Neoplasias Pulmonares , Animales , Humanos , Ratones , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Glicosilación , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Though Ginsenoside F2 (GF2), a protopanaxadiol saponin from Panax ginseng, is known to have an anticancer effect, its underlying mechanism still remains unclear. In our model, the anti-glycolytic mechanism of GF2 was investigated in human cervical cancer cells in association with miR193a-5p and the ß-catenin/c-Myc/Hexokinase 2 (HK2) signaling axis. Here, GF2 exerted significant cytotoxicity and antiproliferation activity, increased sub-G1, and attenuated the expression of pro-Poly (ADPribose) polymerase (pro-PARP) and pro-cysteine aspartyl-specific protease (procaspase3) in HeLa and SiHa cells. Consistently, GF2 attenuated the expression of Wnt, ß-catenin, and c-Myc and their downstream target genes such as HK2, pyruvate kinase isozymes M2 (PKM2), and lactate dehydrogenase A (LDHA), along with a decreased production of glucose and lactate in HeLa and SiHa cells. Moreover, GF2 suppressed ß-catenin and c-Myc stability in the presence and absence of cycloheximide in HeLa cells, respectively. Additionally, the depletion of ß-catenin reduced the expression of c-Myc and HK2 in HeLa cells, while pyruvate treatment reversed the ability of GF2 to inhibit ß-catenin, c-Myc, and PKM2 in GF2-treated HeLa cells. Notably, GF2 upregulated the expression of microRNA139a-5p (miR139a-5p) in HeLa cells. Consistently, the miR139a-5p mimic enhanced the suppression of ß-catenin, c-Myc, and HK2, while the miR193a-5p inhibitor reversed the ability of GF2 to attenuate the expression of ß-catenin, c-Myc, and HK2 in HeLa cells. Overall, these findings suggest that GF2 induces apoptosis via the activation of miR193a-5p and the inhibition of ß-catenin/c-Myc/HK signaling in cervical cancer cells.
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Ginsenósidos , Hexoquinasa , MicroARNs , Proteínas Proto-Oncogénicas c-myc , Transducción de Señal , Neoplasias del Cuello Uterino , beta Catenina , Humanos , Ginsenósidos/farmacología , beta Catenina/metabolismo , beta Catenina/genética , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Femenino , Transducción de Señal/efectos de los fármacos , Hexoquinasa/metabolismo , Hexoquinasa/genética , Células HeLa , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , Efecto Warburg en Oncología/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
Lipopolysaccharide (LPS) triggers a severe systemic inflammatory reaction in mammals, with the dimerization of TLR4/MD-2 upon LPS stimulation serving as the pivotal mechanism in the transmission of inflammatory signals. Ginsenoside Rh2 (G-Rh2), one of the active constituents of red ginseng, exerts potent anti-inflammatory activity. However, whether G-Rh2 can block the TLR4 dimerization to exert anti-inflammatory effects remains unclear. Here, we first investigated the non-cytotoxic concentration of G-Rh2 on RAW 264.7 cells, and detected the releases of pro-inflammatory cytokines in LPS-treated RAW 264.7 cells, and then uncovered the mechanisms involved in the anti-inflammatory activity of G-Rh2 through flow cytometry, fluorescent membrane localization, Western blotting, co-immunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis in LPS-stimulated macrophages. Our results show that G-Rh2 stimulation markedly inhibited the secretion of LPS-induced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Additionally, G-Rh2 blocked the binding of LPS with the membrane of RAW 264.7 cells through direct interaction with TLR4 and MD-2 proteins, leading to the disruption of the dimerization of TLR4 and MD-2, followed by suppression of the TLR4/NF-κB signaling pathway. Our results suggest that G-Rh2 acts as a new inhibitor of TLR4 dimerization and may serve as a promising therapeutic agent against inflammation.
