Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 54
Filtrar
1.
Medicine (Baltimore) ; 99(46): e23164, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181690

RESUMO

BACKGROUND: Recently, many studies have been conducted to investigate the relationship between the A46G polymorphism in the ß2-adrenergic receptor (ADRB2) gene and essential hypertension risk in the Chinese population. However, the results of previous studies were conflicting. OBJECTIVES: The present study aimed to investigate the association between the ADRB2 A46G polymorphism and the risk of essential hypertension in the Chinese population. METHODS: We performed a systematic search of possible relevant studies on PubMed, Embase, Ovid, Web of Science, China National Knowledge Infrastructure, Wanfang, and China Biology Medicine disc databases up to January 3, 2020. Two authors independently extracted information from included articles and assessed the quality of each study by the use of the Newcastle-Ottawa Scale. According to the extent of interstudy heterogeneity, either a random-effect model or a fixed-effect model was used to calculate the combined odds ratio (OR) and 95% confidence interval (CI). RESULTS: Finally, 16 studies containing 3390 cases and 2528 controls were included in our meta-analysis. Significant associations were found between the ADRB2 A46G polymorphism and essential hypertension risk in the Chinese population under four genetic models: allele genetic model (OR: 1.14, 95% CI: 1.06-1.23, P = .001, Pheterogeneity = .09), homozygote genetic model (OR: 1.29, 95% CI: 1.11-1.51, P = .001, Pheterogeneity = .25), dominant genetic model (OR: 1.17, 95% CI: 1.05-1.32, P = .005, Pheterogeneity = .04), and recessive genetic model (OR: 1.21, 95% CI: 1.05-1.38, P = .007, Pheterogeneity = .72). CONCLUSION: The ADRB2 A46G polymorphism may increase the risk of essential hypertension in the Chinese population.


Assuntos
Hipertensão Essencial , Receptores Adrenérgicos beta 2/genética , Grupo com Ancestrais do Continente Asiático/genética , Hipertensão Essencial/etnologia , Hipertensão Essencial/genética , Predisposição Genética para Doença/etnologia , Humanos , Polimorfismo de Nucleotídeo Único
2.
Medicine (Baltimore) ; 99(31): e21612, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756217

RESUMO

BACKGROUND: Emerging evidence indicates the role of gut microbiota in the development of cardiovascular diseases. Thus, gut microbiota is increasingly recognized as a potential therapeutic target of cardiovascular disease. However, the effects of gut microbiome-targeted therapies on cardiometabolic outcomes in children and adolescents remain unclear. METHODS: We plan to perform a systematic search from PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. Two authors will independently select the relevant studies and extract data according to a previously defined data extraction sheet. We will use the Stata 14.0 statistical software and RevMan V.5.3 software to conduct data analyses. RESULTS AND CONCLUSION: The results of this study will be published in a peer-reviewed journal and provide more evidence for the application of gut microbiome-targeted therapies in children and adolescents for the intervention of cardiovascular risk factors in clinical practice. PROTOCOL REGISTRATION NUMBER: INPLASY202060050.


Assuntos
Doenças Cardiovasculares/epidemiologia , Suplementos Nutricionais , Probióticos/administração & dosagem , Simbióticos/administração & dosagem , Adolescente , Glicemia , Pressão Sanguínea , Criança , Pré-Escolar , Feminino , Microbioma Gastrointestinal/fisiologia , Hemoglobina A Glicada , Humanos , Lactente , Insulina/metabolismo , Lipídeos/sangue , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
3.
Am J Emerg Med ; 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32829991

RESUMO

Left ventricular free wall rupture (LVFWR) is a rare and fatal mechanical complication following an acute myocardial infarction (AMI). Cases of survival after LVFWR due to ST-segment elevation myocardial infarction (STEMI) treated with a conservative treatment strategy are extremely rare. In this case, a 55-year-old male patient with several cardiovascular risk factors presented to the emergency department with symptoms of ongoing chest pain and syncope. The patient's electrocardiogram was in sinus rhythm with ST-elevation on I, aVL, and V4-6 leads. His myoglobin and troponin I levels were elevated. Due to the unstable hemodynamic state of the patient, bedside echocardiography was performed. The echocardiography indicated LVFWR after AMI. Pericardiocentesis was used to restore a satisfactory hemodynamic state in the patient. Following the initial treatment, the patient opted for a conservative treatment strategy and was uneventfully discharged after 19 days.

