Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.813
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.
J Oral Maxillofac Surg ; 78(10): 1871.e1-1871.e23, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32640209

RESUMO

PURPOSE: The purpose of this project was to investigate the expression of ß-adrenergic receptors in oral squamous cell carcinoma (OSCC) and the tumor suppressive activity of ß2-adrenergic receptor (ß2-AR) blockade. MATERIALS AND METHODS: Samples of 15 normal oral mucosal epithelial tissues, 60 surgically resected OSCC tissues, and 60 adjacent para-carcinoma tissues were collected. The expression of ß1-adrenergic receptor and ß2-AR was detected by real-time quantitative polymerase chain reaction and the Western blot test. SCC9 and Cal27 cell lines and primary OSCC cells also were included and treated with ICI-118,551 (MedChemExpress, Monmouth Junction, NJ), a selective ß2-AR blocker. In addition, the Cal27 cell line was treated with propranolol (a nonselective ß-adrenergic receptor blocker) to verify the suppressive effect of ß2-AR blockade. For in vivo assays, Cal27 cells were subcutaneously injected in the tongue flank of nude mice. ICI-118,551 was orally administered to the mice in the treatment group daily. High-throughput sequencing was used to screen for changes in gene expression. RESULTS: Real-time quantitative polymerase chain reaction and the Western blot test both showed that ß1-adrenergic receptor and ß2-AR were overexpressed in OSCC tissues and cells. A relationship was found between ß2-AR and a more advanced clinical stage, as well as preoperative lymphatic metastasis. After treatment with ICI-118,551 or propranolol, the capacities for proliferation, invasion, and metastasis of OSCC cells were significantly inhibited. Tumor size was significantly different between the ICI-118,551 and control groups. The survival time in the ICI-118,551 group also was prolonged significantly. Moreover, high-throughput sequencing identified 19 affected signaling pathways, including mitogen-activated protein kinase and PI3K-Akt. We confirmed a significant change to the expression of several genes closely related to the progression of cancer. CONCLUSION: This study showed that ß2-AR is related to a more advanced clinical stage and preoperative lymphatic metastasis. Additionally, a ß2-AR blocker has a significant suppressive effect in OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Camundongos , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Receptores Adrenérgicos beta , Receptores Adrenérgicos beta 2/genética
3.
Cardiovasc Ther ; 2020: 3480276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565909

RESUMO

Wenxin Keli (WXKL) is a traditional Chinese medicine drug approved for the treatment of cardiovascular diseases. This study aimed to identify WXKL-targeting genes involved in antiarrhythmic efficacy of WXKL. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) technology platform was used to screen active compounds of WXKL and WXKL-targeting arrhythmia-related genes. A pig model of myocardial ischemia (MI) was established by balloon-expanding the endothelium of the left coronary artery. Pigs were divided into the model group and WXKL group (n = 6). MI, QT interval, heart rate, and arrhythmia were recorded, and the mRNA expression of target genes in myocardial tissues was detected by PCR. Eleven active ingredients of WXKL and eight WXKL-targeting arrhythmia-related genes were screened. Five pathways were enriched, and an "ingredient-gene-path" network was constructed. WXKL markedly decreased the incidence of arrhythmia in the MI pig model (P < 0.05). The QT interval was significantly shortened, and the heart rate was slowed down in the WXKL group compared with the model group (P < 0.05). In addition, the expression of sodium channel protein type 5 subunit alpha (SCN5A) and beta-2 adrenergic receptor (ADRB2) was downregulated, while muscarinic acetylcholine receptor M2 (CHRM2) was upregulated in the WXKL group (P < 0.05). In conclusion, WXKL may shorten the QT interval and slow down the heart rate by downregulating SCN5A and ADRB2 and upregulating CHRM2 during MI. These findings provide novel insight into molecular mechanisms of WXKL in reducing the incidence of ventricular arrhythmia.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Potenciais de Ação/genética , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Frequência Cardíaca/genética , Masculino , Medicina Tradicional Chinesa , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Mapas de Interação de Proteínas , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Suínos , Porco Miniatura , Fatores de Tempo
4.
PLoS One ; 15(4): e0228121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236094

