RESUMO
BACKGROUND: Information transmission between primary tumor cells and immunocytes or stromal cells in distal organs is a critical factor in the formation of pre-metastatic niche (PMN). Understanding this mechanism is essential for developing effective therapeutic strategy against tumor metastasis. Our study aims to prove the hypothesis that circ-0034880-enriched tumor-derived extracellular vesicles (TEVs) mediate the formation of PMN and colorectal cancer liver metastasis (CRLM), and targeting circ-0034880-enriched TEVs might be an effective therapeutic strategy against PMN formation and CRLM. METHODS: We utilized qPCR and FISH to measure circRNAs expression levels in human CRC plasma, primary CRC tissues, and liver metastatic tissues. Additionally, we employed immunofluorescence, RNA sequencing, and in vivo experiments to assess the effect mechanism of circ-0034880-enriched TEVs on PMN formation and CRC metastasis. DARTS, CETSA and computational docking modeling were applied to explore the pharmacological effects of Ginsenoside Rb1 in impeding PMN formation. RESULTS: We found that circ-0034880 was highly enriched in plasma extracellular vesicles (EVs) derived from CRC patients and closely associated with CRLM. Functionally, circ-0034880-enriched TEVs entered the liver tissues and were absorbed by macrophages in the liver through bloodstream. Mechanically, TEVs-released circ-0034880 enhanced the activation of SPP1highCD206+ pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenvironment and promoting overt metastasis. Importantly, our mechanistic findings led us to discover that the natural product Ginsenoside Rb1 impeded the activation of SPP1highCD206+ pro-tumor macrophages by reducing circ-0034880 biogenesis, thereby suppressing PMN formation and inhibiting CRLM. CONCLUSIONS: Circ-0034880-enriched TEVs facilitate strong interaction between primary tumor cells and SPP1highCD206+ pro-tumor macrophages, promoting PMN formation and CRLM. These findings suggest the potential of using Ginsenoside Rb1 as an alternative therapeutic agent to reshape PMN formation and prevent CRLM.
Assuntos
Neoplasias Colorretais , Vesículas Extracelulares , Neoplasias Hepáticas , Osteopontina , RNA Circular , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Vesículas Extracelulares/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Animais , RNA Circular/genética , Osteopontina/metabolismo , Osteopontina/genética , Linhagem Celular Tumoral , Microambiente Tumoral , Masculino , Feminino , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Ginsenoside Rb1 (Rb1), an active component isolated from traditional Chinese medicine Ginseng, is beneficial to many cardiovascular diseases. However, whether it can protect against doxorubicin induced cardiotoxicity (DIC) is not clear yet. In this study, we aimed to investigate the role of Rb1 in DIC. Mice were injected with a single dose of doxorubicin (20 mg/kg) to induce acute cardiotoxicity. Rb1 was given daily gavage to mice for 7 days. Changes in cardiac function, myocardium histopathology, oxidative stress, cardiomyocyte mitochondrion morphology were studied to evaluate Rb1's function on DIC. Meanwhile, RNA-seq analysis was performed to explore the potential underline molecular mechanism involved in Rb1's function on DIC. We found that Rb1 treatment can improve survival rate and body weight in Dox treated mice group. Rb1 can attenuate Dox induced cardiac dysfunction and myocardium hypertrophy and interstitial fibrosis. The oxidative stress increase and cardiomyocyte mitochondrion injury were improved by Rb1 treatment. Mechanism study found that Rb1's beneficial role in DIC is through suppressing of autophagy and ferroptosis. This study shown that Ginsenoside Rb1 can protect against DIC by regulating autophagy and ferroptosis.
Assuntos
Cardiotoxicidade , Ferroptose , Ginsenosídeos , Animais , Camundongos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Ginsenosídeos/farmacologia , Miócitos Cardíacos/metabolismo , Estresse OxidativoRESUMO
Depression is a common disease that affects physical and mental health and imposes a considerable burden on afflicted individuals and their families worldwide. Depression is associated with a high rate of disability and suicide. It causes a severe decline in productivity and quality of life. Unfortunately, the pathophysiological mechanisms underlying depression have not been fully elucidated, and the risk of its treatment is still presented. Studies have shown that the expression of autophagic markers in the brain and peripheral inflammatory mediators are dysregulated in depression. Autophagy-related genes regulate the level of autophagy and change the inflammatory response in depression. Depression is related to several aspects of immunity. The regulation of the immune system and inflammation by autophagy may lead to the development or deterioration of mental disorders. This review highlights the role of autophagy and neuroinflammation in the pathophysiology of depression, sumaries the autophagy-targeting small moleculars, and discusses a novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat the disease.
Assuntos
Doenças Neuroinflamatórias , Qualidade de Vida , Humanos , Autofagia , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
Recent research has demonstrated the immunomodulatory potential of Panax notoginseng in the treatment of chronic inflammatory diseases and cerebral hemorrhage, suggesting its significance in clinical practice. Nevertheless, the complex immune activity of various components has hindered a comprehensive understanding of the immune-regulating properties of Panax notoginseng, impeding its broader utilization. This review evaluates the effect of Panax notoginseng to various types of white blood cells, elucidates the underlying mechanisms, and compares the immunomodulatory effects of different Panax notoginseng active fractions, aiming to provide the theory basis for future immunomodulatory investigation.
Assuntos
Panax notoginseng , Panax notoginseng/química , Humanos , Animais , Sistema Imunitário/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
After intracerebral hemorrhage (ICH) occurs, the overproduction of reactive oxygen species (ROS) and iron ion overload are the leading causes of secondary damage. Removing excess iron ions and ROS in the meningeal system can effectively alleviate the secondary damage after ICH. This study synthesized ginsenoside Rb1 carbon quantum dots (RBCQDs) using ginsenoside Rb1 and ethylenediamine via a hydrothermal method. RBCQDs exhibit potent capabilities in scavenging ABTS + free radicals and iron ions in solution. After intrathecal injection, the distribution of RBCQDs is predominantly localized in the subarachnoid space. RBCQDs can eliminate ROS and chelate iron ions within the meningeal system. Treatment with RBCQDs significantly improves blood flow in the meningeal system, effectively protecting dying neurons, improving neurological function, and providing a new therapeutic approach for the clinical treatment of ICH.
Assuntos
Ginsenosídeos , Pontos Quânticos , Camundongos , Animais , Espécies Reativas de Oxigênio , Hemorragia Cerebral/tratamento farmacológico , Ferro , ÍonsRESUMO
OBJECTIVES: The objectives of current study were to investigate the role and related mechanism of Ginsenoside Rb1 (GRb1) on regulating apical periodontitis (AP) prognosis. MATERIALS AND METHODS: Clinical specimens were used to determine the involvement of calcium overload-induced macrophage pyroptosis in periapical tissues. Next, a calcium ion-chelating agent (BAPTA-AM) was applied to detect the suppression of intracellular calcium overload in macrophage pyroptosis. Then, network pharmacology, western blot (WB) analysis, and Fluo-4 calcium assay were conducted to explore the role of GRb1 on intracellular calcium overload. To gain a better understanding of GRb1 in calcium overload-induced macrophage pyroptosis linked AP, GRb1-treated AP models were established. RESULTS: We discovered clinically and experimentally that calcium overload-dependent macrophage pyroptosis is involved in AP pathogenesis, and reducing calcium overload greatly decreased macrophage pyroptosis in an AP cell model. Next, based on GRb1's inhibitory role in aberrant intracellular calcium accumulation, we discovered that GRb1 alleviates AP by suppressing calcium-dependent macrophage pyroptosis in both in vitro and in vivo models. CONCLUSIONS: GRb1 is an effective therapeutic strategy to rescue the periapical tissues from inflammation due to its anti-pyroptosis function. Thus, the present study supports further investigation of GRb1 as an adjuvant therapy for AP.