4.
Int J Cardiovasc Imaging ; 36(9): 1659-1666, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32363448

RESUMO

Left ventricular diastolic dysfunction (LVDD) remains challenging to be assessed by echocardiography. We sought to explore the relationship between left atrial strain and left ventricular (LV) diastolic function in patients with normal left ventricular ejection fraction (LVEF) by invasive left-heart catheterization. 55 consecutive individuals with LVEF > 50% underwent LV catheterization. Standard transthoracic echocardiography was performed during 12 h before or after the procedure. Left atrial (LA) strain were obtained by speckle tracking echocardiography. When LVEF ≥ 50%, the group with elevated left ventricular end-diastolic pressure (LVEDP) (n = 35) showed decreased left atrial reservoir strain (LASr) (35.2 ± 7.7% vs 21.3 ± 7.2%, p < 0.001), left atrial conduit strain (LASct) (17.6 ± 6.3% vs 11.9 ± 4.1%, p < 0.001), left atrial contraction strain (LAScd) (16.6 ± 7.2% vs 9.5 ± 5.0%, p < 0.001) and increased E/e' ration(8.9 ± 2.6 vs 10.1 ± 3.5, p = 0.17). LVEDP negatively correlated with LASr (R = 0.662, p < 0.001), LASct (R = 0.575, p < 0.001) and LAScd (R = 0.456, p < 0.001), but not with E/e'. LASr, LASct and LAScd were all independent predictors of elevated LVEDP (p < 0.05), with a higher C-statistic for the model including LASr (0.95, 0.86 and 0.93 respectively). The area under the curve (AUC) for LASr is 0.914 (cutoff value is 26.7%, sensitivity is 90%, specificity is 82.9%). In patients with normal LV ejection fraction, left atrial strain presented good correlation with LVEDP, and LASr was superior to LASct and LAScd to predict LVEDP. LA strain demonstrated better agreement with the invasive reference than E/e'.


Assuntos
Função do Átrio Esquerdo , Cateterismo Cardíaco , Ecocardiografia Doppler , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Pressão Ventricular , Idoso , Cateterismo Cardíaco/instrumentação , Cateteres Cardíacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Transdutores de Pressão , Disfunção Ventricular Esquerda/fisiopatologia
5.
Anal Chem ; 92(2): 1890-1897, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31920079

RESUMO

In this work, fullerenols were found to be able to enhance the ECL signals of the luminol and H2O2 system and were employed for the first time as a reducing, catalyzing, and stabilizing agent in the one-step fast synthesis of fullerenols@AuNPs in only 5 min. First, the prepared fullerenols@AuNPs were applied to fabricate a label-free immunosensor for the detection of human cardiopathy biomarker (cardiac troponin I, cTnI). Second, using the fullerenols@AuNPs as biolabels to establish a sandwich-type immunosensor and catalyzing in situ copper-stained reaction to generate Cu particles capped on the fullerenols@AuNPs, and then a novel electrochemical stripping chemiluminescent (ESCL) method was developed for detection of cTnI and IgG with about 20 times more sensitive than the former one. At the process of ESCL detection, Cu2+was stripped from Cu@fullerenols@AuNPs with significant increase of the ECL signals. This can be attributed to the fact that the fullerenols@AuNPs nanoparticles and the Cu2+ have excellent conductivity and could facilitate the decomposition of H2O2 to generate various reactive oxygen species (ROSs), thereby accelerating the ECL process. Both immunosensors show high sensitivity and selectivity to cTnI and IgG detection with a wide linear range from fg/mL to ng/mL and the low limits of detection down to fg/mL for cTnI and IgG, respectively.

6.
Analyst ; 145(3): 873-879, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31845932

RESUMO

In this work, an Au-Ag alloy nanourchin (Au-Ag alloy NU) based electrochemiluminescent (ECL) sensor for the measurement of cardiac troponin I (cTnI) was developed. The as-prepared Au-Ag alloy NUs exhibited higher specific surface area and better conductivity owing to their unique urchin-like morphology, which resulted in excellent electrocatalytic activity towards H2O2 in the luminol-H2O2 ECL system. We have found that the Au-Ag alloy NUs could enhance the ECL signal in the luminol-H2O2 solution. Based on these facts, a facile and label-free ECL immunosensor has been constructed for the analysis of cTnI, a cardiac biomarker, with a wide linear range of 3.5 pg mL-1-350 µg mL-1. This novel ECL immunosensor has good stability and reproducibility, showing potential application in clinical diagnostics. In addition, a non-enzymatic electrochemical sensor for H2O2 was also fabricated, with a wide linear detection range of 100 nM-200 µM, a low limit of detection of 45 nM and a fast response time (less than 2 s).