RESUMO

Melanopsin is a visual pigment expressed in a small subset of ganglion cells in the mammalian retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs) and is implicated in regulating non-image forming functions such as circadian photoentrainment and pupil constriction and contrast sensitivity in image formation. Mouse melanopsin's Carboxy-terminus (C-terminus) possesses 38 serine and threonine residues, which can potentially serve as phosphorylation sites for a G-protein Receptor Kinase (GRK) and be involved in the deactivation of signal transduction. Previous studies suggest that S388, T389, S391, S392, S394, S395 on the proximal region of the C-terminus of mouse melanopsin are necessary for melanopsin deactivation. We expressed a series of mouse melanopsin C-terminal mutants in HEK293 cells and using calcium imaging, and we found that the necessary cluster of six serine and threonine residues, while being critical, are insufficient for proper melanopsin deactivation. Interestingly, the additional six serine and threonine residues adjacent to the required six sites, in either proximal or distal direction, are capable of restoring wild-type deactivation of melanopsin. These findings suggest an element of plasticity in the molecular basis of melanopsin phosphorylation and deactivation. In addition, C-terminal chimeric mutants and molecular modeling studies support the idea that the initial steps of deactivation and ß-arrestin binding are centered around these critical phosphorylation sites (S388-S395). The degree of functional versatility described in this study, along with ipRGC biophysical heterogeneity and the possible use of multiple signal transduction cascades, might contribute to the diverse ipRGC light responses for use in non-image and image forming behaviors, even though all six sub types of ipRGCs express the same melanopsin gene OPN4.


Assuntos
Transdução de Sinal Luminoso/fisiologia , Proteínas Recombinantes de Fusão/metabolismo , Opsinas de Bastonetes/metabolismo , beta-Arrestina 1/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Fosforilação/fisiologia , Ligação Proteica , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Proteínas Recombinantes de Fusão/genética , Opsinas de Bastonetes/química , Opsinas de Bastonetes/genética , Serina/genética , Serina/metabolismo , Treonina/genética , Treonina/metabolismo , beta-Arrestina 1/química
5.
Int J Mol Sci ; 21(2)2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947522

RESUMO

Altered ß-adrenergic receptor (ß-AR) density has been reported in cells, animals, and humans receiving ß-blocker treatment. In some cases, ß-AR density is upregulated, but in others, it is unaffected or even reduced. Collectively, these results would imply that changes in ß-AR density and ß-blockade are not related. However, it has still not been clarified whether the effects of ß-blockers on receptor density are related to their ability to activate different ß-AR signaling pathways. To this aim, five clinically relevant ß-blockers endowed with inverse, partial or biased agonism at the ß2-AR were evaluated for their effects on ß2-AR density in both human embryonic kidney 293 (HEK293) cells expressing exogenous FLAG-tagged human ß2-ARs and human lymphocytes expressing endogenous ß2-ARs. Cell surface ß2-AR density was measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Treatment with propranolol, carvedilol, pindolol, sotalol, or timolol did not induce any significant change in surface ß2-AR density in both HEK293 cells and human lymphocytes. On the contrary, treatment with the ß-AR agonist isoproterenol reduced the number of cell surface ß2-ARs in the tested cell types without affecting ß2-AR-mRNA levels. Isoproterenol-induced effects on receptor density were completely antagonized by ß-blocker treatment. In conclusion, the agonistic activity of ß-blockers does not exert an important effect on short-term regulation of ß2-AR density.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Imunofluorescência , Humanos , Especificidade de Órgãos
6.
Eur J Appl Physiol ; 120(3): 613-624, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31915906

RESUMO

PURPOSE: To verify the influence of different volumes and intensities of aerobic exercise on cardiac autonomic function (CAF) through heart rate variability (HRV) analysis as well the influence of ß2 adrenergic receptor (ADRB2) variants in overweight/obese individuals. METHODS: 70 physically inactive adults were randomly allocated into the following 16-week training: 1-high-intensity interval training (HIIT) (n = 25, 1 × 4 min bout at 85-95%HR peak, 3×/week), 4-HIIT (n = 26, 4 × 4 min bouts at 85-95%HR peak, interspersed with 3 min of recovery at 50-70%HR peak, 3×/week), and moderate continuous training (MCT) (n = 19, 30 min at 60-70%HR peak, 5×/week). Before and after the exercise training, anthropometric, BP, cardiorespiratory fitness, and HRV measures were evaluated. R-R intervals recorded for 10 min in a supine position at pre- and post-intervention were used to analyze HRV in the plot-Poincare indexes (SD1, SD2), and frequency-domain (LF, HF, LF/HF). Full blood samples were used for genotyping. RESULTS: 4-HIIT and MCT showed positive outcomes for almost all variables while 1-HIIT had a positive influence only on SBP and SD2 index. No associations were observed between isolated ADRB2 variants and changes in HRV. In the analysis of the interaction genotypes, all groups responded positively for the SD1 index of HRV and only the H1 (GG and CC) and H2 (GG and CG + GG) groups presented increases in the RMSSD index. Furthermore, there was an increase in the LF index only in the H3 (CC and AA + AG) and H4 (AA + AG and CG + GG) groups. CONCLUSIONS: ADRB2 variants and aerobic exercise training are important interacting variables to improve autonomic function and other health variables outcomes in overweight or obese individuals.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Frequência Cardíaca , Treinamento Intervalado de Alta Intensidade , Obesidade/reabilitação , Receptores Adrenérgicos beta 2/genética , Adulto , Aptidão Cardiorrespiratória , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia
7.
J Endocrinol ; 244(3): 459-471, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31905166