RESUMO
Ginsenoside Rb1, known as gypenoside III, exerts antidepressant-like effects in previous studies. It has also been indicated that ginsenoside Rb1 regulated neuroinflammation via inhibiting NF-κB signaling. According to the evidence that astrocytes can regulate microglia and neuroinflammation by secreting complement C3, the present study aimed to demonstrate the molecular mechanisms underlying ginsenoside Rb1-induced antidepressant-like effects from the astrocytic and microglial complement C3 pathway. The complement C3 mediated mechanism of ginsenoside Rb1 was investigated in mice exposed to chronic restraint stress (CRS). The results showed that ginsenoside Rb1 reversed the depressive-like behaviors in CRS. Treatment with ginsenoside Rb1 reduced both the number of astrocytes and microglia. In addition, ginsenoside Rb1 suppressed TLR4/NF-κB/C3 signaling in the astrocytes of the hippocampus. Furthermore, ginsenoside Rb1 attenuated the contents of synaptic protein including synaptophysin and PSD95 in microglia, suggesting the inhibition of microglia-mediated synaptic elimination caused by CRS. Importantly, ginsenoside Rb1 also maintained the dendritic spines in mice. In conclusion, our results demonstrate that ginsenoside Rb1 produces the antidepressant-like effects by inhibiting astrocyte TLR4/NF-κB/C3 signaling to covert microglia from a pro-inflammatory phenotype (amoeboid) towards an anti-inflammatory phenotype (ramified), which inhibit the synaptic pruning in the hippocampus.
Assuntos
Astrócitos , Complemento C3 , Depressão , Ginsenosídeos , Microglia , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Complemento C3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos Endogâmicos C57BL , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptor 4 Toll-Like/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , NF-kappa B/metabolismoRESUMO
AIM: Among numerous constituents of Panax ginseng, a constituent named Ginsenoside Rb1 (G-Rb1) has been studied to diminish inflammation associated with diseases. This study investigated the anti-inflammatory properties of G-Rb1 on human dental pulp cells (hDPCs) exposed to lipopolysaccharide (LPS) and aimed to determine the underlying molecular mechanisms. METHODOLOGY: The KEGG pathway analysis was performed after RNA sequencing in G-Rb1- and LPS-treated hDPCs. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis were used for the assessment of cell adhesion molecules and inflammatory cytokines. Statistical analysis was performed with one-way ANOVA and the Student-Newman-Keuls test. RESULTS: G-Rb1 did not exhibit any cytotoxicity within the range of concentrations tested. However, it affected the levels of TNF-α, IL-6 and IL-8, as these showed reduced levels with exposure to LPS. Additionally, less mRNA and protein expressions of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were shown. With the presence of G-Rb1, decreased levels of PI3K/Akt, phosphorylated IκBα and p65 were also observed. Furthermore, phosphorylated ERK and JNK by LPS were diminished within 15, 30 and 60 min of G-Rb1 exposure; however, the expression of non-phosphorylated ERK and JNK remained unchanged. CONCLUSIONS: G-Rb1 suppressed the LPS-induced increase of cell adhesion molecules and inflammatory cytokines, while also inhibiting PI3K/Akt, phosphorylation of NF-κB transcription factors, ERK and JNK of MAPK signalling in hDPCs.
Assuntos
Polpa Dentária , Ginsenosídeos , Lipopolissacarídeos , NF-kappa B , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Ginsenosídeos/farmacologia , Humanos , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , NF-kappa B/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inflamação/metabolismo , Células Cultivadas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Citocinas/metabolismo , Western BlottingRESUMO
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.
Assuntos
Microbioma Gastrointestinal , Ginsenosídeos , Células-Tronco , Animais , Ginsenosídeos/farmacologia , Camundongos , Células-Tronco/metabolismo , Células-Tronco/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Simulação de Ausência de Peso/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Elevação dos Membros Posteriores , Disbiose , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Intestinos/efeitos dos fármacos , Intestinos/microbiologiaRESUMO
(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
Hyperlipidemia, characterized by elevated serum lipid concentrations resulting from lipid metabolism dysfunction, represents a prevalent global health concern. Ginsenoside Rb1, compound K (CK), and 20(S)-protopanaxadiol (PPD), bioactive constituents derived from Panax ginseng, have shown promise in mitigating lipid metabolism disorders. However, the comparative efficacy and underlying mechanisms of these compounds in hyperlipidemia prevention remain inadequately explored. This study investigates the impact of ginsenoside Rb1, CK, and PPD supplementation on hyperlipidemia in rats induced by a high-fat diet. Our findings demonstrate that ginsenoside Rb1 significantly decreased body weight and body weight gain, ameliorated hepatic steatosis, and improved dyslipidemia in HFD-fed rats, outperforming CK and PPD. Moreover, ginsenoside Rb1, CK, and PPD distinctly modified gut microbiota composition and function. Ginsenoside Rb1 increased the relative abundance of Blautia and Eubacterium, while PPD elevated Akkermansia levels. Both CK and PPD increased Prevotella and Bacteroides, whereas Clostridium-sensu-stricto and Lactobacillus were reduced following treatment with all three compounds. Notably, only ginsenoside Rb1 enhanced lipid metabolism by modulating the PPARγ/ACC/FAS signaling pathway and promoting fatty acid ß-oxidation. Additionally, all three ginsenosides markedly improved bile acid enterohepatic circulation via the FXR/CYP7A1 pathway, reducing hepatic and serum total bile acids and modulating bile acid pool composition by decreasing primary/unconjugated bile acids (CA, CDCA, and ß-MCA) and increasing conjugated bile acids (TCDCA, GCDCA, GDCA, and TUDCA), correlated with gut microbiota changes. In conclusion, our results suggest that ginsenoside Rb1, CK, and PPD supplementation offer promising prebiotic interventions for managing HFD-induced hyperlipidemia in rats, with ginsenoside Rb1 demonstrating superior efficacy.
Assuntos
Microbioma Gastrointestinal , Ginsenosídeos , Hiperlipidemias , Sapogeninas , Ratos , Animais , Ginsenosídeos/metabolismo , Dieta Hiperlipídica , Metabolismo dos Lipídeos , Peso Corporal , Ácidos e Sais BiliaresRESUMO
Based on the Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappaB(NF-κB) signaling pathway, this study observed the regulatory effect of ginsenoside Rb_1(Rb_1) on liver lipid metabolism in db/db obese mice and explored its potential mechanism. Thirty 6-week-old male db/db mice were randomly divided into a model group, a metformin group, and Rb_1 groups with low, medium, and high doses, with six mice in each group. Additionally, six age-matched male db/m mice were assigned to the normal group. The intervention lasted for five weeks. Body weight, fasting blood glucose, and food intake were mea-sured weekly. At the end of the experiment, serum lipid levels and liver function were detected. Hematoxylin-eosin(HE) staining and oil red O staining were performed to observe pathological changes in liver tissue. Real-time quantitative PCR and immunohistochemistry on paraffin sections were used to detect the mRNA and protein expression of TLR4, MyD88, and NF-κB p65. RESULTS:: showed that compared with the normal group, the model group exhibited significant increases in body weight, liver weight, liver index, epididymal fat mass, epididymal fat index, total cholesterol, low-density lipoprotein cholesterol, liver function parameters, and fasting blood glucose levels. Liver lipid accumulation significantly increased, along with elevated mRNA and protein expression of TLR4, MyD88, and NF-κB p65 in the liver. After Rb_1 treatment, the above-mentioned parameters in the intervention groups showed significant reversals. In conclusion, Rb_1 can improve obesity and obesity-related hepatic steatosis in mice while regulating abnormal lipid and glucose meta-bolism. Mechanistically, Rb_1 may improve liver steatosis in db/db obese mice by modulating the TLR4/MyD88/NF-κB signaling pathway.
Assuntos
Fígado Gorduroso , Ginsenosídeos , Fator 88 de Diferenciação Mieloide , NF-kappa B , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Ginsenosídeos/farmacologia , Ginsenosídeos/administração & dosagem , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Camundongos , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/genética , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/genética , Camundongos Obesos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Humanos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Under physiological or pathological conditions, transient receptor potential (TRP) channel vanilloid type 1 (TRPV1) and TRP ankyrin 1 (TRPA1) possess the ability to detect a vast array of stimuli and execute diverse functions. Interestingly, increasing works have reported that activation of TRPV1 and TRPA1 could also be beneficial for ameliorating postoperative ileus (POI). Increasing research has revealed that the gastrointestinal (GI) tract is rich in TRPV1/TRPA1, which can be stimulated by capsaicin, allicin and other compounds. This activation stimulates a variety of neurotransmitters, leading to increased intestinal motility and providing protective effects against GI injury. POI is the most common emergent complication following abdominal and pelvic surgery, and is characterized by postoperative bowel dysfunction, pain, and inflammatory responses. It is noteworthy that natural herbs are gradually gaining recognition as a potential therapeutic option for POI due to the lack of effective pharmacological interventions. Therefore, the focus of this paper is on the TRPV1/TRPA1 channel, and an analysis and summary of the processes and mechanism by which natural herbs activate TRPV1/TRPA1 to enhance GI motility and relieve pain are provided, which will lay the foundation for the development of natural herb treatments for this disease.
Assuntos
Íleus , Plantas Medicinais , Humanos , Canal de Cátion TRPA1 , Íleus/tratamento farmacológico , Dor , Extratos Vegetais , Canais de Cátion TRPV/fisiologiaRESUMO
Shenmai Injection (SMI), which tonifies Qi and prevents exhaustion, nourishes Yin and generates body fluid, is usually used in the treatment of shock with deficiency of Qi and Yin, coronary artery disease, viral myocarditis, granulocytopenia and chronic pulmonary heart disease clinically. Ginsenosides Rg1 and Rb1 are the main active ingredients of SMI. In this study, high-performance liquid chromatography tandem mass spectrometry methods for quantification of Rb1 and Rg1 in beagle dogs were developed and validated according to international regulatory guidelines. The methods were applied to measure the pharmacokinetics parameters of the two ginsenoside after intravenous administration. The linear ranges of the analytes were 3.9-1,000 ng/ml for Rg1 and Rb1. After injection of single and multiple doses of SMI (1 ml/kg), the plasma concentration-time profiles of Rg1 and Rb1 met the characteristics of one-compartment and typical two-compartment intravenous injection.
Assuntos
Medicamentos de Ervas Chinesas , Ginsenosídeos , Cães , Animais , Ginsenosídeos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem , Medicamentos de Ervas Chinesas/farmacocinética , Administração IntravenosaRESUMO
The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 min of potassium chloride-induced CA, male C57BL/6 mice were resuscitated. Gn-Rb1 was blindly randomized to mice after 20 s of CPR. We assessed the cardiac systolic function before CA and 3 h after CPR. Mortality rates, neurological outcome, mitochondrial homeostasis, and the levels of oxidative stress were evaluated. We found that Gn-Rb1 improved the long-term survival during the post-resuscitation period but did not affect the ROSC rate. Further mechanistic investigations revealed that Gn-Rb1 ameliorated CA/CPR-induced mitochondrial destabilization and oxidative stress, partially via the activation of Keap1/Nrf2 axis. Gn-Rb1 improved the neurological outcome after resuscitation partially by balancing the oxidative stress and suppressing apoptosis. In sum, Gn-Rb1 protects against post-CA myocardial stunning and cerebral outcomes via the induction of the Nrf2 signaling pathway, which may offer a new insight into therapeutic strategies for CA.
Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca , Miocárdio Atordoado , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2RESUMO
The aim of this study was to investigate NAD+/NADH redox regulation in astrocytes by Ginsenoside Rb1 subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) and to reveal the neuroprotective mechanism of ginseng. Neonatal mouse brain was used to culture primary astrocytes. The third generation of the primary astrocytes was used for the experiments. OGD/R was introduced by culturing the cells in a glucose-free media under nitrogen for 6 h followed by a regular culture for 24 h. Ginsenoside Rb1 attenuated OGD/R-induced astrocyte injury in a dose-dependent manner. It improved the mitochondrial function of OGD/R astrocytes indicated by improving mitochondrial distribution, increasing mitochondrial membrane potential, and enhancing mitochondrial DNA copies and ATP production. Ginsenoside Rb1 significantly lifted intracellular NAD+/NADH, NADPH/NADP+, and GSH/GSSG in OGD/R astrocytes. It inhibited the protein expression of both PARP1 and CD38, while attenuating the SIRT1 drop in OGD/R cells. In line with its effects on PARP1, Ginsenoside Rb1 significantly reduced the expression of poly-ADP-ribosylation (PARylation) proteins in OGD/R cells. Ginsenoside Rb1 also significantly increased the expression of NAMPT and NMNAT2, both of which are key players in NAD/NADH synthesis. The results suggest that the regulation of NAD+/NADH redox involves the protective effects of ginsenoside Rb1 against OGD/R-induced astrocyte injury.
Assuntos
NAD , Oxigênio , Camundongos , Animais , Oxigênio/metabolismo , NAD/metabolismo , Astrócitos/metabolismo , Glucose/metabolismo , Células Cultivadas , OxirreduçãoRESUMO
AD is the most common neurodegenerative disorder characterized by progressive memory impairment and cognitive deficits. The pathology of AD is still unclear; however, several studies have shown that the aggregation of the Aß peptide in the CNS is an exclusively pathological process involved in AD. Currently, there is no proven medication to cure or prevent the disease progression. Nevertheless, various therapeutic approaches for AD show only relief of symptoms and mostly work on cognitive recovery. However, one of the promising approaches for therapeutic intervention is to use inhibitors for blocking the Aß peptide aggregation process. Recently, herbal phenolic compounds have been shown to have a therapeutic property for treatment of AD due to their multifaceted action. In this study, we investigated the effectiveness of SA, Gn Rb1, and DMyr on inhibiting the aggregation and toxicity of Aß40 and Aß42 using different biochemical and cell-based assays. Our results showed that SA and DMyr inhibit Aß40 and Aß42 fibrillation, seeded aggregation, and toxicity. Gn Rb1 did not have any effect on the aggregation or toxicity induced by Aß40 and Aß42. Moreover, SA and DMyr were able to disaggregate the preformed fibrils. Overall, these compounds may be used alone or synergistically and could be considered as a lead for designing new compounds that could be used as effective treatment of AD and related disorders.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Fragmentos de Peptídeos , Humanos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismoRESUMO
Type 2 diabetes (T2D) is characterized by insulin resistance (IR), often accompanied by inflammation. Macrophage activation acts as an inflammatory response, which is characterized by macrophage recruitment in the initial stage. Ginsenoside Rb1 (Rb1) is a main active ingredient, which is known for its fat-reducing, anti-inflammatory effects. To clarify that Rb1 regulates macrophage activation in adipose tissue and improves tissue inflammation, network pharmacology and molecular docking were used for target prediction and preliminary validation. By constructing the co-culture model of adipose-derived stem cells (ADSC) and primary macrophage (PM), the body adipose tissue microenvironment was simulated to observe the adipogenesis degree of adipocytes under the effect of Rb1. The levels of cytokines, macrophage polarization, and protein or RNA expression in the inflammatory signaling pathway were finally detected. The results showed that 89 common targets of T2D-Rb1 were obtained after their intersection. Furthermore, according to the results of the KEGG