7.
Ecotoxicol Environ Saf ; 190: 110090, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874405

RESUMO

Cadmium (Cd), a toxic heavy metal, restrains the growth and development of plants and threatens global food safety. Many studies on the alleviation of heavy metal toxicity by exogenous phytohormones have emerged, but reports on tea (Camellia sinensis) are still scarce. In this study, the effects of indole acetic acid (IAA) (2 µM and 10 µM) on Cd uptake and on the physiological and biochemical characteristics of the 'Xiangfeicui' tea cultivar were investigated for the first time. The order of Cd accumulation in tea seedlings was root > stem > mature leaf > tender leaf. Under Cd stress (30 mg kg-1), photosynthetic pigment levels, antioxidant enzyme activity, root vigor, root IAA content, and the levels of most metabolites (including caffeine, soluble sugar, total amino acids, some amino acid components, and most catechins) were significantly reduced, while levels of malondialdehyde, proline, epicatechin, and some amino acids increased. We therefore propose that by reducing Cd accumulation, exogenous IAA can lessen the adverse effects of Cd on the physiology and biochemistry of tea seedlings, promoting the growth of healthier tea plants.


Assuntos
Cádmio/análise , Camellia sinensis/química , Ácidos Indolacéticos/metabolismo , Poluentes do Solo/análise , Antioxidantes/metabolismo , Cádmio/metabolismo , Cádmio/toxicidade , Fotossíntese/efeitos dos fármacos , Reguladores de Crescimento de Planta/metabolismo , Folhas de Planta/metabolismo , Plântula/efeitos dos fármacos , Poluentes do Solo/metabolismo , Poluentes do Solo/toxicidade , Chá
8.
ACS Sens ; 4(9): 2351-2357, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31448591

RESUMO

A facile strategy for in situ growing triethanolamine (TEOA)-functionalized metal-organic framework (TEOA@MOF) on the two-dimensional graphene oxide (GO) or g-C3N4 nanosheets via the self-assembly technique was introduced. In this method, Zn2+ was first attached on the carbon nanosheets by electrostatic interaction; then, trimesic acid (H3btc) acted as the complex agent and TEOA as a base for the deprotonation of H3btc and a template, which leads to in situ growing the MOF on the carbon nanosheets obtaining a sandwich-like structure. Different types of surface analysis techniques were employed to characterize the GO-TEOA@MOFs and g-C3N4-TEOA@MOFs nanomaterials fabricated. The GO-TEOA@MOFs or g-C3N4-TEOA@MOFs nanomaterial-modified electrode brings out obviously enhanced electrochemiluminescence (ECL) behaviors due to numerous TEOA in the framework structures. Specifically, both TEOA and GO can serve as the co-reactants for the ECL system of Ru(bpy)32+ and have the synergic effect of enhancing the signal. Based on the GO-TEOA@MOFs modified electrodes, we developed a sensitive and rapid label-free ECL immunoassay strategy for human copeptin, and the linear range was 5 pg mL-1 to 500 ng mL-1 as well as the limit of detection was 360 fg mL-1. This work exhibits excellent specificity and good stability of the prepared immunosensor in the practical sample determination, demonstrating it can serve as a very promising method for the clinical diagnostics of acute myocardial infarction disease.


Assuntos
Carbono/química , Etanolaminas/química , Imunoensaio/instrumentação , Medições Luminescentes/instrumentação , Estruturas Metalorgânicas/química , Nanoestruturas/química , Eletroquímica , Eletrodos
9.
Anal Chem ; 90(19): 11622-11628, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30207703

RESUMO

A simple strategy for one-step fabrication of tris(bipyridine)ruthenium(II) (Ru(bpy)32+)-functionalized metal-organic framework (Ru-MOF) thin films using a self-assembly approach assisted by an electrochemical way was introduced. In this protocol, the electrochemically driven cooperative reaction of Ru(bpy)32+ as an electrochemiluminescent (ECL) probe and a structure-directing agent, trimesic acid (H3btc) as a ligand, and Zn(NO3)2 as the Zn2+ source leads to an one-step and simultaneous synthesis and deposition of the MOF onto the electrode surface. Characterization of the Ru-MOF thin films was performed with scanning electron microscopy, Fourier transform infrared, and X-ray photoelectron spectroscopy. Scanning ion conductance microscopy was specially applied in situ to image the topography and thickness of the Ru-MOF thin films. The Ru-MOF thin films as a sensing platform show excellent ECL behavior because of plenty of Ru(bpy)32+ molecules encapsulated in the frameworks. On the basis of the Ru-MOF modified electrodes, an ultrasensitive label-free ECL immunosensing method for the human heart-type fatty-acid-binding protein has been developed with a wide linear response range (150 fg mL-1-150 ng mL-1) and a very low limit of detection (2.6 fg mL-1). The prepared immunosensor also displayed excellent stability and good specificity in the test of practical samples.