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Ginsenósidos , Lipopolisacáridos , Antígeno 96 de los Linfocitos , Multimerización de Proteína , Receptor Toll-Like 4 , Ginsenósidos/farmacología , Ginsenósidos/química , Animales , Receptor Toll-Like 4/metabolismo , Ratones , Antígeno 96 de los Linfocitos/metabolismo , Antígeno 96 de los Linfocitos/química , Células RAW 264.7 , Multimerización de Proteína/efectos de los fármacos , Unión Proteica , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Antiinflamatorios/farmacología , Antiinflamatorios/química , Simulación del Acoplamiento Molecular , Transducción de Señal/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-ß, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte-microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression.
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Ácido 2-Aminoadípico , Antidepresivos , Astrocitos , Ginsenósidos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ginsenósidos/farmacología , Masculino , Ácido 2-Aminoadípico/farmacología , Depresión/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Apoptosis/efectos de los fármacosRESUMEN
Ginsenoside Rb1 exhibits a wide range of biological activities, and gut microbiota is considered the main metabolic site for Rb1. However, the impact of gut microbiota on the pharmacokinetics of Rb1 are still uncertain. In this study, we investigated the gut microbiome changes and the pharmacokinetics after a 30 d Rb1 intervention. Results reveal that the systemic exposure and metabolic clearance rate of Rb1 and Rd were substantially affected after orally supplementing Rb1 (60 mg/kg) to rats. Significant increase in the relative abundance of Bacteroides cellulosilyticus in gut microbiota and specific glycoside hydrolase (GH) families, such as GH2, GH92, and GH20 were observed based on microbiome and metagenomic analysis. Moreover, a robust association was identified between the pharmacokinetic parameters of Rb1 and the relative abundance of specific Bacteroides species, and glycoside hydrolase families. Our study demonstrates that Rb1 administration significantly affects the gut microbiome, revealing a complex relationship between B. cellulosilyticus, key GH families, and Rb1 pharmacokinetics.
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Bacteroides , Microbioma Gastrointestinal , Ginsenósidos , Ginsenósidos/farmacocinética , Ginsenósidos/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratas , Masculino , Bacteroides/efectos de los fármacos , Ratas Sprague-Dawley , Glicósido Hidrolasas/metabolismoRESUMEN
BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a prevalent neurological disorder, characterized by the oxidative stress and inflammatory response induced during the ischemia-reperfusion process, leading to significant damage to brain cells. Ginsenoside Rb1, a natural medicinal ingredient, possesses potential neuroprotective effects. This study aims to investigate the mechanism of action of ginsenoside Rb1 in CIRI and its protective effects on brain injury. METHODS: We utilized a mouse CIRI model and randomly divided the mice into control group, CIRI group, and ginsenoside Rb1 treatment group. The effects of Rb1 on brain tissue damage, apoptosis, expression of inflammatory factors, and pyroptotic cell numbers in CIRI mice were observed through triphenyl tetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, real-time reverse transcription polymerase chain reaction (qRT-PCR), and electron microscopy. In a cell model, the regulatory effect of Rb1 on oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell pyroptosis via the nuclear respiratoty factor 2/tumor necrosis factor-α (TNF-α)-induced Protein 3 (TNFAIP3, aka A20)/eukaryotic translation elongation factor 1A2 (Nrf2/A20/eEF1A2) axis was detected using Western blot and TUNEL staining. Additionally, the impact of Nrf2 inhibitor ML385 and eEF1A2 overexpression on the neuroprotective effect of Rb1 was assessed. Using the comprehensive experimental methods mentioned above, the neuroprotective mechanism of Rb1 in CIRI was thoroughly evaluated. RESULTS: Our findings demonstrate that treatment with ginsenoside Rb1 alleviated behavioral deficits induced by CIRI and reduced pathological damage in brain tissue. Furthermore, ginsenoside Rb1 treatment notably decreased oxidative stress and the inflammatory response induced by CIRI, leading to lower levels of inflammatory factors (p < 0.05). Further experimental results indicated that ginsenoside Rb1 promoted antioxidant and anti-inflammatory responses by regulating the activity of the Nrf2/A20/eEF1A2 axis. Additionally, ginsenoside Rb1 inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, thereby reducing the release of inflammatory factors and the occurrence of cell apoptosis. CONCLUSION: Our study results suggest that ginsenoside Rb1 exerts neuroprotective effects and alleviates brain injury induced by CIRI by regulating the Nrf2/A20/eEF1A2 axis and inhibiting the activation of the NLRP3 inflammasome. These findings provide new treatment insights for CIRI and support ginsenoside Rb1's development as a therapeutic drug. However, despite the promising nature of our findings, further research is required to validate these discoveries and explore the feasibility and safety of ginsenoside Rb1 in clinical applications. We hope that our study can provide new directions and strategies for the treatment and prevention of CIRI, contributing to the development of neuroprotective drugs.
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Ginsenósidos , Factor 2 Relacionado con NF-E2 , Daño por Reperfusión , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratones Endogámicos C57BL , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea CelularRESUMEN
OBJECTIVE: This study aimed to further elucidate the mechanism of ginsenoside Rg1 in the treatment of cerebral ischemia-reperfusion. METHODS: In this study, we observed the apoptosis of RM cells (microglia) after oxygen-glucose deprivation/reoxygenation (OGD/R) modeling before and after Rg1 administration, changes in mitochondrial membrane potential, changes in the content of Reactive oxygen species (ROS) and inflammatory vesicles NLR Family Pyrin Domain Containing 3 (NLRP3), and the expression levels of autophagy-related proteins, inflammatory factors, and apoptosis proteins. We further examined the pathomorphological changes in brain tissue, neuronal damage, changes in mitochondrial morphology and mitochondrial structure, and the autophagy-related proteins, inflammatory factors, and apoptosis proteins expression levels in CI/RI rats before and after administration of Rg1 in vivo experiments. RESULTS: In vitro experiments showed that Rg1 induced mitochondrial autophagy, decreased mitochondrial membrane potential, and reduced ROS content thereby inhibiting NLRP3 activation, decreasing secretion of inflammatory factors and RM cell apoptosis by regulating the PTEN induced putative kinase 1(Pink1) /Parkin signaling pathway. In vivo experiments showed that Rg1 induced mitochondrial autophagy, inhibited NLRP3 activation, improved inflammatory response, and reduced apoptosis by regulating the Pink1/Parkin signaling pathway, and Rg1 significantly reduced the area of cerebral infarcts, improved the pathological state of brain tissue, and attenuated the neuronal damage, thus improving cerebral ischemia/reperfusion injury in rats. CONCLUSION: Our results suggest that ginsenoside Rg1 can ameliorate cerebral ischemia-reperfusion injury by modulating Pink1/ Parkin-mediated mitochondrial autophagy in microglia and inhibiting microglial NLRP3 activation.
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Autofagia , Ginsenósidos , Microglía , Mitocondrias , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Quinasas , Daño por Reperfusión , Ubiquitina-Proteína Ligasas , Ginsenósidos/farmacología , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Autofagia/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ratas , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino , Ratas Sprague-Dawley , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fármacos Neuroprotectores/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng (P. ginseng) C.A. Meyer. Has been studied for decades for its various biological activities, especially in terms of immune-regulatory properties. Traditionally, it has been known that root, leaves, and fruits of P. ginseng were eaten for improving body's Qi and homeostasis. Also, these were used to protect body from various types of infectious diseases. However, molecular mechanisms of immunomodulatory activities of ginseng berries have not been systemically studied as often as other parts of the plant. AIM OF THE STUDY: The aim of this research is to discover the regulatory effects of P. ginseng berries, more importantly, their ginsenosides, on innate immune responses and to elucidate the molecular mechanism. MATERIALS AND METHODS: Ginseng berry concentrate (GBC) was orally injected into BALB/c mice for 30 days, and spleens were extracted for evaluation of immune-regulatory effects. Murine macrophage RAW264.7 cells were used for detailed molecular mechanism studies. Splenic natural killer (NK) cells were isolated using the magnetic-activated cell sorting (MACS) system, and the cytotoxic activity of isolated NK cells was measured using a lactate dehydrogenase (LDH) release assay. The splenic immune cell population was determined by flow-cytometry. NF-κB promoter activity was assessed by in vitro luciferase assay. Expression of inflammatory proteins and cytokines of the spleen and RAW264.7 cells were evaluated using western blotting and real-time PCR, respectively. RESULTS: The GBC enhanced cytotoxic activity of NK cells and the immune-regulation-related splenic cell population. Moreover, GBC promoted NF-κB promoter activity and stimulated the NF-κB signaling cascade. In spleen and RAW264.7 cells, expression of pro-inflammatory cytokines was increased upon GBC application, while expression of anti-inflammatory cytokines decreased. CONCLUSIONS: These results suggest that P. ginseng berry can stimulate innate immune responses and help maintain a balanced immune condition, mostly due to the action of its key ginsenoside Re, along with other protopanaxadiol- and protopanaxatriol-type ginsenosides. Such finding will provide a new insight into the field of well-being diet research as well as non-chemical immune modulator, by providing nature-derived and plant-based bioactive materials.
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Citocinas , Frutas , Ginsenósidos , Células Asesinas Naturales , Macrófagos , Ratones Endogámicos BALB C , FN-kappa B , Panax , Regulación hacia Arriba , Animales , Panax/química , Ginsenósidos/farmacología , FN-kappa B/metabolismo , Ratones , Células RAW 264.7 , Citocinas/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Regulación hacia Arriba/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Transducción de Señal/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/citología , Bazo/inmunología , Extractos Vegetales/farmacología , MasculinoRESUMEN
Exposure to the space microenvironment has been found to disrupt the homeostasis of intestinal epithelial cells and alter the composition of the microbiota. To investigate this in more detail and to examine the impact of ginsenoside Rb1, we utilized a mouse model of hindlimb unloading (HU) for four weeks to simulate the effects of microgravity. Our findings revealed that HU mice had ileum epithelial injury with a decrease in the number of intestinal stem cells (ISCs) and the level of cell proliferation. The niche functions for ISCs were also impaired in HU mice, including a reduction in Paneth cells and Wnt signaling, along with an increase in oxidative stress. The administration of Rb1 during the entire duration of HU alleviated the observed intestinal defects, suggesting its beneficial influence on epithelial cell homeostasis. Hindlimb unloading also resulted in gut dysbiosis. The supplementation of Rb1 in the HU mice or the addition of Rb1 derivative compound K in bacterial culture in vitro promoted the growth of beneficial probiotic species such as Akkermansia. The co-housing experiment further showed that Rb1 treatment in ground control mice alone could alleviate the defects in HU mice that were co-housed with Rb1-treated ground mice. Together, these results underscore a close relationship between dysbiosis and impaired ISC functions in the HU mouse model. It also highlights the beneficial effects of Rb1 in mitigating HU-induced epithelial injury by promoting the expansion of intestinal probiotics. These animal-based insights provide valuable knowledge for the development of improved approaches to maintaining ISC homeostasis in astronauts.
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Microbioma Gastrointestinal , Ginsenósidos , Células Madre , Animales , Ginsenósidos/farmacología , Ratones , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Simulación de Ingravidez/efectos adversos , Proliferación Celular/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones Endogámicos C57BL , Suspensión Trasera , Disbiosis , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Intestinos/efectos de los fármacos , Intestinos/microbiologíaRESUMEN
We investigated the role and mechanism of ginsenoside RD (GRD) in acute liver injury. Network pharmacology was used to analyze the correlations among GRD-liver injury-pyroptosis targets. A mouse model of acute liver injury was established by lipopolysaccharide + d-galactoseï¼LPS + d/Gal). After pretreatment with GRD, the changes in mouse liver function were detected. The histopathological changes were assayed by hematoxylin and eosin and Masson staining, the tissue expressions of inflammatory cytokines were detected by enzyme-linked immunosorbent assay, and the protein expressions were assayed by immunohistochemical staining and Western blotting. Meanwhile, mechanism research was conducted using STAT3-knockout transgenic mice and STAT3-IN13, a STAT3 inhibitor. GRD inhibited liver injury, mitigated tissue inflammation, and suppressed STAT3-mediated pyroptosis in mice. After applying STAT3-knockout mouse model or STAT3-IN13, GRD did not further inhibit the liver injury. GRD can resist liver injury by inhibiting the STAT3-mediated pyroptosis, which is one of the hepatoprotective mechanisms of GRD.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Ginsenósidos , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Factor de Transcripción STAT3 , Animales , Ginsenósidos/farmacología , Factor de Transcripción STAT3/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Masculino , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Piroptosis/efectos de los fármacosRESUMEN
BACKGROUND: Panax ginseng C. A. Mey is a precious medicinal resource that could be used to treat a variety of diseases. Saponins are the most important bioactive components of, and rare ginsenosides (Rg3, Rh2, Rk1 and Rg5, etc.) refer to the chemical structure changes of primary ginsenosides through dehydration and desugarization reactions, to obtain triterpenoids that are easier to be absorbed by the human body and have higher activity. PURPOSE: At present, the research of P. ginseng. is widely focused on anticancer related aspects, and there are few studies on the antibacterial and skin protection effects of rare ginsenosides. This review summarizes the rare ginsenosides related to bacterial inhibition and skin protection and provides a new direction for P. ginseng research. METHODS: PubMed and Web of Science were searched for English-language studies on P. ginseng published between January 2002 and March 2024. Selected manuscripts were evaluated manually for additional relevant references. This review includes basic scientific articles and related studies such as prospective and retrospective cohort studies. CONCLUSION: This paper summarizes the latest research progress of several rare ginsenosides, discusses the antibacterial effect of rare ginsenosides, and finds that ginsenosides can effectively protect the skin and promote wound healing during use, so as to play an efficient antibacterial effect, and further explore the other medicinal value of ginseng. It is expected that this review will provide a wider understanding and new ideas for further research and development of P. ginseng drugs.
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Ginsenósidos , Panax , Ginsenósidos/farmacología , Ginsenósidos/química , Panax/química , Humanos , Antibacterianos/farmacología , Antibacterianos/química , AnimalesRESUMEN
In this study, the postoperative cognitive dysfunction (POCD) mouse model was established to observe the changes in inflammation, blood-brain barrier permeability, and myelin sheath, and we explore the effect of ginsenoside Rg1 pretreatment on improving POCD syndrome. The POCD model of 15- to 18-month-old mice was carried out with internal fixation of tibial fractures under isoflurane anesthesia. Pretreatment was performed by continuous intraperitoneal injection of ginsenoside Rg1(40â mg/kg/day) for 14 days before surgery. The cognitive function was detected by the Morris water maze. The contents of interleukin-1ß and tumor necrosis factor-α in the hippocampus, cortex, and serum were detected by ELISA. The permeability of blood-brain barrier was observed by Evans blue. The mRNA levels and protein expression levels of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin basic protein (MBP), beta-catenin, and cyclin D1 in the hippocampus were analyzed by quantitative PCR and western blotting. The protein expression levels of ZO-1 and Wnt1 in the hippocampus were analyzed by western blotting. Finally, the localizations of CNPase and MBP in the hippocampus were detected by immunofluorescence. Ginsenoside Rg1 can prevent POCD, peripheral and central inflammation, and blood-brain barrier leakage, and reverse the downregulation of ZO-1, CNPase, MBP, and Wnt pathway-related molecules in aged mice. Preclinical studies suggest that ginsenoside Rg1 improves postoperative cognitive function in aged mice by protecting the blood-brain barrier and myelin sheath, and its specific mechanism may be related to the Wnt/ß-catenin pathway.