RESUMO

MicroRNA-7 (miR-7) is an important modulator of a plenty of gene expressions and the interrelated biological processes, highly expressed in porcine pituitary. Norepinephrine (NE), acting as an important neurotransmitter or/and a hormone secreted excessively under stress, affects the synthesis and secretion of various hormones, including pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are the key hormones which regulate sexual maturation and reproductive functions. However, the relationship among NE, miR-7 and gonadotropin needs to be elucidated. The aim of this study was to identify whether miR-7 involved in the NE-adrenoceptor signaling pathway affects the synthesis and secretion of FSH and LH in porcine pituitary. Our results showed that the NE intracerebroventricular injection increased pituitary miR-7 level and the synthesis and secretion of FSH and LH in porcine, whereas the inhibition of either endogenous miR-7 or ß-adrenergic receptors hindered the rise of FSH and LH synthesis induced by NE in cultured primary porcine anterior pituitary cells. Further, we identified the molecular type of ß-adrenergic receptors and the signaling pathway in porcine pituitary, and we found that NE played its roles relying on adrenoceptor beta 2 (ß2AR) and the RAF/MEK/ERK1/2 signaling pathway. The phosphorylation of ERK1/2 upregulated miR-7 level which subsequently enhanced FSH and LH synthesis by targeting to Golgi glycoprotein 1 (GLG1). These suggest that miR-7 mediates NE's effect on promoting FSH and LH synthesis in porcine pituitary.


Assuntos
Hormônio Foliculoestimulante/biossíntese , Hormônio Luteinizante/biossíntese , Norepinefrina/metabolismo , Hipófise/metabolismo , Suínos/metabolismo , Animais , Hormônio Foliculoestimulante/genética , Hormônio Luteinizante/genética , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Suínos/genética
8.
Reproduction ; 159(1): 49-58, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705794

RESUMO

The aim of the present study was to reveal the effect of hyperlipidemia on ß2- and ß3-adrenergic signaling in late pregnant rat uterus. Hyperlipidemia was induced in female Wistar rats by feeding a high-fat high-cholesterol diet for 8 weeks before and after mating upto the 21st day of gestation. The effect of hyperlipidemia on ß-adrenergic signaling was studied with the help of tension experiments, real-time PCR and cAMP ELISA in 21-day pregnant rat uterus. In tension experiments, hyperlipidemia neither altered the spontaneous contractility nor the oxytocin-induced contractions. However, it decreased the -logEC50 values of ß2-adrenoceptor agonist, salbutamol and ß3-adrenoceptor agonist, BRL37344. It also decreased the efficacy of adenylyl cyclase activator, forskolin. Further, there was a significant decrease in salbutamol and BRL37344-stimulated cAMP content in uterine tissues. However, there was no alteration in mRNA expressions of ß2-adrenoceptor (Adrb2), ß3-adrenoceptor (Adrb3) and Gs protein (Gnas) though there was a significant increase in the mRNA expression of Gi protein (Gnai). In conclusion, reduced cAMP content after beta-adrenergic receptor stimulation, which correlates with an increase in Gnai mRNA, may explain the mechanism of the impairment of uterine ß-adrenergic signaling in hyperlipidemic pregnant rats. The clinical implication of the present study may relate to reduced myometrial relaxant response to ß-adrenergic agonists in high fat-induced uterine dysfunction.