Assuntos
Proteínas de Ligação a Ácido Graxo/análise , Imunoensaio/métodos , Estruturas Metalorgânicas/química , Rutênio/química , 2,2'-Dipiridil/química , Técnicas Eletroquímicas , Eletrodos , Proteínas de Ligação a Ácido Graxo/imunologia , Humanos , Imunoensaio/instrumentação , Limite de Detecção , Medições Luminescentes
10.
Anal Chem ; 90(4): 2826-2832, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29411611

RESUMO

In many electrochemiluminescent (ECL) systems, coreactants play crucial roles in the redox-induced light emission process at the electrode surface. In this work, a novel and environment-friendly nanoplatform for ECL immunosensing enabled by triethanolamine (TEOA)-modified gold nanoparticles (TEOA@AuNPs) is reported. The monodisperse TEOA@AuNPs are fabricated by one-pot synthesis using TEOA as both reducing and stabilizing agent. Then the TEOA@AuNPs-modified electrode not only acted as coreactant for Ru(bpy)32+ ECL system but also provided a carrier for antibody 1 to form label-free immunosensor through an interaction between antigen and antibody. The unique structure of the TEOA@AuNPs loaded a large amount of coreactant of Ru(bpy)32+, which shortened the electron-transfer distance from the AuNPs surface to the appended TEOA molecules, thereby greatly enhancing the ECL efficiency and amplifying the ECL signal. In addition, Ru(bpy)32+-doped silica (RuSiO2) nanoparticles and antibody 2 were combined to form a composite for labels and a sandwich-type ECL immunosensor has been constructed. The possible mechanism of those ECL systems have also been proposed and confirmed by the EC-MS hyphenated technique. The human cardiopathy biomarker, cardiac troponin I (cTnI), was detected in a wide linear concentration range and the limit of detection (LOD) was 34 or 5.5 fg mL-1 by using the proposed label-free or labeling ECL immunoassay method.


Assuntos
Técnicas Eletroquímicas , Etanolaminas/química , Ouro/química , Imunoensaio , Medições Luminescentes , Nanopartículas Metálicas/química , Biomarcadores/análise , Eletrodos , Humanos , Tamanho da Partícula , Propriedades de Superfície , Troponina I/análise
11.
J Inequal Appl ; 2018(1): 244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30839678

RESUMO

This paper investigates optimal investment and reinsurance policies for an insurance company under a correlated risk model with common Poisson shocks. The goal of the insurance company is to minimize the ultimate ruin probability. By the dynamic programming principle, the Hamilton-Jacobi-Bellman (HJB for short) equation associated with this control problem is obtained. Since there is no explicit solution to the HJB equation, this paper alternates to find the minimal exponential upper bound of the ruin probability. The exponential upper bound of ruin probability is also called Lundberg inequality. Minimizing Lundberg inequality is equal to finding the maximal Lundberg coefficient. It turns out that the optimal investment and reinsurance polices are constant policies. Some numerical examples are given to illustrate the impact of the dependent structure and the investment chance on the upper bound.

12.
J Med Chem ; 56(24): 10132-41, 2013 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-24294923

RESUMO

Acetyl-CoA carboxylase (ACC) is a target of interest for the treatment of metabolic syndrome. Starting from a biphenyloxadiazole screening hit, a series of piperazine oxadiazole ACC inhibitors was developed. Initial pharmacokinetic liabilities of the piperazine oxadiazoles were overcome by blocking predicted sites of metabolism, resulting in compounds with suitable properties for further in vivo studies. Compound 26 was shown to inhibit malonyl-CoA production in an in vivo pharmacodynamic assay and was advanced to a long-term efficacy study. Prolonged dosing with compound 26 resulted in impaired glucose tolerance in diet-induced obese (DIO) C57BL6 mice, an unexpected finding.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta/efeitos adversos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 23(24): 6625-8, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24215889

RESUMO

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.


Assuntos
Hiperparatireoidismo Secundário/tratamento farmacológico , Tiazóis/química , Tiazóis/uso terapêutico , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Hiperparatireoidismo Secundário/metabolismo , Hiperparatireoidismo Secundário/patologia , Masculino , Hormônio Paratireóideo/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo , Tiazóis/farmacocinética
14.
Nature ; 504(7480): 437-40, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24226772

RESUMO

Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic ß-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Animais , Glicemia/metabolismo , Proteínas de Transporte/metabolismo , Núcleo Celular/enzimologia , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Modelos Animais de Doenças , Hepatócitos , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/enzimologia , Hipoglicemiantes/química , Fígado/citologia , Fígado/enzimologia , Fígado/metabolismo , Masculino , Modelos Moleculares , Especificidade de Órgãos , Fosforilação/efeitos dos fármacos , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
15.
J Lipid Res ; 54(2): 325-32, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23204296

RESUMO

Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fibroblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specificities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.V-Lep(ob)/J leptin-deficient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed significant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising and lipid-lowering actions mediated through different FGF receptors and target tissues, and the results described here provide a potential mechanism that may explain the inconsistency in the reported effects of FGF19 on lipid metabolism.


Assuntos
Fatores de Crescimento de Fibroblastos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Linhagem Celular , Colesterol/sangue , Dieta/efeitos adversos , Fatores de Crescimento de Fibroblastos/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Obesidade/sangue , Obesidade/etiologia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Triglicerídeos/sangue
16.
Sci Transl Med ; 4(162): 162ra153, 2012 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-23197570

RESUMO

Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on lipid, body weight, and glucose metabolism and has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to native FGF21, we have developed a monoclonal antibody, mimAb1, that binds to ßKlotho with high affinity and specifically activates signaling from the ßKlotho/FGFR1c (FGF receptor 1c) receptor complex. In obese cynomolgus monkeys, injection of mimAb1 led to FGF21-like metabolic effects, including decreases in body weight, plasma insulin, triglycerides, and glucose during tolerance testing. Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements in glucose metabolism and body weight. These results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated the essential role of FGFR1c in FGF21 function and suggest fat as a critical target tissue for the cytokine and antibody. Because mimAb1 depends on ßKlotho to activate FGFR1c, it is not expected to induce side effects caused by activating FGFR1c alone. The unexpected finding of an antibody that can activate FGF21-like signaling through cell surface receptors provided preclinical validation for an innovative therapeutic approach to diabetes and obesity.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/imunologia , Glucuronidase/metabolismo , Obesidade/tratamento farmacológico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Anticorpos Monoclonais/farmacologia , Peso Corporal/genética , Diabetes Mellitus/sangue , Epitopos/química , Glucose/metabolismo , Glucuronidase/imunologia , Humanos , Macaca fascicularis , Camundongos , Obesidade/sangue , Obesidade/complicações , Fosfatos/sangue , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/agonistas , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/sangue
17.
PLoS One ; 7(3): e33603, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22457778

RESUMO

Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor ßKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the ßKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Animais , Western Blotting , Linhagem Celular , Dependovirus/genética , Fatores de Crescimento de Fibroblastos/genética , Vetores Genéticos , Teste de Tolerância a Glucose , Fígado/metabolismo , Masculino , Camundongos , Ligação Proteica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
18.
J Mol Biol ; 418(1-2): 82-9, 2012 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-22370560

RESUMO

Three fibroblast growth factor (FGF) molecules, FGF19, FGF21, and FGF23, form a unique subfamily that functions as endocrine hormones. FGF19 and FGF21 can regulate glucose, lipid, and energy metabolism, while FGF23 regulates phosphate homeostasis. The FGF receptors and co-receptors for these three FGF molecules have been identified, and domains important for receptor interaction and specificity determination are beginning to be elucidated. However, a number of questions remain unanswered, such as the identification of fibroblast growth factor receptor responsible for glucose regulation. Here, we have generated a variant of FGF23: FGF23-21c, where the C-terminal domain of FGF23 was replaced with the corresponding regions from FGF21. FGF23-21c showed a number of interesting and unexpected properties in vitro. In contrast to wild-type FGF23, FGF23-21c gained the ability to activate FGFR1c and FGFR2c in the presence of ßKlotho and was able to stimulate glucose uptake into adipocytes in vitro and lower glucose levels in ob/ob diabetic mice model to similar extent as FGF21 in vivo. These results suggest that ßKlotho/FGFR1c or FGFR2c receptor complexes are sufficient for glucose regulation. Interestingly, without the FGF23 C-terminal domain, FGF23-21c was still able to activate fibroblast growth factor receptors in the presence of αKlotho. This suggests not only that sequences outside of the C-terminal region may also contribute to the interaction with co-receptors but also that FGF23-21c may be able to regulate both glucose and phosphate metabolisms. This raises an interesting concept of designing an FGF molecule that may be able to address multiple diseases simultaneously. Further understanding of FGF/receptor interactions may allow the development of exciting opportunities for novel therapeutic discovery.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Proteínas de Membrana/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Adipócitos/metabolismo , Animais , Glicemia/efeitos dos fármacos , Linhagem Celular , Feminino , Fatores de Crescimento de Fibroblastos/farmacologia , Glucose/metabolismo , Masculino , Camundongos , Camundongos Obesos
19.
Chem Biol Drug Des ; 79(4): 398-410, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22248288

