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1.
Biochem Pharmacol ; 175: 113927, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32217100

RESUMO

Dihydromyricetin (DMY) is the most abundant flavonoid in Ampelopsis grossedentata possessing many pharmacological activities. But less is known about its protective effect against nonalcoholic steatohepatitis (NASH) in the context of metabolic syndrome. The present study is aimed to evaluate the pharmacological effects of DMY on NASH induced by feeding a high fat diet to 12-mo-old male LDLr-/- mice for 12 weeks and its molecular mode of action. At the end of the experiment, the blood samples and liver tissues of mice were collected for analysis. The results showed that DMY treatment improved the steatosis, inflammation and fibrosis which are three main aspects of NASH and some of the metabolic basal characteristics. The underlying mechanisms include regulating key regulators of lipid metabolism, oxidative stress, inflammation and fibrosis. Notably, DMY treatment increased hepatic sirtuin 1 (SIRT1) activity and protein expression. DMY also enhanced deacetylation of liver kinase B1 (LKB1) and nuclear transcription factor kappa B (NF-kB). Furthermore, in cultured hepatocyte cells, the benefits of DMY on lipid accumulation, oxidative stress and inflammation as well as the above related genes were abrogated in hepatocytes transfected with SIRT1 siRNA. These results suggest that modulation of SIRT1-mediated signaling cascades contributes to the amelioration of NASH by DMY and DMY may serve as a potentialtherapeuticcandidate for human NASH.

2.
Phytomedicine ; 62: 152935, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31085374

RESUMO

BACKGROUND: Polydatin has been recently shown to possess extensive cardiovascular pharmacological activities. However, its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to evaluate the potential effects of polydatin on high fat diet (HFD)-induced atherosclerosis using ApoE-/- mice, and explore the underlying mechanisms involved, especially focusing on reverse cholesterol transport (RCT) regulation. METHODS: after 12 weeks treatment, serum samples, mouse aorta, liver, peritoneal macrophages were collected to determine lipid profiles, atherosclerotic lesions, hepatic steatosis, foam cell formation and expression of related molecules. RAW264.7 macrophages were used to study cholesterol efflux. RESULTS: Polydatin improved serum lipid profiles, attenuated atherosclerosis and hepatic steatosis. Furthermore, polydatin may facilitate RCT by stimulating cholesterol efflux through ATP-binding cassette transporters (ABC) A1, ABCG1 and scavenger receptor class B type I (SR-BI) in macrophages, increasing serum levels of high density lipoprotein and apolipoprotein A-I, promoting of SR-BI-mediated cholesterol uptake of liver, increasing secretion of cholesterol into bile by ABCG5/ABCG8 and improving cholesterol metabolism by CYP7A1 pathway. Polydatin also regulated the protein expressions of hepatic fatty acid synthase and peroxisome proliferator-activated receptor-α. Additionally, polydatin reduced hepatic and aortic reactive oxygen species generation, normalized activities of antioxidant enzymes and increased protein expressions of NADPH-oxidase (NOX) 2 and NOX4 in liver. Polydatin also prevented hepatic and aortic inflammation as evidenced by the reduced macrophage infiltration and mRNA expressions of tumor necrosis factor-α and interleukin-6 in both aorta and liver. CONCLUSION: These findings indicated that polydatin can inhibit atherosclerosis through enhancement of overall RCT. In addition, anti-oxidative and anti-inflammatory effect of polydatin may also contribute to its inhibitory effects on atherosclerosis.

3.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939745

RESUMO

The compound, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG), a primary bioactive polyphenolic component of Polygonum multiflorum exerts numerous pharmacological activities. However, its protective effect against non-alcoholic steatohepatitis (NASH), in the context of metabolic syndrome, remains poorly understood. The aim of the present study is to evaluate the effects of TSG treatment on middle-aged (12-mo-old) male LDLr-/- mice, which were fed a high fat diet for 12 weeks to induce metabolic syndrome and NASH. At the end of the experiment, the blood samples of mice were collected for determination of metabolic parameters. Liver and aorta tissues were collected for analysis, such as histology, immunofluorescence, hepatic lipid content, real-time PCR, and western blot. Our data show that TSG treatment improved the different aspects of NASH (steatosis, inflammation, and fibrosis) and atherosclerosis, as well as some of the metabolic basal characteristics. These modulatory effects of TSG are mediated, at least in part, through regulating key regulators of lipid metabolism (SREBP1c, PPARα and their target genes, ABCG5 and CYP7A1), inflammation (CD68, TNF-α, IL-6 and ICAM), fibrosis (α-SMA and TNFß) and oxidative stress (NADPH-oxidase 2/4, CYP2E1 and antioxidant enzymes). These results suggest that TSG may be a promising candidate for preventing and treating the progression of NASH.