Assuntos
AMP Cíclico/metabolismo , Hiperlipidemias/fisiopatologia , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Útero/patologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Feminino , Gravidez , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 3/química , Receptores Adrenérgicos beta 3/genética , Transdução de Sinais , Útero/efeitos dos fármacos , Útero/metabolismo
9.
J Neuroimmunol ; 338: 577082, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31707103

RESUMO

ß2-adrenoceptors are G-protein coupled receptors expressed on both astrocytes and microglia that play a key role in mediating the anti-inflammatory actions of noradrenaline in the CNS. Here the effect of an inflammatory stimulus (LPS + IFN-γ) was examined on glial ß2-adrenoceptor expression and function. Exposure of glia to LPS + IFN-γ decreased ß2-adrenoceptor mRNA and agonist-stimulated production of the intracellular second messenger cAMP. Pre-treatment with the synthetic glucocorticoid and potent anti-inflammatory agent dexamethasone prevented the LPS + IFN-γ-induced suppression of ß2-adrenoceptor mRNA expression. These results raise the possibility that inflammation-mediated ß2-adrenoceptor downregulation in glia may dampen the innate anti-inflammatory properties of noradrenaline in the CNS.


Assuntos
Dexametasona/farmacologia , Inflamação/metabolismo , Neuroglia/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Animais , Células Cultivadas , AMP Cíclico/biossíntese , Interferon beta/farmacologia , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Neuroglia/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/fisiologia , Fator de Necrose Tumoral alfa/biossíntese
10.
Hypertension ; 75(2): 393-404, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31838908

RESUMO

Heart failure is associated with sympatho-ßAR (ß-adrenoceptor) activation and cardiac fibrosis. Gal-3 (galectin-3) and KCa3.1 channels that are upregulated in diverse cells of diseased heart are implicated in mediating myocardial inflammation and fibrosis. It remains unclear whether Gal-3 interacts with KCa3.1 leading to cardiac fibrosis in the setting of ßAR activation. We tested the effect of KCa3.1 blocker TRAM-34 on cardiac fibrosis and inflammation in cardiac-restricted ß2-TG (ß2AR overexpressed transgenic) mice and determined KCa3.1 expression in ß2-TG×Gal-3-/- mouse hearts. Mechanisms of KCa3.1 in mediating Gal-3 induced fibroblast activation were studied ex vivo. Expression of Gal-3 and KCa3.1 was elevated in ß2-TG hearts. Gal-3 gene deletion in ß2-TG mice decreased KCa3.1 expression in inflammatory cells but not in fibroblasts. Treatment of ß2-TG mice with TRAM-34 for 1 or 2 months significantly ameliorated cardiac inflammation and fibrosis and reduced Gal-3 level. In cultured fibroblasts, Gal-3 upregulated KCa3.1 expression and channel currents with enhanced membrane potential and Ca2+ entry through TRPV4 (transient receptor potential V4) and TRPC6 (transient receptor potential C6) channels leading to fibroblast activation. In conclusion, ßAR stimulation promotes Gal-3 production that upregulates KCa3.1 channels in noncardiomyocyte cells and activates KCa3.1 channels in fibroblasts leading to hyperpolarization of membrane potential and Ca2+ entry via TRP channels. Gal-3-KCa3.1 signaling mobilizes diverse cells facilitating regional inflammation and fibroblast activation and hence myocardial fibrosis.


Assuntos
Cardiomiopatias/genética , Galectina 3/genética , Regulação da Expressão Gênica , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , RNA/genética , Receptores Adrenérgicos beta 2/genética , Animais , Western Blotting , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Células Cultivadas , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Galectina 3/biossíntese , Imuno-Histoquímica , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/biossíntese , Masculino , Camundongos , Camundongos Transgênicos , Processamento de RNA , Receptores Adrenérgicos beta 2/biossíntese , Transdução de Sinais
11.
Georgian Med News ; (309): 94-99, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33526736

RESUMO

The study is aimed at studying the relationship of polymorphisms of the ADRB2 (rs1042714) and LPL (rs328) genes with lipid changes and weight gain in adolescents of Kazakh nationality. A total of 184 Kazakh adolescents, aged 15 to 18, were included in the study. The main group included 70 overweight adolescents (BMI>23.5), and the control group included 114 adolescents with normal physique (BMI≤23.4). Single nucleotide polymorphisms rs1042714 [C/G] and rs328 [C/G] were determined by the TaqMan method, using for genotyping the DNA of peripheral blood cells. When comparing the polymorphisms rs1042714 of the ADRB2 gene (p=0.58) and rs328 of the LPL gene (p=0.12) with a body mass index, no relationship was found. The results of the study show that A1 hypoapolipoproteinemia was associated with the rs328 polymorphism of the LPL gene (p=0.002). rs1042714 of the ADRB2 gene is not associated with apoA1 groups (p=0.257). A comparison of body mass index (BMI) by gender showed that boys had a significantly higher BMI compared to girls (p=0.002). Between polymorphisms rs328 and rs1042714 did not reveal a statistically significant relationship with the risk of obesity among adolescents of Kazakh nationality. The rs328 polymorphism has an association with A1 hypoapolipoproteinemia in adolescents of Kazakh nationality. rs1042714 of the ADRB2 gene is not associated with a risk of A1hypoapolipoproteinemia.Low levels of apoA1 are more often accompanied by low levels of HDL (High-Density Lipoprotein) and high levels of insulin, insulin resistance index and apoB.


Assuntos
Obesidade , Receptores Adrenérgicos beta 2 , Adolescente , Índice de Massa Corporal , Feminino , Humanos , Lipídeos , Lipase Lipoproteica/genética , Masculino , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética
12.
Georgian Med News ; (295): 76-84, 2019 Oct.
Artigo em Russo | MEDLINE | ID: mdl-31804204

RESUMO

The work was aimed at studying the relationship between the efficiency of bisoprolol and the polymorphism of ß1- and ß2-adrenergic receptors (ß-AR) genes in patients with heart failure. The two-year study included 251 patients with heart failure (with myocardial infarction on the background of coronary heart disease). During hospitalization, a standardized examination and prescription of therapy was carried out, including ß-adrenergic blocking agent (ß1-AB) - bisoprolol. Afterward, 61 (24.4%) patients stopped taking ß1-AB (bisoprolol) as a result of intolerance or violation of compliance; 190 patients took bisoprolol for 2 years. The frequency of rehospitalization (RH) due to decompensation of heart failure (HF) (or intravenous injection of loop diuretics), mortality, and the development of a composite endpoint (CE) for 2 years was taken into account. The control group consisted of 55 healthy individuals. Genotyping was performed using 3 polymorphisms (Gly389Arg of the ß1-АR gene, Ser49Gly of the ß1-АR gene, Gln27Glu of the ß2-АR gene) using the polymerase chain reaction. Genetic and epidemiological analysis was carried out using the SNPStats program. The use of bisoprolol with HF reduces the risk of re-hospitalization (odds ratio (OR)=0.519 (0.278-0.967); p=0.037) and CE (OR=0.494 (0.271-0.900); p=0.030) for 2 years of treatment. Treatment of patients with bisoprolol in a dose of >5 mg leads to a decrease in the risk of CE with G/A polymorphism Ser49Gly (c.145A> G) of the ß1-AR gene (OR=0.18 (0.04-0.84), with p=0.014). The use of this drug at this dose also leads to a decrease in the frequency of RH and CE with the homozygous genotype C (C/C) of the Gln27Glu polymorphism (c.79C>G) of the ß2-AR gene (OR=0.09 (0.02-0.46), at p=0.018 and OR=0.14 (0.04-0.58), at p=0.006, respectively).


Assuntos
Antagonistas Adrenérgicos beta , Bisoprolol , Insuficiência Cardíaca , Receptores Adrenérgicos beta 1 , Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacologia , Bisoprolol/farmacologia , Frequência do Gene , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Humanos , Pacientes , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética
13.
PLoS One ; 14(12): e0225030, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31790415

RESUMO

The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest FST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme FST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional/métodos , Índios Norte-Americanos/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Adrenérgicos beta 2/genética , Adulto , África/etnologia , Alelos , Europa (Continente)/etnologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Humanos , Masculino , México/etnologia
14.
Int Immunopharmacol ; 77: 105930, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31685439