RESUMO

The endocrine fibroblast growth factor 21 (FGF21) requires both fibroblast growth factor receptor (FGFR) and ß-Klotho for signaling. In this study, we sought to understand the inter-molecular physical interactions in the FGF21/FGFR/ß-Klotho complex by deleting key regions in FGFR1c or FGF21. Deletion of the D1 and the D1-D2 linker (the D1/linker region) from FGFR1c led to ß-Klotho-independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region-deficient FGFR1c. Consistent with this, the extracellular portion of FGFR1c lacking the D1/linker region blocked FGF21 action in a reporter assay, presumably by binding to and sequestering FGF21 from acting on cell surface receptor complex. In addition, the D1/linker region-deficient FGFR1c had enhanced interaction with ß-Klotho. Further, we demonstrated that deletion of the D1/linker region enhanced the formation of the FGF21/ß-Klotho/FGFR1c ternary complex in both Biacore and asymmetrical flow field flow fractionation studies. Finally, we found that the N-terminus of FGF21 is involved in the interaction with FGFR1c and FGF21/ß-Klotho/FGFR1c ternary complex formation. Taken together, our data suggest that the D1/linker region regulates both the FGF21/FGFR1c and FGFR1c/ß-Klotho interaction, and a direct interaction of FGF21 with FGFR1c may be an important step in receptor-mediated FGF21 signaling.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Linhagem Celular , Fatores de Crescimento de Fibroblastos/química , Humanos , Proteínas de Membrana/química , Domínios e Motivos de Interação entre Proteínas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Transdução de Sinais
20.
J Lipid Res ; 53(4): 643-52, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22287724

RESUMO

The aim of this study is to investigate the capability of an apoA-I mimetic with multiple amphipathic helices to form HDL-like particles in vitro and in vivo. To generate multivalent helices and to track the peptide mimetic, we have constructed a peptibody by fusing two tandem repeats of 4F peptide to the C terminus of a murine IgG Fc fragment. The resultant peptidbody, mFc-2X4F, dose-dependently promoted cholesterol efflux in vitro, and the efflux potency was superior to monomeric 4F peptide. Like apoA-I, mFc-2X4F stabilized ABCA1 in J774A.1 and THP1 cells. The peptibody formed larger HDL particles when incubated with cultured cells compared with those by apoA-I. Interestingly, when administered to mice, mFc-2X4F increased both pre-ß and α-1 HDL subfractions. The lipid-bound mFc-2X4F was mostly in the α-1 migrating subfraction. Most importantly, mFc-2X4F and apoA-I were found to coexist in the same HDL particles formed in vivo. These data suggest that the apoA-I mimetic peptibody is capable of mimicking apoA-I to generate HDL particles. The peptibody and apoA-I may work cooperatively to generate larger HDL particles in vivo, either at the cholesterol efflux stage and/or via fusion of HDL particles that were generated by the peptibody and apoA-I individually.


Assuntos
Apolipoproteína A-I/farmacologia , Peptídeos/farmacologia , Proteínas Recombinantes de Fusão/química , Células 3T3 , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Sequência de Aminoácidos , Animais , Apolipoproteína A-I/química , Colesterol/sangue , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Lipoproteínas de Alta Densidade Pré-beta/química , Humanos , Fragmentos Fc das Imunoglobulinas/química , Lipoproteínas HDL/sangue , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Peptídeos/administração & dosagem , Peptídeos/química , Estabilidade Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes de Fusão/farmacologia , Sequências de Repetição em Tandem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA