RESUMEN
Diabetes is associated with the development of myocardial fibrosis, which is related to various cardiac diseases. Cafestol, one of the active ingredients in coffee, has been reported to exert biological effects. However, whether cafestol can ameliorate diabetes-induced cardiac fibrosis remains unknown. The aim of this study was to evaluate the effects of cafestol on cardiac fibrosis in high-glucose-treated cardiac fibroblasts and streptozocin- (STZ-) induced diabetic rats. Rat cardiac fibroblasts were cultured in high-glucose (25 mM) media in the absence or presence of cafestol, and the changes in collagen synthesis, transforming growth factor-ß1 (TGF-ß1) production, and related signaling molecules were assessed on the basis of 3H-proline incorporation, enzyme-linked immunosorbent assay, and western blotting. Cardiac fibroblasts exposed to high-glucose conditions exhibited increased collagen synthesis, TGF-ß1 production, and Smad2/3 phosphorylation, and these effects were mitigated by cafestol treatment. Furthermore, cafestol increased the translocation of nuclear factor erythroid 2-related factor 2 and increased the expression of heme oxygenase-1. The results of molecular docking analysis suggested a selective interaction of cafestol with Kelch-like ECH-associated protein 1. The rats with untreated STZ-induced diabetes exhibited considerable collagen accumulation, which was ameliorated by cafestol. Moreover, activities of catalase, superoxide dismutase, general matrix metalloproteinase, and reduced glutathione concentration were upregulated, whereas malondialdehyde level was downregulated by treatment with cafestol in rats with cardiac fibrosis. These findings highlight the effects of cafestol, which may be useful in treating diabetes-related cardiac fibrosis.
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Through population-based studies, associations have been found between coffee drinking and numerous health benefits, including a reduced risk of cardiovascular disease. Active ingredients in coffee have therefore received considerable attention from researchers. A wide variety of effects have been attributed to cafestol, one of the major compounds in coffee beans. Because cardiac hypertrophy is an independent risk factor for cardiovascular events, this study examined whether cafestol inhibits urotensin II (U-II)-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed only to U-II (1 nM) or to U-II (1 nM) following 12-h pretreatment with cafestol (1-10 µ M). Cafestol (3-10 µ M) pretreatment significantly inhibited U-II-induced cardiomyocyte hypertrophy with an accompanying decrease in U-II-induced reactive oxygen species (ROS) production. Cafestol also inhibited U-II-induced phosphorylation of redox-sensitive extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor transactivation. In addition, cafestol pretreatment increased Src homology region 2 domains-containing phosphatase-2 (SHP-2) activity, suggesting that cafestol prevents ROS-induced SHP-2 inactivation. Moreover, nuclear factor erythroid-2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression were enhanced by cafestol. Addition of brusatol (a specific inhibitor of Nrf2) or Nrf2 siRNA significantly attenuated cafestol-mediated inhibitory effects on U-II-stimulated ROS production and cardiomyocyte hypertrophy. In summary, our data indicate that cafestol prevented U-II-induced cardiomycyte hypertrophy through Nrf2/HO-1 activation and inhibition of redox signaling, resulting in cardioprotective effects. These novel findings suggest that cafestol could be applied in pharmacological therapy for cardiac diseases.
