RESUMEN
Radix aconiti carmichaeli is a widely used traditional Chinese medicine that has been found to be effective in treating cardiovascular diseases and metabolic disorders. Patients with these diseases often experience a heat generation disorder, which is characterized by chilliness and can worsen the progression of the disease. This study established an in vitro screening model combining the examination of cellular mitochondrial membrane potential and mitochondrial temperature to screen drugs with thermogenic activity. After differentiation and determination of the content of characteristic metabolites of the drug-containing serum blood components, it was found that Fuziline (FZL) is the key thermogenic property in Radix aconiti carmichaeli, responsible for its thermogenic effects with a high relative importance of 33%. Experiments were conducted to evaluate the thermogenic activity of Radix aconiti carmichaeli and FZL in vivo by assessing temperature changes in various organs, including the rectum, liver, and brown adipose tissue. Moreover, the effects of intracellular ß3-adrenergic receptor (ß3-AR) agonistic effects were evaluated using transient ß3-AR transfection and dual-luciferase assay systems. The molecular mechanism by which FZL promotes thermogenesis and improves mitochondrial function was investigated by verifying the ß-adrenergic receptors (ß-AR) downstream signaling pathway. The results suggest that FZL activates ß-AR nonselectively, which in turn activates the downstream cAMP-PKA signaling pathway and leads to an increase in liver glycogenolysis and triglyceride hydrolysis, accompanied by enhancing mitochondrial energy metabolism. Consequently, the liver and brown adipose tissue receive energy to generate heat. In summary, these findings provide insight into the therapeutic application of Radix aconiti carmichaeli for metabolic disorders associated with heat generation disorders.
Asunto(s)
Metabolismo de los Lípidos , Receptores Adrenérgicos beta , Humanos , Receptores Adrenérgicos beta/metabolismo , Glucosa/metabolismo , Tejido Adiposo Pardo/metabolismo , Termogénesis , Receptores Adrenérgicos beta 3/metabolismo , Metabolismo EnergéticoRESUMEN
Yogurt has been widely used in weight-loss foods to prevent obesity, but its molecular nature remains unclear. Lactate is a major ingredient of yogurt, while its cognate cell surface receptor GPR81 is highly expressed in adipose tissues in mammals. Here we hypothesized that dietary lactate supplementation might activate GPR81 to promote adipose browning. Studying mouse models, we observed that GPR81 was substantially lowered in adipose tissue of obese mice compared with that for lean ones, whereas its expression was markedly up-regulated by a ß3-adrenergic receptor (ß3-AR) agonist. The deficiency of GPR81 greatly attenuated experimental adipose browning and thermogenesis. Importantly, oral administration of lactate effectively induced adipose browning, enhanced thermogenesis, improved dyslipidemia, and protected mice against high-fat-diet-induced obesity. Mechanistically, p38 mitogen-activated protein kinase might serve as a key downstream effect or of GPR81. Collectively, our findings revealed a critical role of GPR81 in adipose browning and provided a new insight into obesity management by modulating lactate-GPR81 signaling axis.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Suplementos Dietéticos/análisis , Obesidad/tratamiento farmacológico , Sustancias Protectoras/administración & dosificación , Tejido Adiposo Pardo/efectos de los fármacos , Animales , Metabolismo Energético/efectos de los fármacos , Humanos , Ácido Láctico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/genética , Obesidad/metabolismo , Obesidad/fisiopatología , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Brown adipose tissue is a critical regulator of metabolic health, and contributes to thermogenesis by uncoupling oxidative phosphorylation through the action of mitochondrial uncoupling protein 1 (Ucp1). Recent studies have shown that cold exposure and the stimulation of ß3-adrenergic receptors induce the development of brown cell-like "beige" adipocytes in white adipose tissue. Brown and/or beige adipocyte-mediated thermogenesis suppresses high-fat diet-associated obesity. Therefore, the development of brown/beige adipocytes may prevent obesity and metabolic diseases. In the present study, we elucidated whether naturally occurring compounds contribute to regulating the cellular differentiation of brown/beige adipocytes. We screened for the up-regulated expression of Ucp1 during beige adipogenesis using extracts of crude herbal drugs frequently used in Kampo prescriptions (therapeutic drugs in Japanese traditional medicine). This screening revealed that the extract prepared from Citri Unshiu Pericarpium [the peel of Citrus unshiu (Swingle) Marcov.] increased the expression of Ucp1 in beige adipocytes. We also focused on the function of clock genes in regulating brown/beige adipogenesis. Therefore, another aim of the present study was to evaluate naturally occurring compounds that regulate brain and muscle Arnt-like 1 (Bmal1) gene expression. In this review, we focus on naturally occurring compounds that affect regulatory processes in brown/beige adipogenesis, and discuss better preventive strategies for the management of obesity and other metabolic disorders.
Asunto(s)
Factores de Transcripción ARNTL , Adipocitos Beige/fisiología , Adipocitos Marrones/fisiología , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Diferenciación Celular , Medicamentos Herbarios Chinos/farmacología , Proteína Desacopladora 1 , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/fisiología , Animales , Relojes Biológicos/genética , Frío , Dieta Alta en Grasa/efectos adversos , Expresión Génica , Humanos , Medicina Kampo , Enfermedades Metabólicas/prevención & control , Obesidad/etiología , Obesidad/prevención & control , Fosforilación Oxidativa , Receptores Adrenérgicos beta 3/metabolismo , Termogénesis , Proteína Desacopladora 1/metabolismoRESUMEN
Aged black garlic (ABG) is a functional food with antioxidant and anti-inflammatory properties. Recent studies also report its beneficial metabolic effects in a context of obesity or diabetes, although the mechanisms involved are poorly understood. The aim of this work was to analyze the effects of an ABG extract in the vascular and metabolic alterations induced by a high-fat/sucrose diet in rats. For this purpose, male Spragueâ»Dawley rats were fed either a standard chow (controls; n = 12) or a high-fat/sucrose diet (HFD; n = 24) for 16 weeks. From week 8 on, half of the HFD rats were treated with a commercial ABG extract concentrated in S-allyl cysteine and melanoidins (ABG10+®; 250 mg/kg daily by gavage; 5 mL/kg). ABG10+®-treated rats showed lower mean caloric intake, body weight, triglycerides, low density lipoprotein cholesterol (LDL-c), insulin and leptin serum concentrations and higher high density lipoprotein cholesterol (HDL-c) and adiponectin serum concentrations than non-treated rats. In the hypothalamus, ABG10+® treatment induced an increase in the gene expression of proopiomelanocortin (POMC) and a decrease in leptin receptor (ObR) mRNA levels. No significant changes were found in visceral adipose tissue except for an overexpression of ß3-adrenergic receptor (ß3-ADR) in ABG-treated rats. In subcutaneous adipose tissue, ABG10+® treatment decreased adipose weight and downregulated the gene expression of PPAR-γ, LPL, ObR and HSL. In brown adipose tissue, an overexpression of InsR, GLUT-4, UCP-1 and ß3-ADR in ABG10+®-treated rats was found, whereas PPAR-γ mRNA levels were significantly decreased. Regarding vascular function, ABG10+® treatment attenuated the obesity-induced vasoconstriction in response to potassium chloride both in presence/absence of perivascular adipose tissue (PVAT). On the contrary, aorta segments from ABG-treated rats showed and improved relaxation in response to acetylcholine only when PVAT was present, with this fact possible being related to the decreased gene expression of proinflammatory cytokines in this tissue. In conclusion, ABG10+® administration partially improves the metabolic and vascular alterations induced by a high-fat/high-sucrose diet in rats through modifications in the gene expression of proteins and neuropeptides involved in inflammation, fat metabolism and food intake regulation. Further studies are required to assess the bioavailability of ABG between rats and humans.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/administración & dosificación , Ajo/química , Extractos Vegetales/farmacología , Adiponectina/sangre , Adiposidad/efectos de los fármacos , Animales , Antioxidantes/farmacología , Peso Corporal , HDL-Colesterol/sangre , Regulación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hipotálamo/efectos de los fármacos , Insulina/sangre , Leptina/sangre , Masculino , Tamaño de los Órganos/efectos de los fármacos , PPAR gamma/genética , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Triglicéridos/sangre , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
ß-Adrenergic stimulation of adipose tissue increases mitochondrial density and activity (browning) that are associated with improved whole-body metabolism. Whereas chronically elevated levels of reactive oxygen species (ROS) in adipose tissue contribute to insulin resistance, transient ROS elevation stimulates physiological processes such as adipogenesis. Here, using a combination of biochemical and cell and molecular biology-based approaches, we studied whether ROS or antioxidant treatment affects ß3-adrenergic receptor (ß3-AR) stimulation-induced adipose tissue browning. We found that ß3-AR stimulation increases ROS levels in cultured adipocytes, but, unexpectedly, pretreatment with different antioxidants (N-acetylcysteine, vitamin E, or GSH ethyl ester) did not prevent this ROS increase. Using fluorescent probes, we discovered that the antioxidant treatments instead enhanced ß3-AR stimulation-induced mitochondrial ROS production. This pro-oxidant effect of antioxidants was, even in the absence of ß3-AR stimulation, associated with decreased oxygen consumption and increased lactate production in adipocytes. We observed similar antioxidant effects in WT mice: N-acetylcysteine blunted ß3-AR stimulation-induced browning of white adipose tissue and reduced mitochondrial activity in brown adipose tissue even in the absence of ß3-AR stimulation. Furthermore, N-acetylcysteine increased the levels of peroxiredoxin 3 and superoxide dismutase 2 in adipose tissue, indicating increased mitochondrial oxidative stress. We interpret this negative impact of antioxidants on oxygen consumption in vitro and adipose tissue browning in vivo as essential adaptations that prevent a further increase in mitochondrial ROS production. In summary, these results suggest that chronic antioxidant supplementation can produce a paradoxical increase in oxidative stress associated with mitochondrial dysfunction in adipocytes.
Asunto(s)
Acetilcisteína/farmacología , Adipocitos Marrones/metabolismo , Antioxidantes/farmacología , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células 3T3-L1 , Adipocitos Marrones/fisiología , Animales , Ácido Láctico/metabolismo , Masculino , Ratones , Mitocondrias/patología , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
Brown adipose tissue (BAT) is the site of non-shivering thermogenesis in mammals, wherein energy is dissipated as heat. We observed that aqueous extract of black sesame seed triggers an increase in the expression of Uncoupling Protein 1 (UCP1) in brown adipocytes from mice. The active component from the extract was purified and identified to be sesaminol diglucoside (SDG). SDG treatment decreased mass of white fat pads and serum glucose levels and increased UCP1 levels in BAT thereby protecting mice against high fat induced weight gain. Further in silico and in vitro studies revealed that these effects are due to the agonist like behaviour of SDG towards beta 3 adrenergic receptors (ß3-AR). Together, our results suggest that SDG induces BAT mediated thermogenesis through ß3-AR and protects mice against diet-induced obesity.
Asunto(s)
Tejido Adiposo Pardo/fisiología , Dioxoles/farmacología , Furanos/farmacología , Lignanos/farmacología , Semillas/química , Sesamum/química , Termogénesis/efectos de los fármacos , Adipocitos Marrones/efectos de los fármacos , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Animales , Dieta Alta en Grasa , Dioxoles/aislamiento & purificación , Furanos/aislamiento & purificación , Lípidos/química , Ratones Endogámicos C57BL , Extractos Vegetales/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Proteína Desacopladora 1/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein-coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the ß3-adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)-α- and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.
Asunto(s)
Adipocitos/metabolismo , Adiposidad , Metabolismo Energético , Hígado Graso/metabolismo , Obesidad/metabolismo , Proteína Quinasa C/metabolismo , Grasa Subcutánea/metabolismo , Células 3T3-L1 , Adipocitos/patología , Animales , Proteína delta de Unión al Potenciador CCAAT/genética , Proteína delta de Unión al Potenciador CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Hígado Graso/genética , Hígado Graso/patología , Femenino , Humanos , Masculino , Ratones , Ratones Mutantes , Obesidad/genética , Obesidad/patología , Proteína Quinasa C/genética , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Sistemas de Mensajero Secundario/genética , Grasa Subcutánea/fisiologíaRESUMEN
Mirabegron is a ß3-adrenoceptor agonist and released on the marked for the treatment of overactive bladder. Because mirabegron is the only ß3-adrenoceptor agonist available and substances that increase the levels of cyclic adenosine monophosphate (cAMP) inhibit platelet activity, we tested the hypothesis that mirabegron could have antiplatelet activity. Collagen- and thrombin induced platelet aggregation, thromboxane B2 (TXB2) and cyclic nucleotides quantification and calcium (Ca2+) mobilization were determined in the absence and presence of mirabegron in human washed platelets. Our results revealed that mirabegron (10-300⯵M) produced significant inhibitions on platelet aggregation induced by collagen- or thrombin, accompanied by greater intracellular levels of cAMP. The ß3-adrenoceptor antagonist L 748,337 (1⯵M) and the adenylate cyclase inhibitor, SQ 22,536 (100⯵M) reversed the inhibition induced by mirabegron in thrombin-stimulated platelets. The selective antagonists for ß1-and ß2-adrenoceptors, atenolol and ICI 117,551 (3⯵M), respectively did not interfere on the inhibition induced by mirabegron. In Fluo-4 loaded platelets, mirabegron reduced the total and intracellular Ca2+ levels. Pre-incubation with mirabegron almost abolished the levels of TXB2. Mirabegron did not augment the intracellular levels of cyclic guanosine monophosphate. In conclusion, mirabegron inhibited human platelet aggregation through cAMP accumulation, thus suggesting that substances that activate ß3-adrenoceptor could be beneficial as adjuvant antiplatelet therapy.
Asunto(s)
Acetanilidas/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , AMP Cíclico/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Receptores Adrenérgicos beta 3/metabolismo , Tiazoles/farmacología , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Humanos , Tromboxano B2/metabolismoRESUMEN
This study aims (i) to verify expression of the UCPs, PLIN1, PPARG2, and ADRB3 genes in the abdominal subcutaneous adipose tissue of obese women at baseline and after 8 weeks of supplementation with decaffeinated green tea extract, and (ii) to associate findings with clinical parameters. This is a longitudinal study during which 11 women with obesity grade III were submitted to supplementation with 450 mg of (-)-epigallocatechin gallate (EGCG) (intervention group); the control group consisted of 10 eutrophic women. Anthropometric parameters [weight, height, and body mass index (BMI)], resting metabolic rate (RMR, measured by indirect calorimetry), and gene expression (measured by real-time PCR, RT-qPCR) were determined before and after supplementation. After 8 weeks, clinical parameters and UCP1, PLIN1, PPARG2, and ADRB3 expression remained unaltered in the intervention group (p > .05). Genetic analysis also showed that the UCP3 gene was upregulated (p = .026), but its upregulation did not promote weight loss.
Asunto(s)
Tejido Adiposo/metabolismo , Obesidad/terapia , Té/química , Proteína Desacopladora 3/metabolismo , Pérdida de Peso , Adolescente , Adulto , Metabolismo Basal , Índice de Masa Corporal , Catequina/análogos & derivados , Catequina/farmacología , Suplementos Dietéticos , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Obesidad/genética , PPAR gamma/genética , PPAR gamma/metabolismo , Perilipina-1/genética , Perilipina-1/metabolismo , Extractos Vegetales/farmacología , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 3/genética , Regulación hacia Arriba , Adulto JovenRESUMEN
A role for oxidative stress in the brain has been suggested in the pathogenesis of diet-induced obesity (DIO), although the underlying neural regions and mechanisms remain incompletely defined. We tested the hypothesis that NADPH oxidase-dependent oxidative stress in the paraventricular nucleus (PVN), a hypothalamic energy homeostasis center, contributes to the development of DIO. Cre/LoxP technology was coupled with selective PVN adenoviral microinjection to ablate p22phox , the obligatory subunit for NADPH oxidase activity, in mice harboring a conditional p22phox allele. Selective deletion of p22phox in the PVN protected mice from high-fat DIO independent of changes in food intake or locomotor activity. This was accompanied by ß3-adrenoceptor-dependent increases in energy expenditure, elevations in brown adipose tissue thermogenesis, and browning of white adipose tissue. These data reveal a potentially novel role for brain oxidative stress in the development of DIO by modulating ß3-adrenoceptor mechanisms and point to the PVN as an underlying neural site.
Asunto(s)
Grupo Citocromo b/genética , Dieta Alta en Grasa , Metabolismo Energético/genética , NADPH Oxidasas/genética , Obesidad/genética , Estrés Oxidativo , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Termogénesis/genética , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Encéfalo/metabolismo , Grupo Citocromo b/metabolismo , Ingestión de Alimentos , Hipotálamo/metabolismo , Locomoción , Ratones , NADPH Oxidasas/metabolismo , Obesidad/metabolismoRESUMEN
OBJECTIVE: To evaluate whether active immunization producing ß1- or ß3-antibodies (ß1-ABs and ß3-ABs) detected in sera of patients with dilated cardiomyopathies has deleterious effects on vascular reactivity in Lewis rat thoracic aorta (TA) and small mesenteric arteries (SMA). DESIGN AND METHOD: Lewis rats were immunized for 6months with peptidic sequences corresponding to the second extracellular loop of ß1- and ß3-adrenoceptors (ARs). During the immunization, systolic blood pressure (SBP) was monitored using the tail cuff method. The vascular reactivity of immunized rats was assessed by ex vivo studies on SMA and TA using various ß-AR agonists, phenylephrine and KCl. RESULTS: The immunizations producing functional ß1-ABs and ß3-ABs did not affect the SBP. However, in TA from ß1-AR-immunized rats, the relaxations mediated by dobutamine and salbutamol were significantly impaired in comparison with adjuvant rats whereas nebivolol-induced relaxation was not modified. Moreover, phenylephrine and KCl-mediated contractions were enhanced in these rats. In contrast, immunization with ß3-AR peptide led to the increase of relaxations induced by dobutamine in TA but did not change those induced by salbutamol and nebivolol. Surprisingly, in SMA from both rats immunized with ß1- or ß3-peptides, relaxations induced by the various ß-agonists were not changed whereas phenylephrine and KCl-mediated contractions were impaired. CONCLUSIONS: Our study shows that ß1- and ß3-ABs can affect vascular reactivity. ß1-ABs would have a pathogenic action whereas ß3-ABs would have a beneficial effect on aorta reactivity.
Asunto(s)
Autoanticuerpos/inmunología , Receptores Adrenérgicos beta 1/inmunología , Receptores Adrenérgicos beta 3/inmunología , Vacunación/métodos , Agonistas Adrenérgicos beta/farmacología , Animales , Aorta Torácica/inmunología , Aorta Torácica/metabolismo , Masculino , Arterias Mesentéricas/inmunología , Arterias Mesentéricas/metabolismo , Péptidos/administración & dosificación , Péptidos/inmunología , Fenilefrina/farmacología , Cloruro de Potasio/farmacología , Ratas , Ratas Endogámicas Lew , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
The effects of dietary Cinnamomum camphora seed kernel oil (CCSKO) containing medium-chain triacylglycerols on lipid metabolism and mRNA and protein expression of ß-3 adrenergic receptor in adipose tissue were studied in diet-induced obese rats. High fat food-induced obese rats were randomly divided into CCSKO group, Lard group, Soybean oil (SOY) group and naturally restoring group (n = 10). Rats fed with low fat food were used as a normal control group. Significant decreases in body mass and abdominal fat mass/body mass after 12 weeks were found in CCSKO group as compared with Lard and SOY groups (p < 0.05). Levels of blood total cholesterol (TC), triglyceride, free fatty acid, fasting insulin and insulin resistance in the CCSKO group were decreased significantly, and noradrenaline level and insulin sensitivity index in the CCSKO group were significantly higher than other groups. Meanwhile liver TC and triglyceride levels in the CCSKO group were also decreased markedly. Expression levels of ß3-adrenergic receptor mRNA and protein were higher in CCSKO group than in Lard and SOY groups. These results suggest that CCSKO may contribute to reduction of the body fat mass, promote lipid metabolism and up-regulate ß3-adrenergic receptor expression in high fat diet-induced obese rats.
Asunto(s)
Cinnamomum camphora/química , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad/dietoterapia , Aceites de Plantas/administración & dosificación , Receptores Adrenérgicos beta 3/genética , Tejido Adiposo/efectos de los fármacos , Animales , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Masculino , Obesidad/inducido químicamente , Obesidad/genética , Obesidad/metabolismo , Aceites de Plantas/farmacología , Distribución Aleatoria , Ratas , Receptores Adrenérgicos beta 3/metabolismo , Aceite de Soja/administración & dosificación , Aceite de Soja/farmacología , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the effect of Suoquan Wan(SQW) and Jinkui Shenqi Wan(JKSQW) on urethra function and ß6-AR function of detrusor in natural aged rats. METHODS: young rats(3 months) and Aged rats(15 months) were chosen. Young rats were chosen as control, aged rats were randomly divided into three groups: model, JKSQW and SQW groups, 12 rats in each group. JKSQW and SQW were given the appropriate concentration once a day for six weeks. The effects of SQW and JKSQW on relaxation function of bladder detrusor was investigated, and their effects on bladder induced by ß3-AR agonist and ß3-AR agonist were further studied. Then, their effects on pressure of urethra were observed. RESULTS: Compared with the young group, detrusor compliance of natural aged model rats was increased, Emax and IA of agonist of ß3-AR including BRL37344 and ISO were decreased(P <0. 01), while PA2 of antagonist of ß3-AR were increased(P <0. 05). Compared with model group, SQW and JKSQW decreased the bladder compliance(P <0. 05), and increased Emax, IA and PD2 due to sensitivity of detrusor to agonist of ß3-AR and ß3-AR including BRL37344 and ISO(P <0. 05 or P < 0. 01) ,while decreased PA2 of antagonist of ß3-AR(P <0. 05). MUCP, MUP and FUL of aged rats were lower than those of normal rats. But SQW and JKSQW increased MUCP and MUP, and JKSQW increased FUL of aged rats(P <0. 05 or P <0. 01). CONCLUSION: SQW and JKSQW can remarkably adjust ß3-AR function on the detrusor and improve the closure ability of bladder detrusor of the natural aged rats.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Músculo Liso/efectos de los fármacos , Receptores Adrenérgicos beta 3/metabolismo , Uretra/efectos de los fármacos , Animales , Masculino , Ratas , Vejiga Urinaria/efectos de los fármacosRESUMEN
Matrine, an alkaloid isolated from the traditional Chinese medicine Sophora flavescens AIT has exhibited a number of therapeutic effects on cardiovascular and liver diseases. The purpose of the present study was to investigate whether matrine has a protective effect on heart failure in rats. Coronary artery ligation was used to induce a heart failure (CHF) model in rats. Four weeks following the procedure, the rats were treated with different doses of matrine for one month. Histopathological examination demonstrated that matrine treatment alleviated myocardial hypertrophy and cardiac fibrosis in failing hearts. Furthermore, matrine administration also inhibited the increase of plasma aspartate amino transferase, creatine phosphokinase and lactate dehydrogenase levels in CHF rats. The rats with heart failure exhibited a significant reduction in ejection fraction and fractional shortening, as well as an increase in the left ventricular end systolic dimension, and matrine attenuated this decline in heart function. Further investigation demonstrated that matrine treatment also inhibited the upregulation of Bax and increase in the Bcl2 expression in the failing hearts. Furthermore, the upregulation of ß3-adrenoreceptor (AR) and endothelial nitric oxide synthase proteins following heart failure were also attenuated by matrine. In conclusion, matrine had a preventive role in heart failure in rats at least in part by inhibiting myocardial apoptosis and the ß3-AR pathway.
Asunto(s)
Alcaloides/farmacología , Apoptosis/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo III/metabolismo , Quinolizinas/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Creatina Quinasa/metabolismo , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Miocardio/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo , MatrinasRESUMEN
Pancreatic islet blood perfusion varies according to the needs for insulin secretion. We examined the effects of blood lipids on pancreatic islet blood flow in anesthetized rats. Acute administration of Intralipid to anesthetized rats increased both triglycerides and free fatty acids, associated with a simultaneous increase in total pancreatic and islet blood flow. A preceding abdominal vagotomy markedly potentiated this and led acutely to a 10-fold increase in islet blood flow associated with a similar increase in serum insulin concentrations. The islet blood flow and serum insulin response could be largely prevented by pretreatment with propranolol and the selective ß3-adrenergic inhibitor SR-59230A. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester prevented the blood flow increase but was less effective in reducing serum insulin. Increased islet blood flow after Intralipid administration was also seen in islet and whole pancreas transplanted rats, i.e., models with different degrees of chronic islet denervation, but the effect was not as pronounced. In isolated vascularly perfused single islets Intralipid dilated islet arterioles, but this was not affected by SR-59230A. Both the sympathetic and parasympathetic nervous system are important for the coordination of islet blood flow and insulin release during hyperlipidemia, with a previously unknown role for ß3-adrenoceptors.
Asunto(s)
Hiperlipidemias/fisiopatología , Insulina/metabolismo , Islotes Pancreáticos/irrigación sanguínea , Receptores Adrenérgicos beta 3/metabolismo , Flujo Sanguíneo Regional , Regulación hacia Arriba , Nervio Vago/fisiopatología , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Emulsiones/efectos adversos , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Hiperlipidemias/sangre , Hiperlipidemias/etiología , Hiperlipidemias/metabolismo , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/inervación , Islotes Pancreáticos/metabolismo , Masculino , Ratones Endogámicos C57BL , Páncreas/irrigación sanguínea , Páncreas/efectos de los fármacos , Páncreas/inervación , Páncreas/metabolismo , Perfusión , Fosfolípidos/efectos adversos , Propanolaminas/farmacología , Ratas Endogámicas WF , Receptores Adrenérgicos beta 3/química , Flujo Sanguíneo Regional/efectos de los fármacos , Aceite de Soja/efectos adversos , Triglicéridos/sangre , Triglicéridos/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Vagotomía Troncal , Nervio Vago/efectos de los fármacos , Nervio Vago/cirugíaRESUMEN
The beta-3 adrenoceptor (ß3-AR) protects against the progression of atherosclerosis. However, the specific mechanism of this antiatherosclerotic effect is still not clear. Thus, the aim of this study was to understand the antiatherosclerotic effects of ß3-AR. Thirty-six male homozygous apolipoprotein E-deficient mice and wild-type C57BL/6J mice were randomized into 6 treatment groups: wild-type, atherosclerotic model, atorvastatin, low-dose ß3-AR agonist, high-dose ß3-AR agonist, and ß3-AR antagonist groups. The serum lipids, aortic-free cholesterol (FC), and cholesteryl ester (CE) concentrations were measured at the end of the treatments. The mRNA expression levels of liver apolipoprotein A-I (apoA-I), peroxisome proliferator-activated receptor-α (PPARα), and peroxisome proliferator-activated receptor-γ (PPARγ) were detected by quantitative real-time PCR. Protein expression levels of apoA1, PPARα, and PPARγ in the liver were determined by western blot analysis. Treatment with ß3-AR significantly increased the plasma levels of high-density lipoprotein cholesterol and apoA-I, whereas the levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol decreased. The ß3-AR agonist treatment markedly decreased both the FC and the CE concentrations in the aorta compared with the atherosclerotic model mice. The ß3-AR agonist increased the mRNA and protein expression levels of apoA-I, PPARα, and PPARγ in the liver. This study demonstrates that long-term ß3-AR activation can regulate lipid metabolic disorders and reduces the aortic FC and the CE concentrations. These effects may be related to apoA-I, PPARα, and PPARγ.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3/farmacología , Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Receptores Adrenérgicos beta 3/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Aterosclerosis/patología , Atorvastatina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Pirroles/farmacología , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
OBJECTIVE: To review the place in therapy of mirabegron, a new oral ß3-adrenergic receptor agonist, for the treatment of overactive bladder (OAB). DATA SOURCES: A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-April 2013) was conducted using the key words mirabegron, receptor, adrenergic, beta-3; adrenergic beta-3 receptor; beta-3 receptor, and overactive bladder; urinary bladder; overactive. All published articles regarding mirabegron were included. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. STUDY SELECTION AND DATA EXTRACTION: Available English-language data from reviews, abstracts, presentations, and clinical trials of mirabegron in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: Mirabegron is the newest option for treatment of OAB with symptoms of urge incontinence. As a ß3-receptor agonist, it reduces bladder muscle contractions. In two 12-week, randomized, double-blind, placebo-controlled Phase 3 studies, mirabegron significantly reduced the number of incontinence episodes per 24 hours from baseline (-1.47, -1.63, and -1.13; p < 0.05; and -1.57, -1.46, and -1.17; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). Micturitions per 24 hours were also reduced from baseline (-1.66, -1.75, and -1.05; p < 0.05; and -1.93, -1.77, and -1.34; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). A 12-month trial found mirabegron to have a safety and efficacy profile similar to that of tolterodine. CONCLUSIONS: Treatment of OAB initially includes lifestyle and nonpharmacologic intervention; for patients with persistent symptoms despite these treatments, drug therapy represents a next-step approach for symptom control. Mirabegron alleviates symptoms of OAB while having a mechanism of action that provides an alternative for patients who are intolerant of or who have contraindications to anticholinergic agents. The place in therapy of mirabegron relative to anticholinergics in the treatment of urge incontinence has not yet been established.
Asunto(s)
Acetanilidas/administración & dosificación , Agonistas Adrenérgicos/administración & dosificación , Receptores Adrenérgicos beta 3 , Tiazoles/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Acetanilidas/farmacocinética , Administración Oral , Agonistas Adrenérgicos/farmacocinética , Animales , Ensayos Clínicos como Asunto/métodos , Humanos , Receptores Adrenérgicos beta 3/metabolismo , Tiazoles/farmacocinética , Resultado del Tratamiento , Vejiga Urinaria Hiperactiva/diagnóstico , Vejiga Urinaria Hiperactiva/metabolismoRESUMEN
In the search for potent and selective human ß3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human ß3-, ß2-, and ß1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the ß3-AR with functional selectivity over the ß1- and ß2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.
Asunto(s)
Acetamidas/química , Agonistas de Receptores Adrenérgicos beta 3/síntesis química , Hipoglucemiantes/síntesis química , Fenoxipropanolaminas/química , Receptores Adrenérgicos beta 3/química , Administración Oral , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Masculino , Ratones , Obesidad/tratamiento farmacológico , Receptores Adrenérgicos beta 1/química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
1. Human cytochrome P450 (CYP) enzymes and esterases involved in the metabolism of mirabegron, a potent and selective human ß(3)-adrenoceptor agonist intended for the treatment of overactive bladder, were identified in in vitro studies. 2. Incubations of mirabegron with recombinant human CYP enzymes showed significant metabolism of mirabegron by CYP2D6 and CYP3A4 only. Correlation analyses showed a significant correlation between mirabegron metabolism and testosterone 6ß-hydroxylation (CYP3A4/5 marker activity). In inhibition studies using antiserum against CYP3A4, a strong inhibition (at maximum 80% inhibition) of the metabolism of mirabegron was observed, whereas the inhibitory effects of monoclonal antibodies against CYP2D6 were small (at maximum 10% inhibition). These findings suggest that CYP3A4 is the primary CYP enzyme responsible for in vitro oxidative metabolism of mirabegron, with a minor role of CYP2D6. 3. Mirabegron hydrolysis was catalyzed in human blood, plasma and butyrylcholinesterase (BChE) solution, but not in human liver microsomes, intestinal microsomes, liver S9, intestinal S9 and recombinant acetylcholinesterase solution. K(m) values of mirabegron hydrolysis in human blood, plasma and BChE solution were all similar (13.4-15.2 µM). The inhibition profiles in human blood and plasma were also similar to those in BChE solution, suggesting that mirabegron hydrolysis is catalyzed by BChE.
Asunto(s)
Acetanilidas/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Esterasas/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Tiazoles/metabolismo , Acetanilidas/sangre , Acetanilidas/química , Acetilcolinesterasa/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/sangre , Agonistas de Receptores Adrenérgicos beta 3/química , Anticuerpos Monoclonales/farmacología , Butirilcolinesterasa/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , ADN Complementario/genética , Esterasas/antagonistas & inhibidores , Femenino , Humanos , Hidrólisis/efectos de los fármacos , Sueros Inmunes/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Cinética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Oxigenasas/metabolismo , Proteínas Recombinantes/metabolismo , Soluciones , Tiazoles/sangre , Tiazoles/químicaRESUMEN
OBJECTIVE: To investigate the antiobesity effect of Jueming Prescription (JMP), a Chinese herbal medicine formula, and its influence on mRNA expressions of beta3 adrenergic receptor (beta3-AR) and uncoupling protein-2 (UCP-2) in adipose tissue of diet-induced obese rats. METHODS: Fifty male Sprague-Dawley rats were randomly divided into the normal control group (n =8) that was on a standard chow diet, and the obese model group (n =42) that was on a diet of high fat chow. Two weeks after the high fat diet, 29 obese rats in the obese model group were further randomly divided into 3 groups: the untreated obese model group (n =9), the metformin group (n =10, metformin 300 mg kg⻹ day)⻹, and the JMP group (n =10, JMP 4 g kg⻹ day⻹). After 8-week treatment, body weight, wet weight of visceral fat, and percentage of body fat (PBF) were measured. The levels of fasting blood glucose, serum lipids, and insulin were assessed, and insulin sensitivity index (ISI) was calculated. The adipose tissue section was stained with hematoxylin-Eosin, and the cellular diameter and quantity of adipocytes were evaluated by light microscopy. The mRNA expressions of beta3-AR and UCP-2 from the peri-renal fat tissue were determined by real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with the obese model group, treatment with JMP resulted in significantly lower body weight, wet weight of visceral fat, PBF, and diameter of adipocytes, and significantly higher level of high-density lipoprotein cholesterol, ISI (all P<0.01), JMP increased the mRNA expressions of beta3-AR and UCP-2 from perirenal fat tissue (P <0.05, P<0.01). CONCLUSIONS: JMP could reduce body weight and adipocyte size; and the effect was associated with the up-regulation of beta3-AR and UCP-2 expressions in the adipose tissue and improvement of insulin sensitivity.