RESUMO

PURPOSE: This study aimed to explore the associations between polymorphisms of a very important pharmacogene, ADRB2, two inflammation-related genes, IL33 and IL2RB, and the risk of lung cancer. METHODS: Six polymorphisms of ADRB2, IL33, and IL2RB were genotyped in 300 lung cancer patients and 300 healthy controls using MassARRAY. The relationship between genotypes and lung cancer risk was evaluated using chi-square tests. RESULTS: The minor allele of rs1042711 was a risk allele for lung cancer, whereas the minor alleles of rs7025417 and rs5756523 had protective effects against lung cancer (p<0.05). The CT genotype of rs1042711 and the GT genotype of rs1560642 were associated with increased risk of lung cancer, whereas the CC and AA genotypes of rs7025417 and the CT and CC genotypes of rs5756523 were associated with decreased disease risk (p < 0.05). Genetic model analysis shows that rs1042711 and rs1560642 were associated with increased risk of lung cancer; whereas rs7025417, rs5756523, and rs2284033 were associated with decreased disease risk (p < 0.05). Stratification analysis showed that rs1042711 and rs1560642 were associated with increased risk of lung cancer in nonsmokers and smokers, respectively, whereas rs7025417 and rs5756523 were associated with decreased disease risk in both subgroups (p<0.05). CONCLUSION: Our results shed new light on the association between polymorphisms of ADRB2, IL33, and IL2RB and the risk of lung cancer.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Subunidade beta de Receptor de Interleucina-2/genética , Interleucina-33/genética , Neoplasias Pulmonares/genética , Receptores Adrenérgicos beta 2/genética , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
15.
BMC Pulm Med ; 19(1): 202, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699066

RESUMO

BACKGROUND: The published data on the association between ß2-adrenergic receptor gene polymorphisms and asthma susceptibility are inconclusive. To derive a more precise estimation of this association, a meta-analysis was performed. METHODS: A literature search was conducted in PubMed, Web of Science, EMBASE, Wanfang, and the China National Knowledge Infrastructure (CNKI) databases to identify eligible studies. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to calculate the strength of the association. A sensitivity analysis was performed to evaluate the influence of individual studies on the overall effect estimates, and funnel plots and Egger's tests were used for indications of publication bias. RESULTS: Seventy three studies with three single nucleotide polymorphisms (SNP) (rs1042713, c.G46A, p.Gly16Arg; rs1042714, c.G79C, p.Gln27Glu; rs1042711, c.T-47C, p.Cys19Arg) were finally identified. For the rs1042713 polymorphism, no significant association with asthma risk was found in the overall population. However, a significant protective association was found in the Indian population in the dominant model comparison (OR = 0.72, 95% CI = 0.59-0.87, I2 = 25%, studies = 5, cases = 1190, controls = 1241). A significant risk association was found in the Arab population in the dominant model comparison (OR = 1.75, 95% CI = 1.14-2.70, I2 = 0%, studies = 2, cases = 307, controls = 361) and the homozygote model comparison (OR = 1.88, 95% CI = 1.17-3.02, I2 = 0%, studies = 2, cases = 307, controls = 361), and in the Hispanic-Latino population in the dominant model comparison (OR = 1.68, 95% CI = 1.10-2.55, I2 = 77%, studies = 5, cases = 1026, controls = 1412). For the rs1042714 polymorphism, we found a significant association in the recessive model comparison (OR = 0.83, 95% CI = 0.70-0.98, I2 = 44%, studies = 52, cases = 8242, controls = 16,832), the homozygote genotype comparison (OR = 0.84, 95% CI = 0.72-0.98, I2 = 25%, studies = 52, cases = 8242, controls = 16,832) and the allelic genetic model (OR = 0.91, 95% CI = 0.83-0.99, I2 = 59%, studies = 52, cases = 8242, controls = 16,832) in the overall population. When stratified by age, a significant association was also found in children in the recessive model comparison (OR = 0.59, 95% CI = 0.39-0.88, I2 = 58%, studies = 18, cases = 2498, controls = 2510) and the homozygote genotype comparison (OR = 0.63, 95% CI = 0.43-0.92, I2 = 46%, studies = 18, cases = 2498, controls = 2510), but not in adult. For the rs1042711 polymorphism, no significant associations were found in the any genetic model. CONCLUSION: The meta-analysis suggests that the ADRB2 rs1042714 polymorphism has a protective association with asthma in the overall population and the pediatric subgroup.


Assuntos
Asma/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Alelos , Asma/metabolismo , Criança , Genótipo , Humanos , Receptores Adrenérgicos beta 2/metabolismo , Fatores de Risco
16.
Bull Exp Biol Med ; 167(5): 706-710, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31630305

RESUMO

We created a translational model of chronic heart failure in rats that developed in 3 months after reproducing experimental anterior transmural myocardial infarction. The model simulated the basic clinicodiagnostic criteria of this disease: impaired contractility and dilatation of heart ventricles, signs of venous congestion, elevated plasma content of biochemical markers, and abnormal overexpression of AT1aR and ß-adrenoceptors.


Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Animais , Animais não Endogâmicos , Biomarcadores/metabolismo , Ecocardiografia , Expressão Gênica , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/metabolismo , Hemodinâmica/fisiologia , Humanos , Masculino , Contração Miocárdica/fisiologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Pesquisa Médica Translacional/métodos
17.
Nat Commun ; 10(1): 4752, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628314

RESUMO

Meningococcus utilizes ß-arrestin selective activation of endothelial cell ß2 adrenergic receptor (ß2AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that ß2AR activation requires two asparagine-branched glycan chains with terminally exposed N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues located at a specific distance in its N-terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on ß2AR glycans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation. This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. It represents an additional mechanism of evolutionary adaptation of a pathogen to its host.


Assuntos
Fímbrias Bacterianas/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Neisseria meningitidis/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Animais , Linhagem Celular , Membrana Celular/metabolismo , Fímbrias Bacterianas/genética , Células HEK293 , Humanos , Lectinas/metabolismo , Microscopia Confocal , Neisseria meningitidis/fisiologia , Polissacarídeos/metabolismo , Receptores Adrenérgicos beta 2/genética , Homologia de Sequência de Aminoácidos , beta-Arrestinas/metabolismo
18.
Cell Death Dis ; 10(11): 788, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624248

RESUMO

An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of ß-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of ß2 adrenergic receptor (ADRB2) activation and blockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays. Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonists significantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition, chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest ß2 blockade as a novel strategy to complement existing therapies for GC.


Assuntos
Receptores Adrenérgicos beta 2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Estresse Fisiológico/fisiologia , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Metástase Neoplásica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Adrenérgicos beta 2/biossíntese , Receptores Adrenérgicos beta 2/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
19.
Respir Res ; 20(1): 221, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619245

RESUMO

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3-25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.


Assuntos
Genótipo , Hipoventilação/genética , Distrofia Muscular de Duchenne/genética , Polimorfismo Genético/genética , Receptores Adrenérgicos beta 2/genética , Respiração Artificial , Adolescente , Adulto , Criança , Pré-Escolar , Bases de Dados Genéticas , Humanos , Hipoventilação/diagnóstico , Hipoventilação/epidemiologia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/epidemiologia , Respiração Artificial/tendências , Adulto Jovem
20.
J Neuroimmune Pharmacol ; 14(4): 697-708, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31620969

RESUMO

Assessment of Beta-AR protein expression on tumour tissues might be a plausible strategy to select cancer patients who can benefit from Beta-blockers therapy. The aim of this study is to evaluate the differences between resected tissue specimens from primary lung cancer (adenocarcinoma (ADC) and squamous cell carcinoma (SCC)) in terms of expression pattern of Beta1- and Beta2-AR in both tumour and adjacent surrounding non-tumour tissue. This retrospective study was based on the analysis of 80 patients with histologically confirmed diagnosis of primary Non-Small Cell Lung Cancer (NSCLC) who received surgical treatment. The cases were carefully selected in order to obtain the most homogeneous sample in terms of histologic subtype (40 ADCs and 40 SCCs) and clinical stage (10 each). Beta1- and Beta2-AR expression was determined by immunohistochemistry and the staining evaluated by semi-quantitative scoring using the H-score method. In our NSCLC series, Beta1- and Beta2-AR are differentially expressed. Beta1-AR expression is present at low levels in both SCC and ADC. Likewise, when compared with the matched surrounding non-tumour tissues, Beta1-AR expression level was significantly lower in both histologic subtypes. Conversely, Beta2-AR is highly expressed in both histologic subtypes, but clearly highly expressed in ADC when compared with SCC and with their matched surrounding non-tumour tissue. Overall, this clinicopathological study highlights the differential expression of Beta1- and Beta2-AR in ADC and SCC. Repurposing non-selective Beta-blockers in oncologic setting might be a suitable therapeutic strategy for lung ADC. Graphical abstract.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Enzimológica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Receptores Adrenérgicos beta 1/biossíntese , Receptores Adrenérgicos beta 2/biossíntese , Células A549 , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Estudos Retrospectivos , Fase S/efeitos dos fármacos , Fase S/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA