RESUMO
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.
Assuntos
Antitussígenos , Tosse , Regulação para Baixo , Flores , Ginsenosídeos , Canal de Sódio Disparado por Voltagem NAV1.7 , Panax notoginseng , Canais de Cátion TRPV , Animais , Canais de Cátion TRPV/metabolismo , Cobaias , Flores/química , Tosse/tratamento farmacológico , Ginsenosídeos/farmacologia , Antitussígenos/farmacologia , Masculino , Camundongos , Panax notoginseng/química , Regulação para Baixo/efeitos dos fármacos , Humanos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Células HEK293 , Simulação de Acoplamento Molecular , Cricetulus , Modelos Animais de Doenças , Células CHO , Saponinas/farmacologia , OvalbuminaRESUMO
Minor ginsenosides produced by ß-glucosidase are interesting biologically and pharmacologically. In this study, new ginsenoside-hydrolyzing glycosidase from Furfurilactobacillus rossiae DCYL3 was cloned and expressed in Escherichia coli strain BL21. The enzyme converted Rb1 and Gyp XVII into Rd and compound K following the pathways: Rb1âRd and Gyp XVIIâF2âCK, respectively at optimal condition: 40 °C, 15 min, and pH 6.0. Furthermore, we examined the cytotoxicity, NO production, ROS generation, and gene expression of Gynostemma extract (GE) and bioconverted Gynostemma extract (BGE) in vitro against A549 cell lines for human lung cancer and macrophage RAW 264.7 cells for antiinflammation, respectively. As a result, BGE demonstrated significantly greater toxicity than GE against lung cancer at a dose of 500 µg/mL but in normal cells showed lower toxicity. Then, we indicated an enhanced generation of ROS, which may be boosting cancer cell toxicity. By blocking the intrinsic way, BGE increased p53, Bax, Caspase 3, 9, and while Bcl2 is decreased. At 500 µg/mL, the BGE sample was less toxic in normal cells and decreased the LPS-treated NO and ROS level to reduce inflammation. In addition, BGE inhibited the expression of pro-inflammatory genes COX-2, iNOS, IL-6, and IL-8 in RAW 264.7 cells than the sample of GE. In conclusion, FrBGL3 has considerable downstream applications for high-yield, low-cost, effective manufacture of minor ginsenosides. Moreover, the study's findings imply that BGE would be potential materials for anti-cancer and anti-inflammatory agent after consideration of future studies.
â¢The first time ß-glucosidase (FrBGL3) from Furfurilactobacillus rossiae was identified and characterized.â¢FrBGL3 activity in ginsenoside and gypenoside bioconversion were found and confirmed.â¢Application in Gynostemma extract bioconversion by FrBGL3 boosts anti-inflammatory and anti-cancer activities.
Assuntos
beta-Glucosidase , Camundongos , Animais , Humanos , Células RAW 264.7 , Células A549 , beta-Glucosidase/genética , beta-Glucosidase/metabolismo , beta-Glucosidase/química , Clonagem Molecular , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacologia , Escherichia coli/genética , Escherichia coli/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Macrófagos/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Óxido Nítrico/metabolismo , Clostridiales/genética , Clostridiales/enzimologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismoRESUMO
Diabetic cardiomyopathy (DCM) triggers a detrimental shift in mitochondrial dynamics, characterized by increased fission and decreased fusion, contributing to cardiomyocyte apoptosis and cardiac dysfunction. This study investigated the impact of modulating mitochondrial dynamics on DCM outcomes and underlying mechanisms in a mouse model. DCM induction led to upregulation of fission genes (Drp1, Mff, Fis1) and downregulation of fusion genes (Mfn1, Mfn2, Opa1). Inhibiting fission with Mdivi-1 or promoting fusion with Ginsenoside Rg1 preserved cardiac function, as evidenced by improved left ventricular ejection fraction (LVEF), fractional shortening (FS), and E/A ratio. Both treatments also reduced infarct size and attenuated cardiomyocyte apoptosis, indicated by decreased caspase-3 activity. Mechanistically, Mdivi-1 enhanced mitochondrial function by improving mitochondrial membrane potential, reducing reactive oxygen species (ROS) production, and increasing ATP generation. Ginsenoside Rg1 also preserved mitochondrial integrity and function under hypoxic conditions in HL-1 cardiomyocytes. These findings suggest that restoring the balance of mitochondrial dynamics through pharmacological interventions targeting either fission or fusion may offer a promising therapeutic strategy for mitigating MI-induced cardiac injury and improving patient outcomes.
Assuntos
Apoptose , Cardiomiopatias Diabéticas , Ginsenosídeos , Dinâmica Mitocondrial , Miócitos Cardíacos , Disfunção Ventricular Esquerda , Animais , Dinâmica Mitocondrial/efeitos dos fármacos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/metabolismo , Camundongos , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Humanos , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Modelos Animais de Doenças , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
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.
Assuntos
Ginsenosídeos , Lipopolissacarídeos , Antígeno 96 de Linfócito , Receptor 4 Toll-Like , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Ginsenosídeos/farmacologia , Ginsenosídeos/química , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Interleucina-6/metabolismo , Antígeno 96 de Linfócito/metabolismo , Antígeno 96 de Linfócito/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Ligação Proteica , Multimerização Proteica/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Acute kidney injury (AKI) is characterized by a sudden decline in renal function. The inflammatory response is the fundamental pathologic alteration throughout AKI, regardless of the various causal factors. Macrophages are the main immune cells involved in the inflammatory microenvironment in AKI. Consequently, targeting macrophages might become a novel strategy for the treatment of AKI. In this study, we demonstrated that pseudoginsenoside-F11 (PF11), a distinctive component of Panax quinquefolius L., regulated macrophage function and protected renal tubular epithelial cells TCMK-1 from lipopolysaccharide (LPS) in vitro. PF11 also alleviated renal injuries in an LPS-induced AKI mouse model, decreased the levels of inflammatory cytokines, reduced macrophage inflammatory infiltration, and promoted the polarization of M1 macrophages to M2c macrophages with suppression of the nuclear factor-κB/NOD-like receptor thermal protein domain-associated protein 3/interleukin-1ß (NF-κB/NLRP3/IL-1ß) signaling pathway. To further investigate whether this nephroprotective effect of PF11 is mediated by macrophages, we performed macrophage depletion by injection of clodronate liposomes in mice. Macrophage depletion abolished PF11's ability to protect against LPS-induced kidney damage with downregulating the NF-κB/NLRP3/IL-1ß signaling pathway. In summary, this is the first study providing data on the efficacy and mechanism of PF11 in the treatment of AKI by regulating macrophage function.
Assuntos
Injúria Renal Aguda , Ginsenosídeos , Lipopolissacarídeos , Macrófagos , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/metabolismo , Ginsenosídeos/farmacologia , Ginsenosídeos/administração & dosagem , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Panax/química , Transdução de Sinais/efeitos dos fármacosRESUMO
Even though considerable progress has been made to reduce insult, ischemic stroke is still a significant cause of mortality and morbidity in the world, and new therapeutic strategies are urgently needed. In the present study, the magnesium salt of salvianolic acid B (SalB) and ginsenoside Rg1 (Rg1) combination as a multicomponent strategy against stroke was evaluated. The synergistic effect of Sa1B and Rg1 was evaluated by Bliss independence analysis on the middle cerebral artery occlusion model. The infarct volume, neuroethology, cerebral structure, and neurocyte number were evaluated by 3,5-triphenyltetrazolium chloride staining, Longa score, Garcia score, hematoxylin-eosin staining, and Nissl staining, respectively. Metabolomics was used to search for potential biomarkers and explore the mechanism of Sa1B/Rg1. First, the superior effects of SalB/Rg1 than SalB or Rg1 at the same dose were evaluated. Compared with SalB ( P â <â 0.001) or Rg1 ( P â <â 0.01), SalB/Rg1 significantly decreased infarct volume through 3,5-triphenyltetrazolium chloride staining and protected the structural integrity of cortex and striatum. The superior effect of SalB/Rg1 on neurological behavior was also detected compared with SalB or Rg1 significantly. Accompanying behavioral improvement, a considerable increase of SalB/Rg1 on neurons detected by Nissl staining was found on the cortex compared with SalB ( P â <â 0.05) or Rg1 ( P â <â 0.01). Second, the synergistic effect between SalB and Rg1 was strictly verified by Bliss independence analysis ( P â <â 0.01) based on infarct volume. Finally, alleviation of cerebral metabolic disorders may be the possible mechanism of SalB/Rg1. Our study provided a multicomponent strategy against ischemic stroke, with not only dose reduction but also improved efficacy relative to single agents.
Assuntos
Benzofuranos , Sinergismo Farmacológico , Ginsenosídeos , AVC Isquêmico , Fármacos Neuroprotetores , Ginsenosídeos/farmacologia , Animais , Benzofuranos/farmacologia , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/patologia , AVC Isquêmico/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ratos , DepsídeosRESUMO
OBJECTIVE: Radiation proctitis (RP) refers to rectal injury caused by radiation treatment of pelvic and retroperitoneal malignancies, which has a major impact on the treatment prognosis and quality of life of patients with cancer. The tetracyclic triterpene saponin monomer ginsenoside Rg3 (GRg3), the primary bioactive ingredient in ginseng extracts, has therapeutic effects against RP in rats. Here, we validated its efficacy and elucidated its mechanism of action. METHODS: A rat RP model was established in 48 Wistar rats. Rats were randomly divided into control (untreated), irradiation, irradiation + dexamethasone, and irradiation + GRg3 (low-, medium-, and high-dose) groups. After 2 weeks' treatment, serum IL-4, IL-10, and TNF-α levels were tested by enzyme-linked immunosorbent assays. In rectal tissue, Ikbkb, Ikka, and Casp8 mRNA expression was detected by a reverse transcription-quantitative polymerase chain reaction. IKK-ß, IκB-α, p-IκB-α, p50, and caspase-8 protein levels were determined by western blot analysis. RESULTS: GRg3 significantly improved the general condition and histopathological damage in rats with RP. Moreover, GRg3 decreased the levels of factors that promote inflammation (TNF-α) and increased the levels of factors that reduce inflammation (IL-4 and IL-10). GRg3 markedly reduced the activation of NF-κB and caspase-8 signaling pathways. CONCLUSIONS: Thus, GRg3 may reduce the inflammatory response by blocking the NF-κB signaling pathway and improving the balance of inflammation-related factors. GRg3 may also inhibit intestinal cell apoptosis by suppressing the TNF-α/caspase-8 signaling cascade, thereby reducing radiological rectal injury. Our results verify that GRg3 is a promising therapeutic agent for RP treatment and shed light on its mechanism.
Assuntos
Ginsenosídeos , Proctite , Ratos Wistar , Animais , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Ratos , Proctite/etiologia , Proctite/tratamento farmacológico , Masculino , Lesões por Radiação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Caspase 8/metabolismo , Modelos Animais de DoençasRESUMO
(1) Objective: To optimize the preparation process of hyaluronic acid-modified ginsenoside Rb1 self-assembled nanoparticles (HA@GRb1@CS NPs), characterize and evaluate them in vitro, and investigate the mechanism of action of HA@GRb1@CS NPs in treating cardiovascular diseases (CVDs) associated with inflammation and oxidative stress. (2) Methods: The optimal preparation process was screened through Plackett-Burman and Box-Behnken designs. Physical characterization of HA@GRb1@CS NPs was conducted using transmission electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. Stability experiments, in vitro drug release studies, and lyophilisate selection were performed to evaluate the in vitro performance of HA@GRb1@CS NPs. The anti-inflammatory and antioxidant capabilities of HA@GRb1@CS NPs were assessed using H9c2 and RAW264.7 cells. Additionally, bioinformatics tools were employed to explore the mechanism of action of HA@GRb1@CS NPs in the treatment of CVDs associated with inflammation and oxidative stress. (3) Results: The optimal preparation process for HA@GRb1@CS NPs was achieved with a CS concentration of 2 mg/mL, a TPP concentration of 2.3 mg/mL, and a CS to TPP mass concentration ratio of 1.5:1, resulting in a particle size of 126.4 nm, a zeta potential of 36.8 mV, and a PDI of 0.243. Characterization studies confirmed successful encapsulation of the drug within the carrier, indicating successful preparation of HA@GRb1@CS NPs. In vitro evaluations demonstrated that HA@GRb1@CS NPs exhibited sustained-release effects, leading to reduced MDA (Malondialdehyde) content and increased SOD (Superoxide Dismutase) content in oxidatively damaged H9c2 cells. Furthermore, it showed enhanced DPPH (2,2-Diphenyl-1-picrylhydrazyl) and ABTS+ [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] free radical scavenging rates and inhibited the release of inflammatory factors NO (Nitric Oxide) and IL-6 (Interleukin-6) from RAW264.7 cells. (4) Conclusions: The HA@GRb1@CS NPs prepared in this study exhibit favorable properties with stable quality and significant anti-inflammatory and antioxidant capabilities. The mechanisms underlying their therapeutic effects on CVDs may involve targeting STAT3, JUN, EGFR, CASP3, and other pathways regulating cell apoptosis, autophagy, anti-lipid, and arterial sclerosis signaling pathways.
Assuntos
Antioxidantes , Doenças Cardiovasculares , Ginsenosídeos , Ácido Hialurônico , Nanopartículas , Ácido Hialurônico/química , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Animais , Nanopartículas/química , Camundongos , Doenças Cardiovasculares/tratamento farmacológico , Células RAW 264.7 , Antioxidantes/farmacologia , Antioxidantes/química , Biologia Computacional/métodos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Liberação Controlada de Fármacos , Linhagem Celular , Ratos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/químicaRESUMO
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.
Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Ginsenosídeos , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Glicosilação , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Ginsenosídeos , Hexoquinase , MicroRNAs , Proteínas Proto-Oncogênicas c-myc , Transdução de Sinais , Neoplasias do Colo do Útero , beta Catenina , Humanos , Ginsenosídeos/farmacologia , beta Catenina/metabolismo , beta Catenina/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Feminino , Transdução de Sinais/efeitos dos fármacos , Hexoquinase/metabolismo , Hexoquinase/genética , Células HeLa , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Efeito Warburg em Oncologia/efeitos dos fármacos , Apoptose/efeitos dos fármacosRESUMO
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.
Assuntos
Ácido 2-Aminoadípico , Antidepressivos , Astrócitos , Ginsenosídeos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ginsenosídeos/farmacologia , Masculino , Ácido 2-Aminoadípico/farmacologia , Depressão/tratamento farmacológico , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Modelos Animais de Doenças , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Apoptose/efeitos dos fármacosRESUMO
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.
Assuntos
Colite Ulcerativa , Ferroptose , Ginsenosídeos , MicroRNAs , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Ginsenosídeos/farmacologia , MicroRNAs/genética , Camundongos , Ferroptose/efeitos dos fármacos , Humanos , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Regulação para Cima/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Sulfato de Dextrana/toxicidade , Apoptose/efeitos dos fármacosRESUMO
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.
Assuntos
Bacteroides , Microbioma Gastrointestinal , Ginsenosídeos , Ginsenosídeos/farmacocinética , Ginsenosídeos/farmacologia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Ratos , Masculino , Bacteroides/efeitos dos fármacos , Ratos Sprague-Dawley , Glicosídeo Hidrolases/metabolismoRESUMO
Five previously undescribed protopanaxatriol-type saponins, notoginsenosides Ta-Te (1-5), together with eighteen known triterpenoid saponins (6-23) were isolated from the roots of Panax notoginseng. The structures of new compounds were determined by HRESIMS and NMR spectroscopic analyses and chemical methods. Compounds 1 and 2 were the first examples of ginsenosides featuring a 6-deoxy-ß-d-glucose moiety from Panax species. Compounds 1-4, 7, 10, 12, 21-22 showed protective effects on L02 cells against the injury of acetaminophen (APAP). Among them, notoginsenoside R1 (12), ginsenoside Rg1 (21), and ginsenoside Re (22) were the most potent ones, with cell viabilities >80%. Moreover, compounds 12 and 22 remarkably alleviated APAP-induced liver injury in mice. These saponins are potential hepatoprotective agents.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Ginsenosídeos , Panax notoginseng , Raízes de Plantas , Saponinas , Animais , Panax notoginseng/química , Raízes de Plantas/química , Camundongos , Estrutura Molecular , Saponinas/farmacologia , Saponinas/isolamento & purificação , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Masculino , Ginsenosídeos/farmacologia , Ginsenosídeos/isolamento & purificação , Humanos , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , Substâncias Protetoras/farmacologia , Substâncias Protetoras/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Linhagem Celular , ChinaRESUMO
Ginsenoside Rh2 (GRh2) exhibits significant potential as an anticancer agent; however, progress in developing chemotherapeutic drugs is impeded by their toxicity toward off-target tissues. Specifically, anemia caused by chemotherapy is a debilitating side effect and can be caused by red blood cell (RBC) hemolysis and eryptosis. Cells were exposed to GRh2 in the antitumor range and hemolytic and eryptotic markers were examined under different experimental conditions using photometric and cytofluorimetric methods. GRh2 caused Ca2+-independent, concentration-responsive hemolysis in addition to disrupted ion trafficking with K+ and Cl- leakage. Significant increases in cells positive for annexin-V-fluorescein isothiocyanate, Fluo4, and 2,7-dichlorofluorescein were noted upon GRh2 treatment coupled with a decrease in forward scatter and acetylcholinesterase activity. Importantly, the cytotoxic effects of GRh2 were mitigated by ascorbic acid and by blocking casein kinase 1α (CK1α) and mixed lineage kinase domain-like (MLKL) signaling. In contrast, Ca2+ omission, inhibition of KCl efflux, and isosmotic sucrose aggravated GRh2-induced RBC death. In whole blood, GRh2 selectively targeted reticulocytes and lymphocytes. Altogether, this study identified novel mechanisms underlying GRh2-induced RBC death involving Ca2+ buildup, loss of membrane phospholipid asymmetry and cellular volume, anticholinesterase activity, and oxidative stress. These findings shed light on the hematologic toxicity of GRh2 which is crucial for optimizing its utilization in cancer treatment.
Assuntos
Cálcio , Eriptose , Eritrócitos , Ginsenosídeos , Hemólise , Espécies Reativas de Oxigênio , Ginsenosídeos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Eriptose/efeitos dos fármacos , Cálcio/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , AnimaisRESUMO
Aging is an irresistible natural law of the progressive decline of body molecules, organs, and overall function with the passage of time, resulting in eventual death. World Health Organization data show that aging is correlated with a wide range of common chronic diseases in the elderly, and is an essential driver of many diseases. Panax Ginseng C.A Meyer is an ancient herbal medicine, which has an effect of "long service, light weight, and longevity" recorded in the ancient Chinese medicine book "Compendium of Materia Medica." Ginsenoside Rg2, the main active ingredient of ginseng, also exerts a marked effect on the treatment of liver injury. However, it remains unclear whether Rg2 has the potential to ameliorate aging-induced liver injury. Hence, exploring the hepatoprotective properties of Rg2 and its possible molecular mechanism by Senescence Accelerate Mouse Prone 8 (SAMP8) and gut microbiota. Our study demonstrated that Rg2 can inhibit pyroptosis and apoptosis through caspase 8, and regulate the gut-liver axis to alleviate liver inflammation by changing the composition of gut microbiota, thus improving aging-induced liver injury. These findings provide theoretical support for the pharmacological effects of ginsenosides in delaying aging-induced liver injury.
Assuntos
Envelhecimento , Apoptose , Caspase 8 , Microbioma Gastrointestinal , Ginsenosídeos , Piroptose , Ginsenosídeos/farmacologia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos , Caspase 8/metabolismo , Masculino , Panax/química , Fitoterapia , Fígado/efeitos dos fármacosRESUMO
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.
Assuntos
Ginsenosídeos , Panax , Ginsenosídeos/farmacologia , Ginsenosídeos/química , Panax/química , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , AnimaisRESUMO
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.
Assuntos
Barreira Hematoencefálica , Ginsenosídeos , Bainha de Mielina , Complicações Cognitivas Pós-Operatórias , Animais , Ginsenosídeos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Complicações Cognitivas Pós-Operatórias/metabolismo , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
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.
Assuntos
Disfunção Cognitiva , Ácidos Graxos Voláteis , Galactose , Microbioma Gastrointestinal , Ginsenosídeos , Ginsenosídeos/farmacologia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Camundongos , Masculino , Ácidos Graxos Voláteis/metabolismo , Camundongos Endogâmicos C57BL , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Modelos Animais de Doenças , Receptor 4 Toll-Like/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacosRESUMO
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.