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Aumento de la Célula/efectos de los fármacos , Diterpenos/farmacología , Miocitos Cardíacos/patología , Factor 2 Relacionado con NF-E2/metabolismo , Urotensinas/efectos adversos , Urotensinas/antagonistas & inhibidores , Animales , Cardiomegalia/tratamiento farmacológico , Células Cultivadas , Depresión Química , Diterpenos/uso terapéutico , Receptores ErbB/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hemo-Oxigenasa 1/metabolismo , Fosforilación/efectos de los fármacos , Fitoterapia , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
Tanshinone IIA is the main effective component of Salvia miltiorrhiza, known as "Danshen," which has been used in many therapeutic remedies in traditional Chinese medicine. However, the direct effects of tanshinone IIA on vascular endothelial cells have not yet been fully described. In the present study, we demonstrated that tanshinone IIA increased heme oxygenase-1 (HO-1) expression in human umbilical vein endothelial cells. Western blot analyses and experiments with specific inhibitors indicated tanshinone IIA enhanced HO-1 expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt and the subsequent induction of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. In addition, tanshinone IIA inhibited cyclic strain induced interleukin-8 (IL-8) expression. HO-1 silencing significantly abrogated the repressive effects of tanshinone IIA on strain-induced IL-8 expression, which suggests HO-1 has a role in mediating the effects of tanshinone IIA. This study reports for the first time that tanshinone IIA inhibits cyclic strain-induced IL-8 expression via the induction of HO-1 in endothelial cells, providing valuable new insight into the molecular pathways that may contribute to the effects of tanshinone IIA.
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Benzofuranos/farmacología , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Salvia miltiorrhiza/química , Benzofuranos/aislamiento & purificación , Inducción Enzimática/efectos de los fármacos , Silenciador del Gen , Hemo-Oxigenasa 1/fisiología , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
OBJECTIVES: We aimed to determine the efficacy of an 8-week direct blood pressure (BP) biofeedback training program for prehypertensive or stage I hypertensive patients with a particular focus on the impact of the authenticity of feedback signals on the efficacy of BP regulation. DESIGNS: This study has a randomized, double-blind, parallel-group design. PARTICIPANTS AND METHODS: Fifty-nine individuals with ages from 18 to 64 years and who met the criteria for the diagnosis of prehypertenion or stage 1 hypertension participated in this study. The participants were referrals from physicians or community-dwelling volunteers. No participants had taken antihypertensive medication within the previous 2 months prior to enrollment. The participants were randomly assigned to the biofeedback group (n = 31) trained with real-time BP feedback signals or the control group (n = 28) trained with pseudofeedback signals. The primary outcome measures were systolic BP (SBP) and diastolic BP (DBP). Systolic BP and DBP were assessed at baseline, 1 week after training (week 9), and 8 weeks after training (week 16) in both groups. Only 54 participants had week 16 data. RESULTS: The changes in SBP and DBP from baseline to week 9, from baseline to week 16, and from week 9 to week 16 were not significantly different between the groups (All P > 0.05). Both groups were able to significantly decrease BP after completing the training. A percentage of 45.2% of the participants in the biofeedback group and 63.0% of the participants in the control group lowered their SBP by 5 mm Hg or more at week 9. The SBP-lowering effects were also maintained for at least 8 weeks after the completion of training. CONCLUSIONS: The equivalent magnitude of BP reduction between the 2 study groups suggests that repeated practice in BP self-regulation was more likely responsible for the efficacy of direct BP biofeedback training than was the type of feedback signals.
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Biorretroalimentación Psicológica , Hipertensión/terapia , Autocontrol , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
This study investigated how lycopene affected urotensin-II- (U-II-) induced cardiomyocyte hypertrophy and the possible implicated mechanisms. Neonatal rat cardiomyocytes were exposed to U-II (1 nM) either exclusively or following 6 h of lycopene pretreatment (1-10 µ M). The lycopene (3-10 µ M) pretreatment significantly inhibited the U-II-induced cardiomyocyte hypertrophy, decreased the production of U-II-induced reactive oxygen species (ROS), and reduced the level of NAD(P)H oxidase-4 expression. Lycopene further inhibited the U-II-induced phosphorylation of the redox-sensitive extracellular signal-regulated kinases. Moreover, lycopene treatment prevented the increase in the phosphorylation of serine-threonine kinase Akt and glycogen synthase kinase-3beta (GSK-3 ß ) caused by U-II without affecting the protein levels of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). However, lycopene increased the PTEN activity level, suggesting that lycopene prevents ROS-induced PTEN inactivation. These findings imply that lycopene yields antihypertrophic effects that can prevent the activation of the Akt/GSK-3 ß hypertrophic pathway by modulating PTEN inactivation through U-II treatment. Thus, the data indicate that lycopene prevented U-II-induced cardiomyocyte hypertrophy through a mechanism involving the inhibition of redox signaling. These findings provide novel data regarding the molecular mechanisms by which lycopene regulates cardiomyocyte hypertrophy.
RESUMEN
BACKGROUND: Doxorubicin, one of the original anthracyclines, remains among the most effective anticancer drugs ever developed. Clinical use of doxorubicin is, however, greatly limited by its serious adverse cardiac effects that may ultimately lead to cardiomyopathy and heart failure. Tanshinone IIA is the main effective component of Salvia miltiorrhiza known as 'Danshen' in traditional Chinese medicine for treating cardiovascular disorders. The objective of this study was set to evaluate the protective effect of tanshinone IIA on doxorubicin-induced cardiomyocyte apoptosis, and to explore its intracellular mechanism(s). METHODS: Primary cultured neonatal rat cardiomyocytes were treated with the vehicle, doxorubicin (1 µM), tanshinone IIA (0.1, 0.3, 1 and 3 µM), or tanshinone IIA plus doxorubicin. RESULTS: We found that tanshinone IIA (1 and 3 µM) inhibited doxorubicin-induced reactive oxygen species generation, reduced the quantity of cleaved caspase-3 and cytosol cytochrome c, and increased BcL-x(L) expression, resulting in protecting cardiomyocytes from doxorubicin-induced apoptosis. In addition, Akt phosphorylation was enhanced by tanshinone IIA treatment in cardiomyocytes. The wortmannin (100 nM), LY294002 (10 nM), and siRNA transfection for Akt significantly reduced tanshinone IIA-induced protective effect. CONCLUSIONS: These findings suggest that tanshinone IIA protects cardiomyocytes from doxorubicin-induced apoptosis in part through Akt-signaling pathways, which may potentially protect the heart from the severe toxicity of doxorubicin.
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Abietanos/farmacología , Apoptosis/efectos de los fármacos , Doxorrubicina/toxicidad , Medicamentos Herbarios Chinos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/fisiología , Animales , Animales Recién Nacidos , Apoptosis/fisiología , Cardiotónicos/farmacología , Células Cultivadas , Doxorrubicina/antagonistas & inhibidores , Miocitos Cardíacos/enzimología , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
1. Tanshinone IIA, one of the active components of the Radix of Salvia miltiorrhiza, is used in traditional Chinese medicine to treat cardiovascular diseases. However, the intracellular mechanism of action of tanshinone IIA remain to be determined. The aims of the present study were to test the hypothesis that tanshinone IIA alters strain-induced endothelin (ET)-1 expression and nitric oxide (NO) production, as well as to identify the putative signalling pathways involved, in human umbilical vein endothelial cells (HUVEC). 2. Cultured HUVEC were exposed to cyclic strain in the presence of 1-10 µmol/L tanshinone IIA. Expression of ET-1 was examined by reverse transcription-polymerase chain reaction and ELISA. Phosphorylation of endothelial NO synthase (eNOS) and activating transcription factor (ATF) 3 was assessed by western blot analysis. 3. Tanshinone IIA (3 and 10 µmol/L) inhibited strain-induced ET-1 expression. In contrast, NO production, eNOS phosphorylation and ATF3 expression were enhanced by tanshinone IIA. The eNOS inhibitor N(G) -nitro-L-arginine methyl ester (l-NAME; 100 µmol/L), the phosphatidylinositol 3-kinase inhibitor LY294002 (5 µmol/L) and the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; 10 µmol/L) inhibited tanshinone IIA-induced increases in ATF3 expression. Moreover, treatment of HUVEC with either an NO donor (3,3-bis [aminoethyl]-1-hydroxy-2-oxo-1-triazene; 500 µmol/L) or an ATF3 activator (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; 5 µmol/L) resulted in the repression of strain-induced ET-1 expression. The inhibitory effect of tanshinone IIA on strain-induced ET-1 expression was significantly attenuated by l-NAME, ODQ and the transfection of small interfering RNA for ATF3. 4. In conclusion, tanshinone IIA inhibits strain-induced ET-1 expression by increasing NO and upregulating ATF3 in HUVEC. The present study provides important new insights into the molecular pathways that may contribute to the beneficial effects of tanshinone IIA in the cardiovascular system.
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Abietanos/farmacología , Enfermedades Cardiovasculares/prevención & control , Microambiente Celular , Regulación hacia Abajo/efectos de los fármacos , Endotelina-1/metabolismo , Endotelio Vascular/efectos de los fármacos , Factor de Transcripción Activador 3/agonistas , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Células Cultivadas , Endotelina-1/genética , Endotelio Vascular/metabolismo , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Guanilil Ciclasa SolubleRESUMEN
Tanshinone IIA extracted from danshen, a popular medicinal herb used in traditional Chinese medicine, exhibits cardio-protective effects. However, the mechanism of its cardioprotective effect is not well established. The aims of this study were to examine whether tanshinone IIA may alter angiotensin II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Cultured rat cardiac fibroblasts were pre-treated with tanshinone IIA and stimulated with Ang II, cell proliferation and endothelin-1 (ET-1) expression were examined. The effect of tanshinone IIA on Ang II-induced reactive oxygen species (ROS) formation, and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effect of tanshinone IIA on nitric oxide (NO) production, and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. The increased cell proliferation and ET-1 expression by Ang II (100 nM) were partially inhibited by tanshinone IIA. Tanshinone IIA also inhibited Ang II-increased ROS formation, and ERK phosphorylation. In addition, tanshinone IIA was found to increase the NO generation, and eNOS phosphorylation. N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of tanshinone IIA on Ang II-induced cell proliferation. The results suggest that tanshinone IIA prevents cardiac fibroblast proliferation by interfering with the generation of ROS and involves the activation of the eNOS-NO pathway.
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Abietanos/farmacología , Angiotensina II/antagonistas & inhibidores , Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Miocardio/citología , Miofibroblastos/efectos de los fármacos , Angiotensina II/metabolismo , Animales , Células Cultivadas , Medicamentos Herbarios Chinos/química , Endotelina-1/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Corazón/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Salvia miltiorrhiza/química , Transducción de Señal/efectos de los fármacos , TransfecciónRESUMEN
AIM: to examine the effects of tanshinone IIA, the main effective component of Salvia miltiorrhiza (known as 'Danshen' in traditional Chinese medicine) on angiotensin II (Ang II)-mediated cardiomyocyte apoptosis. METHODS: rat neonatal cardiomyocytes were primarily cultured with Ang II or Ang II plus tanshinone IIA. Myocyte apoptosis was evaluated by caspase-3 activity and DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL) staining. Western blot analysis was employed to determine the related protein expression and flow cytometry assay was used to determine the TUNEL positive cells and the intracellular reactive oxygen species (ROS) production. SiRNA targeted to Akt was used. RESULTS: ang II (0.1 micromol/L) remarkably increased caspase-3 activity, TUNEL positive cells, and cleaved caspase-3 and cytochrome c expression, but reduced Bcl-X(L) expression. These effects were effectively antagonized by pretreatment with tanshione IIA (1-3 micromol/L). Tanshinone IIA had no effect on basal ROS level, while attenuated the ROS production by Ang II. Interestingly, tanshione IIA significantly increased the phosphorylated Akt level, which was countered by the PI3K antagonist wortmannin or LY294002. Knockdown of Akt with Akt siRNA significantly reduced Akt protein levels and tanshinone IIA protective effect. CONCLUSION: tanshinone IIA prevents Ang II-induced apoptosis, thereby suggesting that tanshinone IIA may be used for the prevention of the cardiac remodeling process.
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Angiotensina II/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Abietanos , Animales , Animales Recién Nacidos , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocromos c/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Salvia miltiorrhizaRESUMEN
The heart is unable to synthesize L-carnitine and is strictly dependent on the L-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of L-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of L-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with L-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by L-carnitine. L-carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, L-carnitine increased prostacyclin (PGI(2)) generation in cardiac fibroblasts. siRNA transfection of PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI(2) receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR alpha) and delta, revealed that siRNA-mediated blockage of PPAR alpha considerably reduced the anti-proliferation effect of L-carnitine. In summary, these results suggest that L-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI(2) and PPAR alpha-signaling pathways.
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Angiotensina II/fisiología , Carnitina/farmacología , Corazón/efectos de los fármacos , Lisofosfolípidos/metabolismo , Miocardio/citología , NADPH Oxidasas/antagonistas & inhibidores , Esfingosina/análogos & derivados , Animales , Animales Recién Nacidos , Cardiotónicos/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Endotelina-1/genética , Endotelina-1/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Miocardio/metabolismo , NADPH Oxidasas/metabolismo , Concentración Osmolar , Fosforilación/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Esfingosina/metabolismo , Factor de Transcripción AP-1/metabolismoRESUMEN
1. Chuanxiong is a Chinese herb that has been used widely in China to treat vascular disorders. 2,3,5,6-Tetramethylpyrazine (TMP) is one of the major components purified from chuanxiong. Many studies have demonstrated that TMP is effective in the treatment of cardiovascular diseases. However, the mechanism of action by which TMP exerts relaxation in vascular vessels remains unclear. 2. Endothelin (ET)-1 is a potent vasopressor synthesised by endothelial cells both in culture and in vivo. The aims of the present study were to test the hypothesis that TMP may alter strain-induced ET-1 secretion and to identify the putative underlying signalling pathways in endothelial cells. 3. We showed that TMP inhibits strain-induced ET-1 secretion. 2,3,5,6-Tetramethylpyrazine also inhibits the strain-induced formation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. Furthermore, pretreating cells with TMP or the anti-oxidant N-acetyl-cysteine decreased strain-induced increases in ET-1 secretion and ERK1/2 phosphorylation. Using a reporter gene assay, TMP and N-acetyl-cysteine were demonstrated to also attenuate the strain-induced activity of the activator protein-1 reporter. 4. In summary, we have demonstrated, for the first time, that TMP inhibits strain-induced ET-1 gene expression, in part by interfering with the ERK1/2 pathway via attenuation of ROS formation. Thus, the present study provides important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the vascular system.
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Endotelina-1/metabolismo , Pirazinas/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Ligusticum , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Pirazinas/química , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción AP-1/metabolismoRESUMEN
Isosteviol is a derivative of stevioside, a constituent of Stevia rebaudiana, and is commonly used as a non-caloric sugar substitute in Japan and Brazil. The present study attempted to elucidate the role of potassium (K (+)) channels in the action of isosteviol on intracellular calcium concentrations ([Ca (2+)]i) in cultured vascular smooth muscle (A7r5) cells using the Ca (2+)-sensitive dye Fura-2 as an indicator. The increase of [Ca (2+)]i in A7r5 cells produced by vasopressin (1 micromol/L) or phenylephrine (1 micromol/L) was attenuated by isosteviol from 0.01 micromol/L to 10 micromol/L. The attenuation by isosteviol of the vasopressin- and phenylephrine-induced increase in [Ca (2+)]i was inhibited by glibenclamide, apamin and 4-aminopyridine but not by charybdotoxin. Furthermore, the inhibitory action of isosteviol on [Ca (2+)]i was blocked when A7r5 cells co-treated with glibenclamide and apamin in conjunction with 4-aminopyridine were present. Therefore, not only did the ATP-sensitive potassium (K (ATP)) channel affect the action of isosteviol on [Ca (2+)]i modulation in A7r5 cells, but also those on the small conductance calcium-activated potassium (SK (Ca)) channels and voltage-gated (Kv) channels. However, the blockers of large-conductance Ca (2+)-activated potassium channels failed to modify the inhibitory action of isosteviol on [Ca (2+)]i. The obtained results indicated that a decrease of [Ca (2+)]i in A7r5 cells by isosteviol is mainly mediated by the selective opening of K (ATP) channel or/and SK (Ca) channel. Alteration in the Kv channel also plays a critical role in the inhibitory action of isosteviol.
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Calcio/metabolismo , Diterpenos de Tipo Kaurano , Diterpenos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Fitoterapia , Canales de Potasio Calcio-Activados/efectos de los fármacos , Stevia , Animales , Aorta/efectos de los fármacos , Línea Celular , Diterpenos/administración & dosificación , Diterpenos/uso terapéutico , Relación Dosis-Respuesta a Droga , Músculo Liso Vascular/metabolismo , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Canales de Potasio Calcio-Activados/fisiología , RatasRESUMEN
BACKGROUND: Stevioside, a natural glycoside isolated from the plant Stevia rebaudiana Bertoni, has been used as a commercial sweetening agent in Japan and Brazil for >20 years. Previous animal and human studies have indicated that stevioside has an antihypertensive effect. OBJECTIVES: This study was undertaken to investigate the long-term (2-year) efficacy and tolerability of stevioside in patients with mild essential hypertension. Secondary objectives were to determine the effects of stevioside on left ventricular mass index (LVMI) and quality of life (QOL). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial in Chinese men and women aged between 20 and 75 years with mild essential hypertension (systolic blood pressure [SBP] 140-159 mm Hg and diastolic blood pressure [DBP] 90-99 mm Hg). Patients took capsules containing 500 mg stevioside powder or placebo 3 times daily for 2 years. Blood pressure was measured at monthly clinic visits; patients were also encouraged to monitor blood pressure at home using an automated device. LVMI was determined by 2-dimensional echocardiography at baseline and after 1 and 2 years of treatment. QOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey. Electrocardiographic, laboratory, and QOL parameters were assessed at the beginning of treatment, and at 6 months, 1 year, and 2 years. RESULTS: One hundred seventy-four patients (87 men, 87 women) were enrolled in the study, and 168 completed it: 82 (42 men, 40 women; mean [SD] age, 52 [7] years) in the stevioside group and 86 (44 women, 42 men; mean age, 53 [7] years) in the placebo group. After 2 years, the stevioside group had significant decreases in mean (SD) SBP and DBP compared with baseline (SBP, from 150 [7.3] to 140 [6.8] mm Hg; DBP, from 95 [4.2] to 89 [3.2] mm Hg; P < 0.05) and compared with placebo (P < 0.05). Based on patients' records of self-monitored blood pressure, these effects were noted beginning approximately 1 week after the start of treatment and persisted throughout the study. There were no significant changes in body mass index or blood biochemistry, and the results of laboratory tests were similar in the 2 groups throughout the study. No significant difference in the incidence of adverse effects was noted between groups, and QOL scores were significantly improved overall with stevioside compared with placebo (P < 0.001). Neither group had a significant change in mean LVMI. However, after 2 years, 6 of 52 patients (11.5%) in the stevioside group had left ventricular hypertrophy (LVH), compared with 17 of 50 patients (34.0%) in the placebo group (P < 0.001). Of those who did not have LVH at baseline, 3 of 46 patients (6.5%) in the stevioside group had developed LVH after 2 years, compared with 9 of 37 patients (24.3%) in the placebo group (P < 0.001). CONCLUSIONS: In this 2-year study in Chinese patients with mild hypertension, oral stevioside significantly decreased SBP and DBP compared with placebo. QOL was improved, and no significant adverse effects were noted.