pathway and PPI analysis, PTGS2 (COX-2) is the downstream protein of PPARγ-NF-κB. The molecular binding energy of PPARγ-Rb1 is -6.8 kcal/mol. Rb1 significantly inhibited the increase in MCP-1, TNF-α, and IL-1ß induced by hypertrophic adipocytes supernatant and promoted the expression of IL-10. Rb1 inhibited the activation of inflammatory macrophages and PM migration and upregulated PPARγ expression with the blocking of NF-κB activation. Additionally, Rb1 promoted the expression of IRS1 and PI3K in the insulin signal pathway, which had a similar effect with ROS. Therefore, Rb1 might affect macrophage activation through PPARγ, which might alleviate obese insulin resistance in T2D early stage.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , PPAR gama/metabolismo , Ativação de Macrófagos , NF-kappa B/metabolismo , Diabetes Mellitus Tipo 2/complicações , Simulação de Acoplamento Molecular , Obesidade/metabolismo , Inflamação/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismoRESUMO
(1) Background: Ginsenoside Rb1-PLGA nanoparticles (GRb1@PLGA@NPs) represent a novel nanotherapeutic system, yet their therapeutic efficacy and underlying mechanisms for treating heart failure (HF) remain unexplored. This study aims to investigate the potential mechanisms underlying the therapeutic effects of GRb1@PLGA@NPs in HF treatment; (2) Methods: The left anterior descending coronary artery ligation was employed to establish a HF model in Sprague-Dawley rats, along with an in vitro oxidative stress model using H9c2 myocardial cells. Following treatment with GRb1@PLGA@NPs, cardiac tissue pathological changes and cell proliferation were observed. Additionally, the serum levels of biomarkers such as NT-proBNP, TNF-α, and IL-1ß were measured, along with the expression of the ROS/PPARα/PGC1α pathway; (3) Results: GRb1@PLGA@NPs effectively ameliorated the pathological status of cardiac tissues in HF rats, mitigated oxidative stress-induced myocardial cell damage, elevated SOD and MMP levels, and reduced LDH, MDA, ROS, NT-proBNP, TNF-α, and IL-1ß levels. Furthermore, the expression of PPARα and PGC1α proteins was upregulated; (4) Conclusions: GRb1@PLGA@NPs may attenuate myocardial cell injury and treat HF through the ROS/PPARα/PGC1α pathway.
Assuntos
Insuficiência Cardíaca , PPAR alfa , Ratos , Animais , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fator de Necrose Tumoral alfa , Insuficiência Cardíaca/tratamento farmacológicoRESUMO
Through the non-targeted metabolomics study of endogenous substances in the liver and serum of hyperlipidemia rats, the biomarkers related to abnormal lipid metabolism in hyperlipidemia rats were found, and the target of ginsenoside Rb_1 in improving hyperlipidemia was explored and its mechanism was elucidated. The content of serum biochemical indexes of rats in each group was detected by the automatic biochemical analyzer. The metabolite profiles of liver tissues and serum of rats were analyzed by HPLC-MS. Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were used to compare and analyze the metabolic data in the normal group, the hyperlipidemia group, and the ginsenoside Rb_1 group, and screen potential biomar-kers. The related metabolic pathways were further constructed by KEGG database analysis. The results showed that hyperlipemia induced dyslipidemia in rats, which was alleviated by ginsenoside Rb_1. The non-targeted metabolomics results showed that there were 297 differential metabolites in the liver tissues of hyperlipidemia rats, 294 differential metabolites in the serum samples, and 560 diffe-rential metabolites in the hyperlipidemia rats treated by ginsenoside Rb_1. Perillic acid and N-ornithyl-L-taurine were common metabolites in the liver and serum samples, which could be used as potential biomarkers for ginsenoside Rb_1 in the improvement of hyperlipidemia. As revealed by pathway enrichment in the liver and serum, ginsenoside Rb_1 could participate in the metabolic pathway of choline in both the liver and serum. In addition, ginsenoside Rb_1 also participated in the ABC transporter, alanine, aspartic acid, and glutamate metabolism, protein digestion and absorption, ß-alanine metabolism, taurine and hypotaurine metabolism, caffeine metabolism, valine, leucine, and isoleucine biosynthesis, arachidonic acid metabolism, and methionine and cysteine metabolism to improve dyslipidemia in rats.