RESUMO
Ginsenoside Re is a protopanaxatriol-type saponin extracted from the berry, leaf, stem, flower bud, and root of Panax ginseng. In recent years, ginsenoside Re (Re) has been attracting attention as a dietary phytochemical. In this review, studies on Re were compiled by searching a combination of keywords, namely "pharmacology," "pharmacokinetics," and "toxicology," in the Google Scholar, NCBI, PubMed, and Web of Science databases. The aim of this review was to provide an exhaustive overview of the pharmacological activities, pharmacokinetics, and toxicity of Re, focusing on clinical evidence that has shown effectiveness in specific diseases, such as diabetes mellitus, nervous system diseases, inflammation, cardiovascular disease, and cancer. Re is also known to eliminate virus, enhance the immune response, improve osteoporosis, improve skin barrier function, enhance intracellular anti-oxidant actions, regulate cholesterol metabolism, alleviate allergic responses, increase sperm motility, reduce erectile dysfunction, promote cyclic growth of hair follicles, and reduce gastrointestinal motility dysfunction. Furthermore, this review provides data on pharmacokinetic parameters and toxicological factors to examine the safety profile of Re. Such data will provide a theoretical basis and reference for Re-related studies and future applications.
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In this study, we investigated the effects of a petroleum ether fraction of Artemisia sacrorum Ledeb. (Compositae) (PEASL) on glucose production through AMP-activated protein kinase (AMPK) activation in human HepG2 cells. PEASL significantly inhibited glucose production in a concentration-dependent manner, and this effect was reversed in the presence of compound C, a selective AMPK inhibitor. PEASL markedly induced the phosphorylation of AMPK and downstream acetyl-CoA carboxylase (ACC) in a time- and concentration-dependent manner. In addition, it markedly increased the phosphorylations of glycogen synthase kinase 3ß (GSK3ß) in a concentration-dependent manner. In contrast, cAMP response element binding protein (CREB), a key transcription factor for gluconeogenic enzyme phosphorylation, decreased in a concentration-dependent manner. PEASL downregulated the gluconeogenesis gene expression of peroxisome proliferation activated receptor-γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) in a concentration-dependent manner. In addition, the gene expression of orphan nuclear receptor small heterodimer partner (SHP) increased, also in a concentration-dependent manner. These effects were also abolished by pretreatment with compound C, an AMPK inhibitor. This indicates that PEASL inhibited glucose production via the AMPK-GSK-CREB pathway in HepG2 cells, and these effects appeared to be capable of revealing anti-diabetic mechanism of PEASL in HepG2 cells.
Assuntos
Artemisia/química , Diabetes Mellitus Tipo 2/enzimologia , Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Glucose , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Western Blotting , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Glucose/antagonistas & inibidores , Glucose/biossíntese , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Quinases da Glicogênio Sintase/genética , Quinases da Glicogênio Sintase/metabolismo , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Humanos , Hipoglicemiantes/química , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Inibidores de Proteínas Quinases/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Panax ginseng is known to have anti-diabetic activity, but the active ingredients are not yet fully identified. In this study, we found the inhibitory effect of Rg(1) on hepatic glucose production through AMP-activated protein kinase (AMPK) activation in HepG2 cells. Rg(1) significantly inhibited hepatic glucose production in a concentration-dependent manner, and this effect was reversed in the presence of compound C, a selective AMPK inhibitor. In addition, Rg(1) markedly induced the phosphorylations of liver kinase B1 (LKB1), AMPK and forkhead box class O1 (FoxO1), a key transcription factor for gluconeogenic enzymes, in time- and concentration-dependent manners. Glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities were inhibited by 24% and 21%, respectively, when the cells were exposed to 40 microM of Rg(1), resulting from phosphorylation of FoxO1 and inhibition of gluconeogenic gene expression. Taken together, our results demonstrated the suppressive effect of Rg(1) on hepatic glucose production via LKB1-AMPK-FoxO1 pathway in HepG2 human hepatoma cells.
Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Medicamentos de Ervas Chinesas/farmacologia , Ginsenosídeos/farmacologia , Glucose/antagonistas & inibidores , Glucose/biossíntese , Fígado/efeitos dos fármacos , Fígado/metabolismo , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/fisiologia , Células Hep G2 , Humanos , Fígado/enzimologia , PanaxRESUMO
Artemisia sacrorum Ledeb. (Compositae) (ASL) is a traditional Chinese medicine used to treat different hepatic diseases. However, a hypolipidemic effect of ASL on fatty liver disease has not been reported. Therefore, we investigated whether 95% ethanol eluate (EE), an active part of ASL, would attenuate hepatic lipid accumulation in human HepG2 cells by activating AMP-activated protein kinase (AMPK). Significant decreases in triglyceride levels and increases in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation were observed when the cells were treated with 95% EE. EE down-regulated the lipogenesis gene expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), in a time- and dose-dependent manner. In contrast, the lipolytic gene expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) and CD36 increased in a time- and dose-dependent manner. These effects were abolished by pretreatment with compound C, an AMPK inhibitor. However, there were no differences in the gene expression of SREBP2, low density lipoprotein receptor (LDLR), hydroxymethyl glutaryl CoA reductase (HMG-CoA), or glucose transporter 2 (GLUT2). At the same time, 95% EE significantly increased the gene expression of acyl CoA oxidase (ACOX) in a time- and dose-dependent manner. Thus, AMPK mediated 95% EE induced suppression of SREBP1c and activation of PPAR-alpha respectively. These finding indicate that 95% EE attenuates hepatic lipid accumulation through AMPK activation and may be active in the prevention of serious diseases such as fatty liver, obesity, and type-2 diabetic mellitus.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Artemisia/genética , Artemisia/metabolismo , Lipogênese/genética , Fígado/metabolismo , Ativação Enzimática , Células Hep G2 , HumanosRESUMO
In this study, we investigated the protective effects of fermented ginseng (FG) on hyperglycemia induced by streptozotocin (STZ) in Sprague Dawley rats. FG was administered orally at dose of 250 (FGL) or 500 mg/kg (FGH) for 20 days starting one week before STZ injection. FG restored the plasma insulin levels by 266% and 334% in FGL and FGH, respectively, and resulting in reduction of plasma glucose concentration. Histological observation indicated that STZ-induced destruction of pancreatic islets was protected by FG. Consistent with this observation, FG reduced protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as determined by Western blotting and RT-PCR, respectively. The molecular mechanism of FG's inhibition of iNOS and COX-2 gene expressions appeared to involve the inhibition of nuclear factor-kappaB (NF-kappaB) activation via prevention of inhibitor kappaB (IkappaB) phosphorylation and degradation. The cytoprotective effects of FG were also mediated through suppression of extracelluar signal-regulated kinase (ERK) and c-JUN N-terminal kinase (JNK) pathways. Collectively, these results suggest that FG might be used to preserve functional beta-cell mass.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , NF-kappa B/antagonistas & inibidores , Panax/química , Animais , Glicemia , Ciclo-Oxigenase 2/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fermentação , Regulação da Expressão Gênica , Insulina/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Corosolic acid (CA) is the main active component of Lagetstroemia speciosa and has been known to serve as several different pharmacological effects, such as antidiabetic, anti-oxidant, and anticancer effects. In this study, effects of CA on the hepatic lipid accumulation were examined using HepG2 cells and tyloxapol (TY)-induced hyperlipidemia ICR mice. CA significantly inhibited hepatic lipid accumulation via inhibition of SREBPs, and its target genes FAS, SCD1, and HMGCR transcription in HepG2 cells. These effects were mediated through activation of AMPK, and these effects were all abolished in the presence of compound C (CC, an AMPK inhibitor). In addition, CA clearly alleviated serum ALT, AST, TG, TC, low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) levels, and obviously attenuated TY-induced liver steatosis and inflammation. Moreover, CA significantly upregulated AMPK, ACC, LKB1 phosphorylation, and significantly inhibited lipin1, SREBPs, TNF-α, F4/80, caspase-1 expression, NF-κB translocation, and MAPK activation in TY-induced hyperlipidemia mice. Our results suggest that CA is a potent antihyperlipidemia and antihepatic steatosis agent and the mechanism involved both lipogenesis and cholesterol synthesis and inflammation response inhibition via AMPK/SREBPs and NF-κB/MAPK signaling pathways.
Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fitoterapia , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Animais , Células Hep G2 , Humanos , Inflamação , Lagerstroemia/química , Camundongos Endogâmicos ICR , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/metabolismoRESUMO
This study was designed to investigate the protective effects of the active part of Artemisia sacrorum Ledeb. Extract (ASE) against acetaminophen (APAP)-induced hepatotoxicity in mice. As a result, pretreated with ASE prior to the administration of APAP significantly prevented the increases of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-alpha) levels in serum, and glutathione (GSH) depletion, malondialdehyde (MDA) accumulation in liver tissue. In addition, ASE prevented APAP-induced apoptosis and necrosis, as indicated by a liver histopathological analysis and DNA laddering. Furthermore, according to the results from Western blot analysis, ASE markedly decreased APAP-induced caspase-3 and -8 protein expressions in mouse livers. All these results suggest that the protective effects of ASE against APAP-induced liver injury may involve mechanisms associated with its inhibitive effects of lipid peroxidation and the down-regulation of TNF-alpha mediated apoptosis.
Assuntos
Acetaminofen/efeitos adversos , Artemisia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Caspase 3/metabolismo , Caspase 8/metabolismo , DNA , Glutationa/metabolismo , Fígado/fisiopatologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Necrose/prevenção & controle , Componentes Aéreos da Planta , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Tetrahydropalmatine (THP), one of the active components of Rhizoma corydalis, has been reported to exert several pharmacological effects, including antiinflammatory, antitumor and analgesic activities. However, its effect on obesity and the underlying molecular mechanisms that may be involved have not yet been elucidated. In the present study, the inhibitory effects of THP on the adipogenesis in 3T3L1 adipocytes was examined using hstology, western blotting and RTqPCR. THP was identified to significantly suppress lipid accumulation in 3T3L1 cells and it inhibited preadipocyte differentiation in a concentrationdependent manner, as evidenced by the reduced formation of lipid droplets and decreased triglyceride levels and glycerol3phosphate dehydrogenase activity. THP downregulated the adipogenesisassociated protein and gene expressions of sterol regulatory elementbinding protein 1, fatty acid synthase, stearoylCoA desaturase 1, peroxisome proliferator activated receptor γ and CCAAT/enhancer binding proteinα in a concentrationdependent manner. In addition, it reduced adipocyte fatty acid binding protein and glycerol3phosphate acyltransferase gene expression in a concentrationdependent manner. Conversely, THP increased the mRNA expression of carnitine palmitoyltransferase 1 in a concentrationdependent manner. Furthermore, THP increased AMPactivated protein kinase (AMPK) and acetylCoA carboxylase phosphorylation in a concentrationdependent manner. These results suggested that antiadipogenic activity of TPH may be mediated via the AMPK pathway in 3T3L1 cells.
Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Alcaloides de Berberina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células 3T3-L1 , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
To develop a ginseng product possessing an efficacy for diabetes, ginseng radix ethanol extract was treated with pectinase and obtained the GINST. In the present study, we evaluate the beneficial effect of GINST on high fat diet (HFD)-induced hyper-glycemia and hyperlipidemia and action mechanism(s) in ICR mice. The mice were randomly divided into five groups: regular diet group (RD), high fat diet group (HFD), HFD plus GINST at 75 mg/kg (GINST75), 150 mg/kg (GINST150), and 300 mg/kg (GINST300). Oral glucose tolerance test reveals that GINST improves the glucose tolerance after glucose challenge. Fasting plasma glucose and insulin levels were decreased by 4.3% and 4.2% in GINST75, 10.9% and 20.0% in GINST150, and 19.6% and 20.9% in GINST300 compared to those in HFD control group. Insulin resistance indices were also markedly decreased by 8.2% in GINST75, 28.7% in GINST150, and 36.4% in GINST300, compared to the HFD control group. Plasma triglyceride, total cholesterol and non-esterified fatty acid levels in the GINST300 group were decreased by 13.5%, 22.7% and 24.1%, respectively, compared to those in HFD control group. Enlarged adipocytes of HFD control group were markedly decreased in GINST-treated groups, and shrunken islets of HFD control mice were brought back to near normal shape in GINST300 group. Furthermore, GINST enhanced phosphorylation of AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT4). In summary, GINST prevents HFD-induced hyperglycemia and hyperlipidemia through reducing insulin resistance via activating AMPK-GLUT4 pathways, and could be a potential therapeutic agent for type 2 diabetes.
RESUMO
Panax ginseng exhibits pleiotropic beneficial effects on cardiovascular system, central nervous system, and immune system. In the last decade, numerous preclinical findings suggest ginseng as a promising therapeutic agent for diabetes prevention and treatment. The mechanism of ginseng and its active components is complex and is demonstrated to either modulate insulin production/secretion, glucose metabolism and uptake, or inflammatory pathway in both insulin-dependent and insulin-independent manners. However, human studies are remained obscure because of contradictory results. While more studies are warranted to further understand these contradictions, ginseng holds promise as a therapeutic agent for diabetes prevention and treatment. This review summarizes the evidences for the therapeutic potential of ginseng and ginsenosides from in vitro studies, animal studies and human clinical trials with a focus on diverse molecular targets including an AMP-activated protein kinase signaling pathway.
RESUMO
Artemisia sacrorum Ledeb. was extracted by 95% ethanol and water, respectively. By partitioning the 95% ethanol extract successively with different solvents and separating the water extract by macroporous resin, nine separate parts were obtained. According to the results of in vitro experiments, the CH2Cl2 (dichloromethane) fraction showed the most pronounced cytotoxic activity against HepG2, HT-29 and MCF-7 cells, with EC50 values 122.35, 49.76 and 28.51 µg mL⻹, respectively, at 48 h. Following this, the compounds of the CH2Cl2 fraction were separated and identified. Ten compounds were isolated from A. sacrorum Ledeb. and identified by spectral analysis. Four compounds, including acacetin, were isolated for the first time from A. sacrorum Ledeb.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Artemisia/química , Flavonas/química , Flavonas/farmacologia , Antineoplásicos/isolamento & purificação , Flavonas/isolamento & purificação , Células HT29 , Células Hep G2 , Humanos , Células MCF-7 , Escopoletina/análogos & derivados , Escopoletina/química , Escopoletina/isolamento & purificação , Escopoletina/farmacologiaRESUMO
Ginsenoside Re is a protopanaxatriol-type saponin isolated from Panax ginseng berry. Although anti-diabetic and anti-hyperlipidemic effects of Re have been reported by several groups, its mechanism of action is largely unknown until now. Here, we examine anti-diabetic and anti-hyperlipidemic activities of Re and action mechanism(s) in human HepG2 hepatocytes and high-fat diet fed C57BL/6J mice. Re suppresses the hepatic glucose production via induction of orphan nuclear receptor small heterodimer partner (SHP), and inhibits lipogenesis via suppression of sterol regulatory element binding protein-1c (SREBP-1c) and its target gene [fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1)] transcription. These effects were mediated through activation of AMP-activated protein kinase (AMPK), and abolished when HepG2 cells were treated with an AMPK inhibitor, Compound C. C57BL/6J mice were randomly divided into five groups: regular diet fed group (RD), high-fat diet fed group (HFD) and the HFD plus Re (5, 10, 20 mg/kg) groups. Re treatment groups were fed a high-fat diet for 6 weeks, and then orally administered Re once a day for 3 weeks. The in vitro results are likely to hold true in an in vivo experiment, as Re markedly lowered blood glucose and triglyceride levels and protected against hepatic steatosis in high-fat diet fed C57BL/6J mice. In conclusion, the current study suggest that ginsenoside Re improves hyperglycemia and hyperlipidemia through activation of AMPK, and confers beneficial effects on type 2 diabetic patients with insulin resistance and dyslipidemia.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Ginsenosídeos/farmacologia , Lipídeos/sangue , Quinases Proteína-Quinases Ativadas por AMP , Análise de Variância , Animais , Medicamentos de Ervas Chinesas , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/metabolismo , Distribuição Aleatória , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Panax ginseng is known to have anti-diabetic activity, but the active ingredients have not been fully explored yet. Here, we test whether ginsenoside Rg2 has an inhibitory effect on hepatic glucose production and determine its mechanism of action. Rg2 significantly inhibits hepatic glucose production and induces phosphorylations of liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3ß (GSK3ß) in time- and concentration-dependent manners in human HepG2 hepatoma cells, and these effects were abolished in the presence of compound C, a selective AMPK inhibitor. In addition, phosphorylated form of cAMP-response element-binding protein (CREB), a key transcription factor for hepatic gluconeogenesis, was decreased in time- and concentration-dependent manners. Next, gene expression of orphan nuclear receptor small heterodimer partner (SHP) was also examined. Rg2 markedly enhanced the gene expression of SHP and its direct interaction with CREB, which results in disruption of CREB·CRTC2 complex. Consequently, expressions of relevant genes such as peroxisome proliferation-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were all significantly suppressed and these effects were also reversed in the presence of compound C. In conclusion, our results propose that ginsenoside Rg2 suppresses the hepatic glucose production via AMPK-induced phosphorylation of GSK3ß and induction of SHP gene expression. Further studies are warranted to elucidate a therapeutic potential of Rg2 for type 2 diabetic patients.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/farmacologia , Glucose , Quinase 3 da Glicogênio Sintase/metabolismo , Hipoglicemiantes/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteína de Ligação a CREB/metabolismo , Gluconeogênese/genética , Glucose/antagonistas & inibidores , Glucose/biossíntese , Glicogênio Sintase Quinase 3 beta , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Transdução de SinaisRESUMO
Artemisia sacrorum Ledeb. (Compositae) (ASL) has long been used in Oriental folk medicine to treat diverse hepatic diseases. In this study, we investigated the effect of ASL on adipocyte differentiation in 3T3-L1 cells. ASL significantly suppressed 3T3-L1 differentiation in a concentration-dependent manner. A significant increase of AMP-activated protein kinase (AMPK) was observed when the cells were treated with ASL. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK. These effects were abolished by pre-treatment with the AMPK inhibitor, compound C. In addition, ASL down-regulated the adipogenesis-related gene expression of the sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) and glycerol-3-phosphate acyltransferase (GPAT) in a concentration-dependent manner. These effects were abolished by pre-treatment with compound C. ASL signiï¬cantly reduced the gene expression of the peroxisome proliferator-activated receptor γ (PPARγ) and of the CCAAT/enhancer binding protein-α (C/EBPα), two key transcription factors in adipogenesis. Meanwhile, adipocyte fatty acid binding protein (aP2) gene expression was also reduced in a concentration-dependent manner. These findings indicated that ASL exerts anti-adipogenic activity via AMPK activation and may act to prevent obesity.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Artemisia/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Diferenciação Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacosRESUMO
IH-901 is an intestinal metabolite of ginsenosides found in Panax ginseng. In the present study, effects of IH-901 on glucose and lipid metabolisms were examined using C2C12 myotubes and C57BL/ksJ db/db mice. A significant increase in phosphorylated adenosine monophosphate-activated protein kinase was observed when differentiated C2C12 myotubes were treated with IH-901. Glucose transporter 4 protein expressions were also up-regulated when muscle cells were treated with of IH-901 up to 60 minutes, resulting in stimulation of glucose uptake by 25% as compared with untreated cells. In addition, phosphatidylinositol-3 kinase and Akt protein expressions were increased when C2C12 myotubes were exposed to IH-901 for up to 3 hours; and these effects including glucose uptake were attenuated by pretreatment with LY294002, a selective phosphatidylinositol-3 kinase inhibitor. In animal study, IH-901 at 25 mg/kg lowered the plasma glucose, triglyceride, cholesterol, and nonesterified fatty acid levels by 20.7%, 41.6%, 20.2%, and 24.6%, respectively, compared with control mice. In the meantime, plasma insulin levels were significantly increased by 2.2 and 3.4 times in 10 and 25 mg/kg-treated mice, respectively, compared with control mice, in parallel with the histologic observation showing a preserved architecture of the pancreatic islet. Protein and gene expression patterns for adenosine monophosphate-activated protein kinase, sterol regulatory element binding protein-1a, and glucose transporter 4 in the liver and skeletal muscles were similar to those in cell studies. In summary, IH-901 might be a promising therapeutic agent improving altered glucose and lipid metabolisms revealed in type 2 diabetes mellitus patients.
Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Sapogeninas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/análiseRESUMO
As part of our search for biologically active anti-osteoporotic agents that enhance differentiation and mineralization of osteoblastic MC3T3-E1 cells, we identified the ginsenoside Rh2(S). Mostly known to exhibit beneficial effects in cancer prevention and metabolic diseases, Rh2(S) is one of the most active ginsenosides. Here, we show that Rh2(S) stimulates osteoblastic differentiation and mineralization, manifested by the up-regulation of differentiation markers (alkaline phosphatase and osteogenic genes) and von Kossa/Alizarin Red staining, respectively. Rh2(S) also activated protein kinase D (PKD) and AMP-activated protein kinase (AMPK) in a time- and concentration-dependent manner, and Rh2(S)-induced differentiation and mineralization of osteoblastic cells were significantly abolished in the presence of specific inhibitors; Go6976 for PKD and Ara-A for AMPK. Furthermore, Go6976 suppressed Rh2(S)-mediated activation of AMPK, indicating that PKD may be an upstream signal for AMPK in Rh2(S)-induced differentiation and mineralization of MC3T3-E1 cells. Taken together, these results indicate that Rh2(S) induces the differentiation and mineralization of MC3T3-E1 cells through activation of PKD/AMPK signaling pathways. These findings provide a molecular basis for the osteogenic effect of Rh2(S).
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ginsenosídeos/farmacologia , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
As part of the search for biologically active anti-osteoporotic agents that enhance differentiation and mineralization of osteoblastic MC3T3-E1 cells, we identified the ginsenoside Rh2(S), which is an active component in ginseng. Rh2(S) stimulates osteoblastic differentiation and mineralization, as manifested by the up-regulation of differentiation markers (alkaline phosphatase and osteogenic genes) and Alizarin Red staining, respectively. Rh2(S) activates p38 mitogen-activated protein kinase (MAPK) in time- and concentration-dependent manners, and Rh2(S)-induced differentiation and mineralization of osteoblastic cells were totally inhibited in the presence of the p38 MAPK inhibitor, SB203580. In addition, pretreatment with Go6976, a protein kinase D (PKD) inhibitor, significantly reversed the Rh2(S)-induced p38 MAPK activation, indicating that PKD might be an upstream kinase for p38 MAPK in MC3T3-E1 cells. Taken together, these results suggest that Rh2(S) induces the differentiation and mineralization of MC3T3-E1 cells through activation of PKD/p38 MAPK signaling pathways, and these findings provide a molecular basis for the osteogenic effect of Rh2(S).