Asunto(s)
Antihipertensivos/uso terapéutico , Diterpenos de Tipo Kaurano , Diterpenos/uso terapéutico , Glucósidos/uso terapéutico , Hipertensión/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antihipertensivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Diterpenos/efectos adversos , Método Doble Ciego , Femenino , Glucósidos/efectos adversos , Humanos , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Masculino , Persona de Mediana Edad , Calidad de VidaRESUMEN
OBJECTIVES: To evaluate the effects on blood pressure, lipid profile, and anxiety status on subjects received a 12-week Tai Chi Chuan exercise program. DESIGN: Randomized controlled study of a Tai Chi Chuan group and a group of sedentary life controls. SETTING: Taipei Medical University Hospitals and University campus in the Taipei, Taiwan, area. SUBJECTS: Two (2) selected groups of 76 healthy subjects with blood pressure at high-normal or stage I hypertension. INTERVENTION: A 12-week Tai Chi Chuan exercise training program was practiced regularly with a frequency of 3 times per week. Each session included 10-minute warm-up, 30-minute Tai Chi exercise, 10-minute cool-down. Exercise intensity was estimated to be approximately 64% of maximal heart rate. OUTCOME MEASURES: Blood pressure, lipid profile and anxiety status (State-Trait Anxiety Inventory; STAI) were evaluated. RESULTS: After 12-weeks of Tai Chi training, the treatment group showed significant decrease in systolic blood pressure of 15.6 mm Hg and diastolic blood pressure 8.8 mm Hg. The serum total cholesterol level decreased 15.2 mg/dL and high-density lipoprotein cholesterol increased 4.7 mg/dL. By using STAI evaluation, both trait anxiety and state anxiety were decreased. CONCLUSIONS: This study shows that under well-designed conditions, Tai Chi exercise training could decrease blood pressure and results in favorable lipid profile changes and improve subjects' anxiety status. Therefore, Tai Chi could be used as an alternative modality in treating patients with mild hypertension, with a promising economic effect.
Asunto(s)
Ansiedad/terapia , Presión Sanguínea , Colesterol/sangre , Hipertensión/terapia , Taichi Chuan , Triglicéridos/sangre , Adulto , Ansiedad/prevención & control , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Frecuencia Cardíaca , Humanos , Hipertensión/prevención & control , Masculino , Persona de Mediana Edad , Taiwán , Factores de Tiempo , Resultado del TratamientoRESUMEN
The tannins are natural polyphenols, able to precipitate water-soluble alkaloids and possess an inhibitory action on the angiotensin converting enzyme (ACE). We identified 18 polyphenolic compounds (tannins) from Chinese herbs and examined the in vitro effects of these tannins on ACE activity, including determination of the 50% inhibitory concentrations (IC50), specificity and mode of inhibition. We also assessed the in vivo inhibitory effect of the tannins on angiotensin I-induced blood pressure elevation in spontaneously hypertensive rats (SHR). Nine tannins with an IC50 <200 microM for ACE inhibitors were identified belonging to three tannin classes: caffeoylquinates, flavan-3-ols and gallotannins. In vitro, we found caffeoylquinates chelate the ACE zinc cofactor. Two of the flavan-3-ols: epigallocatechin-3-O-gallate and epigallocatechin-3-O-methylgallate, and one of gallotannin: 1, 2, 3, 4, 6-penta-O-galloyl-beta-D-glucose were non-specific inhibitors because also reduced the activity of trypsin and chymotrypsin. The ACE inhibition of 1, 2, 3, 4, 6-penta-O-galloyl-beta-D-glucose was also reduced after addition of bovine serum albumin, suggesting a non-specific mode of action. In vivo, 1,2,3,6-tetra-O-galloyl-beta-D-glucose and epigallocatechin-3-O-methylgallate had a strong dose-dependent hypotensive effect reducing the blood pressure significantly in the SHR with infusion of the angiotensin I. These findings indicate that some of the tannins isolated from herbs inhibit ACE activity non-specifically. The ACE inhibitory effect of these tannins may explain the hypotensive effects of some traditional Chinese herbs.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Medicamentos Herbarios Chinos/química , Hipertensión/tratamiento farmacológico , Peptidil-Dipeptidasa A/metabolismo , Taninos/farmacología , Angiotensina I/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Animales , Antihipertensivos/aislamiento & purificación , Cloruros/farmacología , Quimotripsina/metabolismo , Relación Dosis-Respuesta a Droga , Concentración 50 Inhibidora , Medicina Tradicional China , Antisépticos Bucales/farmacología , Ratas , Ratas Endogámicas SHR , Especificidad por Sustrato , Taninos/aislamiento & purificación , Tripsina/metabolismo , Compuestos de Zinc/farmacologíaRESUMEN
Reactive oxygen species have been linked with neuropathological changes in the central nervous system. Epidemiological studies supported the beneficial effect of supplementation of antioxidants. Superoxide dismutase (SOD) is an endogenous enzyme which can scavenge reactive oxygen species. This study investigated the effect of supplementation with ascorbic acid (vitamin C) on the changes of SOD in cultured neurological cells. Rat brain astrocytes (RBA-1 cells) were incubated with vitamin C and divided into four groups: a control group (without vitamin C) and three treatment groups with vitamin C at 40, 80, and 160 micromol/l. After short-term (2 days) and long-term (7 days) incubation, SOD activity, SOD mRNA level by Northern blotting, and SOD protein amounts by Western blotting were measured. After 2 days of incubation, vitamin C resulted in a decrease in the activity of SOD in a concentration-dependent manner (Mn-SOD from 14.8 +/- 1.2 to 13.2 +/- 0.5 U/mg protein and Cu/Zn-SOD from 64.8 +/- 1.2 to 51.7 +/- 0.9 U/mg protein; p < 0.05), and vitamin C also attenuated the Cu/Zn-SOD mRNA level from 100 to 86.3 +/- 6.7%; p < 0.01), whereas the protein amounts of these two SODs remained unchanged. After 7 days of incubation with vitamin C, the SOD activity of RBA-1 cells decreased significantly (Mn-SOD from 14.9 +/- 0.3 to 11.8 +/- 0.3 U/mg protein and Cu/Zn SOD from 61.8 +/- 1.8 to 54.6 +/- 0.9 U/mg protein; p < 0.01), and the mRNA level was also attenuated (Mn-SOD from 100 to 86.8 +/- 8.7% and Cu/Zn-SOD from 100 to 84.7 +/- 4.8%; p < 0.01). These results suggest that 2 and 7 days of incubation with relatively high concentrations of vitamin C may downregulate activity and gene expression of SOD in cultured RBA-1 cells.
Asunto(s)
Ácido Ascórbico/farmacología , Astrocitos/efectos de los fármacos , Superóxido Dismutasa/genética , Animales , Células Cultivadas , Medios de Cultivo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Expresión Génica , Técnicas In Vitro , Ratas , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/fisiología , Factores de TiempoRESUMEN
Cardiovascular disease is still the leading cause of death in Western countries. Epidemiological studies have shown that hypercholesterolemia is a major risk factor for coronary artery disease. Clinical trials of lipid lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor have been shown to decrease coronary events and mortality. Flavonoids are polyphenolic natural antioxidants occurring in natural products such as traditional Chinese herbs, fruits and beverages such as tea and wine. The aim of this study was to evaluate the effects of crude extracts from traditional Chinese herbs on HMG Co-A reductase. The methods for analysis of specific inhibitors of mevalonate biosynthesis have been well-established by using Vero cells, a cell line obtained from kidneys of African green monkeys. Crude extracts from different traditional Chinese herbs were dissolved in 1% Dulbecco's modified Eagle's medium and incubated with Vero cells with or without the addition of 1 mM mevalonate or 5 mM sodium acetate for 24 hours in order to observe cell growth. Pravastatin, a specific HMG Co-A reductase inhibitor, was used as a positive control which inhibits Vero cells growth effectively and cell growth inhibition was reversible after 1 mM mevalonate. Among 100 traditional Chinese herbs used for the study, only two herbs: Curcuma zedoaria Roscoe and Poncirus trifoliata Raf. showed significant growth inhibition of Vero cells. This study shows that some crude extracts isolated from traditional medicinal herbs were effective HMG Co-A reductase inhibitors which might be developed into new hypocholesterolemic agents.