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Barrera Hematoencefálica , Ginsenósidos , Vaina de Mielina , Complicaciones Cognitivas Postoperatorias , Animales , Ginsenósidos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Complicaciones Cognitivas Postoperatorias/prevención & control , Complicaciones Cognitivas Postoperatorias/metabolismo , Ratones , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/metabolismo , Masculino , Fármacos Neuroprotectores/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Pulmonary fibrosis (PF) is a progressive lung disease caused by previous acute lung injury (ALI), but there is currently no satisfactory therapy available. Aerosol inhalation of medicine is an effective way for treating PF. Total ginsenosides (TG) shows potential for the treatment of ALI and PF, but the effects of inhaled TG remain unclear. PURPOSE: To determine the therapeutic effects of TG in ALI and PF, to assess the superiority of the inhaled form of TG over the routine form, and to clarify the mechanism of action of inhaled TG. METHODS: Ultrahigh-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry (UPLC-QE-MS) was applied to determine the chemoprofile of TG. A mouse model of ALI and PF was established to evaluate the effects of inhaled TG by using bronchoalveolar lavage fluid (BALF) analysis, histopathological observation, hydroxyproline assay, and immunohistochemical analysis. Primary mouse lung fibroblasts (MLF) and human lung fibroblast cell line (HFL1) were applied to determine the in vitro effects and mechanism of TG by using cell viability assay, quantitative real time PCR (qPCR) assay, and western blot (WB) analysis. RESULTS: The UPLC-QE-MS results revealed the main types of ginsenosides in TG, including Re (14.15 ± 0.42%), Rd (8.42 ± 0.49%), Rg1 (6.22 ± 0.42%), Rb3 (3.28 ± 0.01%), Rb2 (3.09 ± 0.00%), Rc (2.33 ± 0.01%), Rg2 (2.09 ± 0.04%), Rb1 (1.43 ± 0.24%), and Rf (0.13 ± 0.06%). Inhaled TG, at dosages of 10, 20, and 30 mg/kg significantly alleviated both ALI and PF in mice. Analyses of BALF and HE staining revealed that TG modulated the levels of IFN-γ, IL-1ß, and TGF-ß1, reduced inflammatory cell infiltration, and restored the alveolar architecture of the lung tissues. Furthermore, HE and Masson's trichrome staining demonstrated that TG markedly decreased fibroblastic foci and collagen fiber deposition, evidenced by the reduction of blue-stained collagen fibers. Hydroxyproline assay and immunohistochemical analyses indicated that TG significantly decreased hydroxyproline level and down-regulated the expression of Col1a1, Col3a1, and α-sma. The inhaled administration of TG demonstrated enhanced efficacy over the oral route when comparable doses were used. Additionally, inhaled TG showed superior safety and therapeutic profiles compared to pirfenidone, as evidenced by a CCK8 assay, which confirmed that TG concentrations ranging from 20 to 120 µg/ml were non-cytotoxic. qPCR and WB analyses revealed that TG, at concentrations of 25, 50, and 100 µg/ml, significantly suppressed the phosphorylation of smad2 induced by TGF-ß1 and down-regulated the expression of fibrotic genes and proteins, including α-sma, Col1a1, Col3a1, and FN1, suggesting an anti-fibrotic mechanism mediated by the smad2 signaling pathway. In vitro, TG's safety and efficacy were also found to be superior to those of pirfenidone. CONCLUSIONS: This study demonstrates, for the first time, the therapeutic efficacy of inhaled TG in treating ALI and PF. Inhaled TG effectively inhibits inflammation and reduces collagen deposition, with a particular emphasis on its role in modulating the Smad2 signaling pathway, which is implicated in the anti-fibrotic mechanism of TG. The study also highlights the superiority of inhaled TG over the oral route and its favorable safety profile in comparison to pirfenidone, positioning it as an ideal alternative for ALI and PF therapy.