Assuntos
Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Proteína Quinase C/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células 3T3 , Animais , Calcificação Fisiológica/fisiologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Camundongos , Osteoblastos/citologia , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologiaRESUMO
In the present study, we investigate anti-diabetic effect of pectinase-processed ginseng radix (GINST) in high fat diet-fed ICR mice. The ICR mice were divided into three groups: regular diet group, high fat diet control group (HFD), and GINST-treated group. To induce hyperglycemia, mice were fed a high fat diet for 10 weeks, and mice were administered with 300 mg/ kg of GINST once a day for 5 weeks. Oral glucose tolerance test revealed that GINST improved glucose tolerance after glucose challenge. Compared to the HFD control group, fasting blood glucose and insulin levels were decreased by 57.8% (p<0.05) and 30.9% (p<0.01) in GINST-treated group, respectively. With decreased plasma glucose and insulin levels, the insulin resistance index of the GINST-treated group was reduced by 68.1% (p<0.01) compared to the HFD control group. Pancreas of GINST-treated mice preserved a morphological integrity of islets and consequently having more insulin contents. In addition, GINST up-regulated the levels of phosphorylated AMP-activated protein kinase (AMPK) and its target molecule, glucose transporter 4 (GLUT4) protein expression in the skeletal muscle. Our results suggest that GINST ameliorates a hyperglycemia through activation of AMPK/ GLUT4 signaling pathway, and has a therapeutic potential for type 2 diabetes.
RESUMO
Cinnamaldehyde (CA), one of the active components of cinnamon, has been known to exert several pharmacological effects such as anti-inflammatory, antioxidant, antitumor, and antidiabetic activities. However, its antiobesity effect has not been reported yet. This study investigated the antidifferentiation effect of CA on 3T3-L1 preadipocytes, and the antiobesity activity of CA was further explored using high-fat-diet-induced obese ICR mice. During 3T3-L1 preadipocytes were differentiated into adipocytes, 10-40 µM CA was treated and lipid contents were quantified by Oil Red O staining, along with changes in the expression of genes and proteins associated with adipocyte differentiation and adipogenesis. It was found that CA significantly reduced lipid accumulation and down-regulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding proteins α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1) in concentration-dependent manners. Moreover, CA markedly up-regulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and these effects were blunted in the presence of AMPK inhibitor, compound C. In the animal study, weight gains, insulin resistance index, plasma triglyceride (TG), nonesterified fatty acid (NEFA), and cholesterol levels in the 40 mg/kg of CA-administered group were significantly decreased by 67.3, 55, 39, 31, and 23%, respectively, when compared to the high-fat diet control group. In summary, these results suggest that CA exerts antiadipogenic effects through modulation of the PPAR-γ and AMPK signaling pathways.
Assuntos
Acroleína/análogos & derivados , Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , PPAR gama/fisiologia , Células 3T3-L1 , Acroleína/farmacologia , Adipócitos/citologia , Animais , Sequência de Bases , Primers do DNA , Camundongos , Camundongos Endogâmicos ICR , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Ginseng (Panax ginseng C.A. Meyer) is widely used in Asian countries as a traditional medicine for the treatment of various diseases. It is known to have anti-inflammatory effects, although the mechanism is not clear. In this study, preventive effects of fermented ginseng (FG) against streptozotocin (STZ)-induced pancreatic beta-cell death was assessed in RINm5F insulinoma cells. FG markedly inhibited the production of nitrite in a dose-dependent manner. The decrease in nitrite production was found to correlate with reduced inducible nitric oxide (iNOS) protein and mRNA levels. To characterize the anti-inflammatory mechanism of FG at the transcriptional level, we examined effects of FG on the activity of nuclear factor-kappaB (NF-kappaB). FG reduced a translocation of the NF-kappaB subunit and NF-kappaB-dependent transcriptional activity. FG blocked signaling upstream of NF-kappaB activation, such as degradation of inhibitor factor-kappaBalpha (IkappaBalpha ) and phosphorylations of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK). These results suggest that FG protects against STZ-induced pancreatic beta-cell damage by downregulation of iNOS, cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-alpha ) gene expressions by blocking NF-kappaB and mitogen-activated protein kinase activities.