Assuntos
Envelhecimento/patologia , Aterosclerose/tratamento farmacológico , Glucosídeos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estilbenos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/etiologia , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/farmacologia , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Receptores de LDL/genética , Estilbenos/farmacologia
4.
Eur J Pharmacol ; 830: 76-86, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29704496

RESUMO

Salusin-α is an endogenous bioactive peptide and likely to prevent atherosclerosis. But its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to determine the potential effects of salusin-α on atherosclerosis and its associated metabolic disorders in high fat diet (HFD)-fed low density lipoprotein receptor deficient (LDLr-/-) mice, and also explore the possible underlying mechanisms involved. Our data showed that after 12 weeks treatment, salusin-α ameliorated HFD-induced weight gain, hyperlipidemia, and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Salusin-α suppressed HFD-induced hepatic steatosis and regulated gene expression of fatty acid synthase, acetyl coenzyme A carboxylase-α, peroxisome proliferator-activated receptor-α, camitine palmitoyltransferase-1α and CYP7A1 in liver. Salusin-α reduced atherosclerotic plaque area and macrophage foam cell formation. Salusin-α prevented hepatic and aortic inflammation as evidenced by the reduced macrophage recruitment and mRNA expression of IL-6 and TNF-α in both liver and aorta. Salusin-α also reduced hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in liver and suppressing reactive oxygen species generation and protein expressions of NADPH-oxidase (NOX) 2 and NOX4 in both liver and aorta. Our present data suggest that salusin-α could reduce hepatic steatosis and atherosclerosis via its pleiotropic effects, including amelioration of lipid profiles, regulation of some key molecules involved in lipid metabolism in liver, anti-oxidative effect and anti-inflammatory action.


Assuntos
Aterosclerose/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Acetilcoenzima A/genética , Animais , Aterosclerose/sangue , Aterosclerose/genética , Carnitina O-Palmitoiltransferase/genética , Colesterol 7-alfa-Hidroxilase/genética , Dieta Hiperlipídica , Ácido Graxo Sintases/genética , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Interleucina-6/sangue , Lipídeos/sangue , Masculino , Camundongos Knockout , PPAR alfa/genética , Receptores de LDL/genética , Fator de Necrose Tumoral alfa/sangue , Ganho de Peso/efeitos dos fármacos
5.
Biomed Pharmacother ; 101: 543-552, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29505925

RESUMO

As the most abundant flavonoid in Ampelopsis grossedentata, the protective effects of dihydromyricetin on atherosclerosis have been well established, yet the detailed mechanisms are not fully understood. The aim of the present study was to examine the effect of dihydromyricetin on lipid accumulation and the underlying molecular mechanisms in macrophages and ApoE-/- mice. Incubation with dihydromyricetin significantly attenuated oxidized low-density lipoprotein (ox-LDL)-mediated cholesterol and lipid accumulation in THP-1-derived macrophages, which was due to increased cholesterol efflux. In addition, dihydromyricetin increased mRNA and protein expressions of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 but had no effect on the mRNA and protein expressions of SR-A, CD36, or SR-BI involved in cholesterol homeostasis. Furthermore, the upregulation of ABCA1 and ABCG1 by dihydromyricetin depended on liver X receptor α (LXRα), as evidenced by an increase in the nuclear level of LXRα and its prevention of the expression of ABCA1 and ABCG1 after inhibition of LXRα activity by knockdown of LXRα expression with small interfering RNA (siRNA). Accordingly, dihydromyricetin-mediated suppression of cholesterol and lipid accumulation in macrophages was also abrogated by LXRα siRNA. Moreover, the lesion size of atherosclerosis was smaller in dihydromyricetin-treated ApoE-/- mice compared with the vehicle-treated mice, and the protein expression of CD36, SR-A, ABCA1, ABCG1 and LXRα in aortas was modulated similar to that observed in THP-1-derived macrophages. These data suggest that promotion of LXRα-ABCA1/ABCG1-dependent cholesterol efflux is crucial event in suppression of lipid accumulation by dihydromyricetin in the transformation of macrophage foam cells.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Colesterol/metabolismo , Flavonóis/farmacologia , Células Espumosas/metabolismo , Receptores X do Fígado/biossíntese , Macrófagos/metabolismo , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Relação Dose-Resposta a Droga , Flavonóis/uso terapêutico , Células Espumosas/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células THP-1
6.
Can J Physiol Pharmacol ; 96(1): 8-17, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28863273

RESUMO

The aim of this study was to evaluate the potential effects of 2,3,4',5-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG) on the development of atherosclerotic plaque in ApoE-/- mice, and explore the mechanisms involved. Our data showed that after 8 weeks of treatment, TSG ameliorated serum levels of total cholesterol, triglyceride, and low density lipoprotein cholesterol, and increased serum levels of high density lipoprotein cholesterol in ApoE-/- mice. TSG suppressed hepatic steatosis, the formation of atherosclerotic lesions, and the formation of macrophage foam cells in ApoE-/- mice. Moreover, TSG improved the expressions of hepatic SR-BI, ABCG5, and CYP7A1, and up-regulated the protein expressions of aortic ABCA1 and ABCG1. An in-vitro study showed that TSG promoted macrophage cholesterol efflux and increased the protein expressions of ABCA1 and ABCG1. Our findings provide evidence for a positive role of TSG in preventing atherosclerosis by promoting reverse cholesterol transport. These effects may be achieved by stimulating cholesterol efflux through ABCA1 and ABCG1, promoting SR-BI-mediated cholesterol uptake in the liver, increasing secretion of cholesterol into bile by ABCG5, and improving cholesterol metabolism by the CYP7A1 pathway. In addition, antioxidative and anti-inflammatory effects of TSG may also contribute to its inhibitory effects on atherosclerosis. Further study is needed to investigate whether other potential mechanisms are involved in TSG-mediated atheroprotection.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Colesterol/metabolismo , Glucosídeos/uso terapêutico , Estilbenos/uso terapêutico , Animais , Aterosclerose/complicações , Aterosclerose/patologia , Transporte Biológico/efeitos dos fármacos , Fígado Gorduroso/complicações , Fígado Gorduroso/tratamento farmacológico , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Glucosídeos/farmacologia , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Inflamação/complicações , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Estilbenos/farmacologia
7.
Atherosclerosis ; 262: 39-50, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28500865

RESUMO

BACKGROUND AND AIMS: Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr-/-) mice. METHODS: Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied. RESULTS: (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr-/- mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux. CONCLUSIONS: These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation, amelioration of lipid profiles, anti-inflammatory action and anti-oxidative effect.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Flavonóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Receptores de LDL/deficiência , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Citocinas/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Predisposição Genética para Doença , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mediadores da Inflamação/sangue , Lipoproteínas LDL/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Placa Aterosclerótica , Células RAW 264.7 , Receptores de LDL/genética
8.
J Oncol Pharm Pract ; 23(6): 403-412, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27259339

RESUMO

Background Two pivotal Phase III trials compared the efficacy of palonosetron, ondansetron and granisetron, combined with dexamethasone, for the prevention of nausea and vomiting following highly emetogenic chemotherapy. However, an economic evaluation of these three regimens in the real-world setting of Chinese adult patients has not been determined. Objectives To estimate, from the perspective of the Chinese healthcare system, which of these frequently used strategies consisting of 0.25 mg palonosetron (0.25P), 16 mg ondansetron (Onda), and 3 mg granisetron (Gran), is the most cost-effective option in patients following highly emetogenic chemotherapy. Methods A Markov decision-analytic model was developed. The health and economic outcomes of the three strategies; 0.25P, Onda, and Gran were investigated. The clinical and utility data were taken from published studies. The cost data were calculated according to current local Chinese practices. Sensitivity analyses were performed to determine the impact of uncertainty regarding the results. Results The base-case analysis showed that the 0.25P strategy yielded maximum health benefits compared with the other two strategies. However, the probabilistic sensitivity analysis demonstrated that the Gran strategy was the most cost-effective approach when the willingness-to-pay threshold was not more than US$22,515/quality-adjusted life year. Moreover, palonosetron is not cost-effective in preventing 'overall' nausea and vomiting following highly emetogenic chemotherapy in Chinese patients. Conclusions Our analysis suggests that, compared with palonosetron and ondansetron, 3 mg granisetron may be a cost-effective treatment option in the current Chinese healthcare setting.


Assuntos
Antieméticos/administração & dosagem , Dexametasona/administração & dosagem , Náusea/prevenção & controle , Vômito/prevenção & controle , Adulto , Antieméticos/economia , Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Ensaios Clínicos Fase III como Assunto , Análise Custo-Benefício , Granisetron/administração & dosagem , Humanos , Isoquinolinas/administração & dosagem , Náusea/induzido quimicamente , Ondansetron/efeitos adversos , Palonossetrom , Quinuclidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Vômito/induzido quimicamente
9.
Eur J Pharmacol ; 791: 105-114, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27568841

RESUMO

2, 3, 4', 5-tetrahydroxystilbene-2-0-ß-D glucoside (TSG) could inhibit cardiac remodeling in response to pressure overload. Peroxisome proliferator-activated receptor gamma (PPAR-γ) has been recognized as a potent, endogenous antifibrotic factor and maintaining a proper expression level in myocardium is necessary for assuring that structure and function of heart adapt to pressure overload stress. The aim of the present study was to investigate whether PPAR-γ is involved in the beneficial effect of TSG on pressure overload-induced cardiac fibrosis. TSG (120mg/kg/day) or TSG (120mg/kg/day) plus the PPAR-γ antagonist GW9662 (1mg/kg/day) was administered to rats with pressure overload induced by abdominal aortic banding. 30 days later, pressure overload-induced hypertension, cardiac dysfunction and fibrosis were significantly inhibited by TSG. TSG also significantly reduced collagen I, collagen III, fibronectin and plasminogen activator inhibitor (PAI)-1 expression, as makers of myocardial fibrosis. Theses anti-fibrotic effects of TSG in pressure overloaded hearts could be abrogated by co-treatment with GW9662. Accordingly, upregulated PPAR-γ protein expression by TSG in pressure overloaded hearts was also reversed by co-treatment with GW9662. Additionally, the inhibitory effects of TSG on angiotensin II induced cardiac fibroblasts proliferation, differentiation and expression of collagen I and III, fibronectin and PAI-1 were abrogated by PPAR-γ antagonist GW9662 and PPAR-γ silencing. Furthermore, TSG directly increased PPAR-γ gene expression at gene promoter, mRNA and protein level in angiotensin II-treated cardiac fibroblats in vitro. Our results suggested that upregualtion of endogenous PPAR-γ expression by TSG may be involved in its beneficial effect on pressure overload-induced cardiac fibrosis.


Assuntos
Cardiotônicos/farmacologia , Glucosídeos/farmacologia , Coração/efeitos dos fármacos , Miocárdio/patologia , PPAR gama/metabolismo , Pressão/efeitos adversos , Estilbenos/farmacologia , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Masculino , Miocárdio/metabolismo , PPAR gama/antagonistas & inibidores , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos
10.
Cell Physiol Biochem ; 36(6): 2466-79, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26279448

RESUMO

BACKGROUND/AIMS: salusin-ß is considered to be a potential pro-atherosclerotic factor. Regulation and function of vascular smooth muscle cells (VSMCs) are important in the progression of atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts a vascular protective role beyond its metabolic effects. Salusin-ß has direct effects on VSMCs. The aim of the present study was to assess the effect of salusin-ß on PPARγ gene expression in primary cultured rat VSMCs. METHODS: Western blotting analysis, real-time PCR and transient transfection approach were used to determine expression of target proteins. Specific protein knockdown was performed with siRNA transfection. Cell proliferation was determined by 5-bromo-2'-deoxyuridine incorporation. The levels of inflammation indicators interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined using enzyme-linked immunosorbent assay. RESULTS: Salusin-ß negatively regulated PPARγ gene expression at protein, mRNA and gene promoter level in VSMCs. The inhibitory effect of salusin-ß on PPARγ gene expression contributed to salusin-ß-induced VSMCs proliferation and inflammation in vitro. IκBα-NF-κB activation, but not NF-κB p50 or p65, mediated the salusin-ß-induced inhibition of PPARγ gene expression. Salusin-ß induced nuclear translocation of histone deacetylase 3 (HDAC3). HDAC3 siRNA prevented salusin-ß-induced PPARγ reduction. Nuclear translocation of HDAC3 in response to salusin-ß was significantly reversed by an IκBα inhibitor BAY 11-7085. Furthermore, IκBα-HDAC3 complex was present in the cytosol of VSMCs but interrupted after salusin-ß treatment. CONCLUSION: IκBα-HDAC3 pathway may contribute to salusin-ß-induced inhibition of PPARγ gene expression in VSMCs.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , PPAR gama/genética , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Proteínas I-kappa B/metabolismo , Inflamação/genética , Inflamação/patologia , Ligantes , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , PPAR gama/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Transporte Proteico/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley
11.
J Cardiovasc Pharmacol ; 65(4): 377-85, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25551321

RESUMO

Despite the clear mitogenic effect of salusin-ß on vascular smooth muscle cells (VSMCs), which contributes to its proatherosclerotic effects, additional studies are needed to explore its underlying mechanisms. The aim of this study was to investigate the mechanism of salusin-ß's effects on VSMCs cell cycle regulation and the possible signal pathways. Salusin-ß accelerated the G1/S phase transition in VSMCs and increased the expression levels of cyclins D1 and E. Silencing either cyclin D1 or cyclin E gene inhibited salusin-ß-induced VSMCs proliferation, cell cycle progression, phosphorylation of the Rb protein, and dissociation of the E2F-Rb complex. Importantly, expression of cyclin E was also induced by cyclin D1. Next, we found that salusin-ß increased the protein expressions of activator protein-1 (AP-1) subunits c-Jun and c-Fos, and enhanced binding of AP-1 to the promoter region of cyclin D1. In addition, inhibition of AP-1 activity could lead to significant suppression of salusin-ß-induced cyclin D1 expression. Furthermore, MPAKs pathways were found to mediate salusin-ß-induced VSMCs proliferation, cyclin D1, cyclin E, c-Jun, and c-Fos expression. These results suggest that salusin-ß promotes cell cycle progression of VSMCs by upregulating the cyclin D1 and cyclin E, in an AP-1-dependent manner through mitogen-activated protein kinases signaling pathways.


Assuntos
Proliferação de Células/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Animais , Ciclo Celular/fisiologia , Células Cultivadas , Ciclina D1/metabolismo , Ciclina E/metabolismo , Fator Promotor de Maturação/metabolismo , Ratos , Transdução de Sinais
12.
Chin J Integr Med ; 21(3): 204-10, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25078359

RESUMO

OBJECTIVE: To investigate the effect of 2,3,4',5-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG), an active component extracted from the root of Polygonum multiflorum, on angiotensin II (Ang II)-induced proliferation of cultured rat vascular smooth muscle cells (VSMCs) and to identify the potential mechanism. METHODS: Cell proliferation and cell cycle were determined by cell counting, 5-bromo-2'-deoxyuridine incorporation assay, proliferating cell nuclear antigen protein expression and flow cytometry. Levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), mitogenic extracellular kinase 1/2 (MEK1/2) and Src in VSMCs were measured by Western blot. The expression of c-fos, c-jun and c-myc mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR). Intracellular reactive oxygen species (ROS) was measured by fluorescence assay. RESULTS: TSG significantly inhibited Ang II-induced VSMCs proliferation and arrested cells in the G /S checkpoint (P<0.05 or P<0.01). TSG decreased the levels of phosphorylated ERK1/2, MEK1/2 and Src in VSMCs (P<0.05 or P<0.01). TSG also suppressed c-fos, c-jun and c-myc mRNA expression <0.05 or P<0.01). In addition, the intracellular ROS was reduced by TSG (P<0.01). CONCLUSIONS: TSG inhibited Ang II-induced VSMCs proliferation. Its antiproliferative effect might be associated with down-regulation of intracellular ROS, followed by the suppression of the Src-MEK1/2-ERK1/2 signal pathway, and hence, blocking cell cycle progression.


Assuntos
Angiotensina II/farmacologia , Glucosídeos/farmacologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Estilbenos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Espaço Intracelular/metabolismo , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
13.
Planta Med ; 80(2-3): 130-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24431015

RESUMO

The aim of the present study was to investigate the effects of 2,3,4',5-tetrahydroxystilbene-2-O-beta-D-glucoside, an active component extracted from Polygonum multiflorum, on pressure overload-induced cardiac remodeling in rats. A rat model with cardiac remodeling was induced by abdominal aortic banding. 2,3,4',5-Tetrahydroxystilbene-2-O-beta-D-glucoside (30, 60, 120 mg/kg/day) was administered 3 days after abdominal aortic banding and continued for 30 days. The abdominal aortic banding-treated rats had significantly elevated blood pressure, left ventricular hypertrophy, and myocardial fibrosis. Left ventricular hypertrophy was characterized by an increase in the ratios of the heart and left ventricular weights to body weight, and increased myocyte cross-sectional areas, hypertrophic ventricular septum, and left ventricular posterior wall. The accumulation of myocardial interstitial perivascular collagen and elevated cardiac hydroxyproline content indicated myocardial fibrosis. The pathological changes above were attenuated by 2,3,4',5-tetrahydroxystilbene-2-O-beta-D-glucoside. Additionally, it markedly reduced collagen I and III expressions and regulated matrix metalloproteinase-2,9 and inhibitors of metalloproteinase expressions, as markers of myocardial fibrosis. Furthermore, we explored the underlying mechanisms for such effects of 2,3,4',5-tetrahydroxystilbene-2-O-beta-D-glucoside. The results showed that it significantly reduced myocardium angiotensin II, enhanced the activities of superoxide dismutase and glutathione peroxidase in serum and myocardial tissue, as well as inhibited protein expression of transforming growth factor-ß1 and phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in the myocardial tissue. Our results suggest that 2,3,4',5-tetrahydroxystilbene-2-O-beta-D-glucoside could prevent cardiac remodeling induced by pressure overload in rats. The underlying mechanisms may be related to a decreasing angiotensin II level, an antioxidant effect of the tested compound, suppression of transforming growth factor-ß1 expression, and inhibition of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase activation.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Glucosídeos/farmacologia , Fitoterapia , Extratos Vegetais/uso terapêutico , Estilbenos/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Glucosídeos/química , Glucosídeos/isolamento & purificação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Polygonum , Ratos , Estilbenos/química , Estilbenos/isolamento & purificação , Fator de Crescimento Transformador beta1/metabolismo
14.
Fitoterapia ; 91: 68-73, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23994628

RESUMO

Rhein, a compound found as a glucoside in the root of rhubarb, is currently a subject of interest for its antitumor properties. The apoptosis of tumor cell lines induced by rhein was observed, and the involvement of mitochondria was established; however, the role of mitochondrial permeability transition (MPT) remains unknown. Here we report that MPT plays an important role in the apoptosis of human hepatocellular carcinoma Hep-G2 cells induced by rhein. After adding rhein to the isolated hepatic mitochondria, swelling effects and the leakage of Ca(2+) were observed. These alterations were suppressed by cyclosporin A (CsA), an MPT inhibitor. Furthermore, in Hep-G2 cells, the decrease of ATP production, the loss of mitochondrial transmembrane potential (MTP), the release of cytochrome c (Cyto c), and the activation of caspase 3 were also observed. These toxic effects of rhein can also be attenuated by CsA as well. Moreover, TUNEL assay confirmed that in the presence of CsA, rhein-induced apoptosis was largely inhibited. These results suggest that MPT plays a critical role in the pathogenesis of Hep-G2 cell injury induced by rhein, and imply that MPT may contribute to the anti-cancer activity of rhein.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular , Neoplasias Hepáticas , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rheum/química , Trifosfato de Adenosina/metabolismo , Antraquinonas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Caspase 3/metabolismo , Ciclosporina/farmacologia , Citocromos c/metabolismo , Células Hep G2 , Humanos , Marcação In Situ das Extremidades Cortadas , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/uso terapêutico
15.
Eur J Pharmacol ; 698(1-3): 370-8, 2013 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-23178522

RESUMO

2,3,4',5-tetrahydroxystilbene-2-0-ß-D glucoside (TSG) has been recognized to suppress the proliferation of vascular smooth muscle cells (VSMCs). The aim of the present study was to determine whether TSG inhibits neointimal hyperplasia in a rat carotid arterial balloon injury model. Balloon injury was induced in the left common carotid artery of rats. TSG (30, 60, 120 mg/kg/day) was treated from 3 days prior to, until 14 days after the induction of balloon injury. The ratio of intima-to-media was significantly reduced in the TSG-treated rats at 14 days after the induction of injury, which was associated with reduced expressions of proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA) and platelet-derived growth factor-BB (PDGF-BB), as markers of VSMCs proliferation and migration. Additionally, TSG significantly inhibited PDGF-BB induced cell migration in cultured VSMCs. Furthermore, we explored the underlying mechanisms for such effects of TSG. The result showed that TSG markedly reduced balloon injury-induced AKT, extracellular signal-regulated kinase (ERK1/2) and nuclear factor kappaB (NF-κB) activation as well as mRNA expressions of c-myc, c-fos and c-jun, which is important signal pathway for VSMCs proliferation. And in both vivo and vitro model, TSG markedly regulated matrix metalloproteinase-2, 9 expressions and collagen I, III expressions, which are key factors in extracellular matrix for VSMCs migration. These results suggest that the anti-proliferative and anti-migrative effects of TSG on VSMCs could help to explain the beneficial effects of TSG on neointima hyperplasia induced by balloon injury.


Assuntos
Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Lesões das Artérias Carótidas/tratamento farmacológico , Lesões das Artérias Carótidas/fisiopatologia , Cateteres/efeitos adversos , Glucosídeos/farmacologia , Neointima/tratamento farmacológico , Estilbenos/farmacologia , Animais , Becaplermina , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Movimento Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/uso terapêutico , Hiperplasia/tratamento farmacológico , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-sis/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico
16.
Phytother Res ; 26(7): 1068-74, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22213189

RESUMO

The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. 2,3,4',5-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG), an active component extracted from Polygonum multiflorum, has been found to have an antiatherosclerotic effect. The aim of this study was to investigate the effects of TSG on platelet derived growth factor (PDGF)-BB induced VSMCs proliferation and to explore the possible mechanisms of such effects. Pretreatment of VSMCs with TSG significantly inhibited PDGF-BB-induced cell proliferation in a concentration-dependent but not time-dependent manner. In addition, flow cytometry analysis of the DNA content revealed blocking of the PDGF-BB-inducible cell cycle progression by TSG. On the contrary, an inhibitory effect of TSG on VSMCs proliferation and expression of cell cycle regulators were markedly attenuated by addition of an nitric oxide (NO) synthase inhibitor, a soluble guanylate cyclase inhibitor and a cyclic GMP (cGMP)-dependent protein kinase (PKG) inhibitor: N(G)-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4] oxadiazolo [4,3-α] quinoxalin-1-one (ODQ) and KT5823, respectively. It was also demonstrated that TSG enhanced NO and cGMP formation through up-regulating endothelial NO synthase expression in VSMCs. The findings indicate that TSG inhibited VSMCs proliferation induced by PDGF-BB may involve the NO/cGMP/PKG signal pathway.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Glucosídeos/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estilbenos/farmacologia , Animais , Becaplermina , Carbazóis , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Masculino , Músculo Liso Vascular/citologia , NG-Nitroarginina Metil Éster , Oxidiazóis , Polygonum/química , Proteínas Proto-Oncogênicas c-sis , Quinoxalinas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Clin Exp Pharmacol Physiol ; 38(5): 307-13, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21348889

RESUMO

1. 2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside (TSG) has been shown to have an anti-atherosclerotic effect. Vascular smooth muscle cell (VSMC) proliferation contributes to the pathobiology of atherosclerosis. The aim of the present study was to investigate the effects of TSG on platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation and to explore the molecular mechanisms underlying the effects. 2. Cultured rat VSMC were pretreated with TSG (l-50 µmol/L) for 1 h, followed by exposure to PDGF-BB (10 ng/mL) for 24 h, after which cell proliferation and cell cycle stages were examined. The expression of protein cell cycle regulators, including retinoblastoma (Rb), cyclin D1/E, cyclin-dependent kinase (CDK) 2/4, CDK inhibitors p21 and p27 and proliferative cell nuclear antigen (PCNA), was examined. Activation of extracellular signal-regulated kinase (ERK) 1/2 was evaluated to elucidate the possible upstream mechanism by which TSG affects cell cycle regulators. 3. The results showed that TSG dose-dependently inhibited PDGF-BB-induced VSMC proliferation, possibly by blocking the progression of the cell cycle from the G(1) to S phase. In addition, TSG significantly inhibited PDGF-BB-induced phosphorylation of Rb and the expression of cyclin D1, CDK4, cyclin E, CDK2 and PCNA. In addition, TSG suppressed PDGF-BB-induced downregulation of p27 and upregulation of p21, as well as PDGF-BB-induced activation of ERK1/2. 4. Together, the findings of the present study provide the first evidence that TSG can inhibit PDGF-BB-stimulated VSMC proliferation via cell cycle arrest in association with modulation of the expression of cell cycle regulators, which may be mediated, at least in part, by suppression of ERK1/2 activation.


Assuntos
Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucosídeos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Estilbenos/farmacologia , Animais , Becaplermina , Fármacos Cardiovasculares/farmacologia , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Modelos Biológicos , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-sis , Ratos , Ratos Sprague-Dawley
18.
Planta Med ; 75(11): 1209-14, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19350477

RESUMO

2,3,4',5-Tetrahydroxystilbene 2- O-beta- D-glucoside (TSG), an active component extracted from Polygonum multiflorum, has been found to have an anti-atherosclerotic effect. The aim of this study was to investigate whether the TSG could prevent the development of atherosclerosis through influencing endothelial function in atherogenic-diet rats and to explore the possible mechanisms. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, transmission electron microscopy of the aorta, and levels of nitrate/nitrite (NOx) in serum and aorta. Endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA and protein expression were also measured. After 12 weeks treatment, TSG improved acetylcholine-induced endothelium-dependent relaxation, prevented intimal remodeling, inhibited the decreased NOx content in serum and aorta in atherogenic-diet rats. Furthermore, the observed decreased eNOS mRNA and protein expression and increased iNOS mRNA and protein expression in atherogenic-diet rats were attenuated by TSG treatment. These results suggest that TSG could restore vascular endothelial function, which may be related to its ability to prevent changes of eNOS and iNOS expression, leading to preservation of NO bioactivity.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Glucosídeos/farmacologia , Estilbenos/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/ultraestrutura , Aterosclerose/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Glucosídeos/química , Masculino , Microscopia Eletrônica de Transmissão , Nitratos/sangue , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Polygonum/química , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estilbenos/química
19.
Artigo em Chinês | MEDLINE | ID: mdl-21186625

RESUMO

AIM: To observe the changes of MMP-2, 9 level on atherosclerosis in experimental rats by treatment of 2,3,4',5-tetrahydroxystilbene-2-0-beta-D glucoside (TSG) and to investigate the mechanism of TSG in stabilizing plaque and anti-atherosclerosis. METHODS: The atherosclerosis model of rat was made by feeding high grease food and injecting VitD3. Sixty male SD rats were randomly divided into six groups: control, Simvastatin, model and TSG 120 mg x kg(-1) x d(-1), TSG 60 mg x kg(-1) x d(-1) and TSG 30 mg x kg(-1) x d(-1). After 12 weeks, several aorta were randomly tested, model and TSG 120 mg x kg(-1) x d(-1), TSG 60 mg kg(-1) x d(-1) and TSG 30 mg x kg(-1) x d(-1). After 12 weeks, several aorta were randomly tested, model made was successful when we found plaque. And after six weeks treating, the mRNA expressions of MMP-2 and MMP-9 were measured by RT-PCR. The activities of MMP-2 and MMP-9 were measured by Western blot. The levels of CRP, IL-6 and TNF-alpha in serum were measured in biochemical method. RESULTS: Data of the study demonstrated that the level of TNF-alpha, IL-6, CRP, MMP-2 and MMP-9 were remarkably decreased by TSG60, 120 mg x kg(-1) x d(-1) groups, which showed a dose-dependent effect. CONCLUSION: TSG has the effect of anti-atherogenic and stabilizing plaque on the experimental rats with atherosclerosis, which are induced by the high cholesterol feeding and VitD3 injecting. The effect of TSG seems to be closely involved in regulating the expressions of MMP-2 and MMP-9, and inhibiting inflammation.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Glucosídeos/uso terapêutico , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Estilbenos/uso terapêutico , Animais , Proteína C-Reativa/metabolismo , Glucosídeos/isolamento & purificação , Interferon-alfa/sangue , Interleucina-6/sangue , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Polygonum/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estilbenos/isolamento & purificação
20.
Pharmacology ; 81(4): 325-32, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18349554

RESUMO

Although astragaloside IV, a saponin isolated from Astragalus membranaceus, has been shown to protect the myocardium against ischemia/reperfusion injury, its effect on the status of sarcoplasmic reticulum (SR) Ca2+ transport in the injured myocardium remains largely unknown. In this study, we investigated whether in cultured cardiomyocytes subjected to hypoxia and reoxygenation (H/R) administration of astragaloside IV during H/R attenuates the myocardial cell injury and prevents changes in Ca2+ handling activities and gene expression of SR Ca2+ pump. Cultured cardiomyocytes from neonatal rats were exposed to 6 h of hypoxia followed by 3 h of reoxygenation. Myocyte injury was determined by the release of cardiac troponin I in supernatant. Astragaloside IV significantly inhibited cardiac troponin I release after H/R in a dose-dependent manner. The diastolic [Ca2+]i measured with Fura-2/AM was significantly increased after reoxygenation. Astragaloside IV prevented the rise of diastolic [Ca2+]i and the depression of caffeine-induced Ca2+ transients caused by H/R. Furthermore, the observed depressions in SR Ca2+-ATPase activity as well as the mRNA and protein expression of SR Ca2+-ATPase in hypoxic-reoxygenated cardiomyocytes were attenuated by astragaloside IV treatment. These results suggest that the beneficial effect of astragaloside IV in H/R-induced injury may be related to normalization of SR Ca2+ pump expression and, thus, may prevent the depression in SR Ca2+ handling.


Assuntos
Cálcio/metabolismo , Saponinas/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Animais Recém-Nascidos , Astragalus propinquus/química , Hipóxia Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Corantes Fluorescentes/metabolismo , Fura-2/análogos & derivados , Fura-2/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Saponinas/administração & dosagem , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Triterpenos/administração & dosagem
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