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Lesión Pulmonar Aguda , Ginsenósidos , Fibrosis Pulmonar , Transducción de Señal , Proteína Smad2 , Ginsenósidos/farmacología , Ginsenósidos/administración & dosificación , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Fibrosis Pulmonar/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Masculino , Ratones , Proteína Smad2/metabolismo , Humanos , Administración por Inhalación , Líquido del Lavado Bronquioalveolar/química , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Pulmón/patología , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Aerosoles , Línea Celular , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The occurrence and progression of mild cognitive impairment (MCI) are closely related to dysbiosis of the gut microbiota. Ginsenoside compound K (CK), a bioactive component of ginseng, has been shown to alleviate gut microbiota dysbiosis and neural damage. However, the mechanisms by which CK regulates the gut microbiota to improve MCI remain unexplored. In this study, an MCI mouse model induced by D-galactose was used, and 16S rRNA gene sequencing, metabolomics, transcriptomics, and integrative multi-omics analyses were employed to investigate the potential mechanisms by which CK alleviates MCI through modulation of the gut microbiota. The results demonstrated that CK repaired intestinal barrier dysfunction caused by MCI, improved blood-brain barrier (BBB) integrity, inhibited activation of microglial cells and astrocytes, and significantly ameliorated MCI. Furthermore, CK enhanced gut microbiota diversity, notably enriched beneficial bacteria such as Akkermansia, and modulated the levels of short-chain fatty acids (SCFAs), particularly increasing propionate, thereby alleviating gut microbiota dysbiosis caused by MCI. Germ-free experiments confirmed that gut microbiota is a key factor for ginsenoside CK in relieving MCI. Further investigation revealed that CK regulated the TLR4-MyD88-NF-κB signaling pathway through modulation of gut microbiota-mediated propionate metabolism, significantly reducing systemic inflammation and alleviating MCI. Our findings provide a new theoretical basis for using CK as a potential means of modulating the gut microbiota for the treatment of MCI.
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Disfunción Cognitiva , Ácidos Grasos Volátiles , Galactosa , Microbioma Gastrointestinal , Ginsenósidos , Ginsenósidos/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Ratones , Masculino , Ácidos Grasos Volátiles/metabolismo , Ratones Endogámicos C57BL , Disbiosis/tratamiento farmacológico , Disbiosis/microbiología , Modelos Animales de Enfermedad , Receptor Toll-Like 4/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacosRESUMEN
Heart failure is a multifactorial disease, the percentage of patients with heart failure caused by metabolic syndrome is increasing year by year. The effect of gut flora dysbiosis on metabolic syndrome and heart failure has received widespread attention in recent years. Drugs to treat the condition urgently need to be discovered. C20DM, as a precursor compound of ginsenoside, is a small molecule compound obtained by biosynthetic means and is not available in natural products. In this project, we found that C20DM could improve the diversity of gut flora and elevate the expression of intestinal tight junction proteins-Occludin, Claudin, ZO-1, which inhibited the activity of the TLR4-MyD88-NF-kB pathway, and as a result, reduced myocardial inflammation and slowed down heart failure in metabolic syndrome mice. In conclusion, our study suggests that C20DM can treat heart failure by regulating gut flora, and it may be a candidate drug for treating metabolic syndrome-induced heart failure.
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Microbioma Gastrointestinal , Insuficiencia Cardíaca , Síndrome Metabólico , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Síndrome Metabólico/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/microbiología , Síndrome Metabólico/complicaciones , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/microbiología , Ratones , Masculino , Ratones Endogámicos C57BL , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal/efectos de los fármacos , Ginsenósidos/farmacología , Ginsenósidos/uso terapéuticoRESUMEN
BACKGROUND: Previous researches have demonstrated that the traditional Chinese medicine could therapeutically treat inflammatory and hypoxic diseases by enhancing the functionality of mesenchymal stem cells. However, its mechanism was not yet clear. This research aimed to investigate the impact of the traditional Chinese medicine Sijunzi decoction and its herb monomer ginsenoside Rg1 on the proliferation and differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) and explore the underlying mechanisms. METHODS: Different concentrations of Sijunzi decoction and Rg1 were applied to differentiating induced hUC-MSCs. The CCK-8 test was utilized to evaluate cell proliferation activity and identify suitable drug concentrations. Alizarin Red staining was employed to detect the formation of calcium nodules, and Oil Red O staining was used to assess the formation of lipid droplets. PCR was utilized to examine gene expression related to osteogenic differentiation, adipogenic differentiation, and the HIF-1α signaling pathway in hUC-MSCs. Western blot analysis was conducted to evaluate protein expression in osteogenic differentiation and HIF-1α. ELISA was performed to measure HIF-1α signaling factors and inflammatory cytokine expression. Biochemical assays were used to assess changes in oxidative stress indicators. RESULTS: The Sijunzi decoction and Rg1 both demonstrated a dose-dependent promotion of hUC-MSC proliferation. The Sijunzi decoction significantly increased the expression of genes and proteins relevant to osteogenesis, such as osterix, osteocalcin, RUNX2, and osteopontin, and activated the HIF-1α pathway in hUC-MSCs. (Pâ <â .05). Similar effects were observed at the gene level after treatment with Rg1. Simultaneously, Sijunzi decoction significantly reduced the secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß, while increasing the secretion of the anti-inflammatory cytokine IL-10 during osteogenic differentiation (Pâ <â .05). Moreover, Sijunzi decoction lowered oxidative stress levels and enhanced the antioxidant capacity of hUC-MSCs during osteogenic differentiation (Pâ <â .05). However, the impact of Sijunzi decoction on hUC-MSCs toward adipogenic differentiation was not significant (Pâ >â .05). CONCLUSION: Sijunzi decoction promotes the proliferation and osteogenic differentiation of hUC-MSCs, potentially through the activation of the HIF-1α signaling pathway and by modulating the microenvironment via reducing inflammation and oxidative stress levels. Rg1 might be involved in this process.
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Diferenciación Celular , Proliferación Celular , Medicamentos Herbarios Chinos , Ginsenósidos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Células Madre Mesenquimatosas , Osteogénesis , Cordón Umbilical , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Proliferación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Cordón Umbilical/citología , Osteogénesis/efectos de los fármacos , Ginsenósidos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Adipogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células CultivadasRESUMEN
GFRS is the conversion product of Panax ginseng Meyer berry after citric acid heat treatment, which is rich in rare ginsenosides. However, the anti-melanin role of GFRS in the regulation of skin pigmentation and its material basis remains unclear. To compare the anti-melanin activity before and after citric acid heat treatment, we determined the effects of GFS and GFRS on tyrosinase activity and melanin lever under α-MSH stimulation and found the potential anti-melanin effect of GFRS. Further, Western blot and immunofluorescence methods were used to reveal the mechanism by which GFRS detects anti-melanin activity by promoting autophagy flux levels. In zebrafish models, GFRS inhibited endogenous melanin and tyrosinase better than arbutin and promoted the accumulation of autophagy levels in vivo. To determine the material basis of the anti-melanin effect of GFRS, HPLC was used to isolate and prepare 12 ginsenosides from GFRS, and their activity evaluation and structure-activity relationship analysis were performed. The results showed that the inhibitory effect of GFRS on melanin was Rg3 > Rg5 > Rk1 > Rd. Molecular docking showed that their docking fraction with mushroom tyrosinase was significantly better than that of arbutin, but the presence of C-20 glycosylation decreased the anti-melanin activity of Rd. To maximize the content of Rg3, Rg5, and Rk1, we optimized the process by using citric acid heat treatment of ginsenoside Rd and found that citric acid heat treatment at 100°C almost completely transformed Rd and obtained a high content of active ingredients. In summary, our data demonstrated that GFRS exerted anti-melanin effects by inducing autophagy. It was further revealed that Rg3, Rg5, and Rk1, as effective active components, could be enriched by the improved process of converting ginsenoside Rd by citric acid heat treatment.
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Autofagia , Ácido Cítrico , Ginsenósidos , Calor , Melaninas , Panax , Pez Cebra , Panax/química , Melaninas/metabolismo , Melaninas/antagonistas & inhibidores , Ginsenósidos/farmacología , Ginsenósidos/química , Ginsenósidos/aislamiento & purificación , Animales , Relación Estructura-Actividad , Autofagia/efectos de los fármacos , Ácido Cítrico/química , Ácido Cítrico/farmacología , Estructura Molecular , Frutas/química , Simulación del Acoplamiento Molecular , Relación Dosis-Respuesta a Droga , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/antagonistas & inhibidoresRESUMEN
Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H2O2-induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1ß, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H2O2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.