RESUMO
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetically inherited cardiac disorder with diverse clinical presentations. Adrenergic activity, primarily mediated through beta-adrenoceptors, plays a central role in the clinical course of HCM. Adrenergic stimulation increases cardiac contractility and heart rate through beta-1 adrenoceptor activation. Beta-blocker drugs are recommended as the primary treatment for symptomatic HCM patients to mitigate these effects. METHODS: This prospective study aimed to investigate the impact of common ADRB-1 gene polymorphisms, specifically serine-glycine at position 49 and arginine-glycine at position 389, on the clinical and structural aspects of HCM. Additionally, the study explored the association between these genetic variations and the response to beta-blocker therapy in HCM patients. RESULTS: A cohort of 147 HCM patients was enrolled, and comprehensive assessments were performed. The findings revealed that the Ser49Gly polymorphism significantly influenced ventricular ectopic beats, with beta-blocker therapy effectively reducing them in Ser49 homozygous patients. Moreover, natriuretic peptide levels decreased, particularly in Ser49 homozygotes, indicating improved cardiac function. Left ventricular outflow obstruction, a hallmark of HCM, was also reduced following beta-blocker treatment in all patient groups. In contrast, the Arg389Gly polymorphism did not significantly impact baseline parameters or beta-blocker response. CONCLUSION: These results emphasize the role of the Ser49Gly polymorphism in the ADRB-1 gene in shaping the clinical course and response to beta-blocker therapy in HCM patients. This insight may enable a more personalized approach to managing HCM by considering genetic factors in treatment decisions. Further research with larger populations and longer follow-up periods is needed to confirm and expand upon these findings.
Assuntos
Cardiomiopatia Hipertrófica , Polimorfismo Genético , Humanos , Estudos Prospectivos , Antagonistas Adrenérgicos beta/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/genética , Receptores Adrenérgicos/genética , Progressão da Doença , Glicina/genéticaRESUMO
OBJECTIVE: Psychosocial stress is transduced into disease risk through energy-dependent release of hormones from the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes. The levels of glucocorticoid and adrenergic hormones, together with the sensitivity of tissues to their signaling, define stress responses. To understand existing pathways responsible for the psychobiological transduction of stressful experiences, we provide a quantitative whole-body map of glucocorticoid and adrenergic receptor (AR) expression. METHODS: We systematically examined gene expression levels for the glucocorticoid receptor (GR), α- and ß-ARs (AR-α1B, AR-α2B AR-ß2, and AR-ß3), across 55 different organs using the Human Protein Atlas and Human Proteome Map datasets. Given that mitochondria produce the energy required to respond to stress, we leveraged the Human Protein Atlas and MitoCarta3.0 data to examine the link between stress hormone receptor density and mitochondrial gene expression. Finally, we tested the functional interplay between GR activation and AR expression in human fibroblast cells. RESULTS: The GR was expressed ubiquitously across all investigated organ systems, whereas AR subtypes showed lower and more localized expression patterns. Receptor co-regulation, meaning the correlated gene expression of multiple stress hormone receptors, was found between GR and AR-α1B, as well as between AR-α1B and AR-α2B. In cultured human fibroblasts, activating the GR selectively increased AR-ß2 and AR-α1B expression. Consistent with the known energetic cost of stress responses, GR and AR expressions were positively associated with the expression of specific mitochondrial pathways. CONCLUSIONS: Our results provide a cartography of GR and AR expression across the human body. Because stress-induced GR and AR signaling triggers energetically expensive cellular pathways involving energy-transforming mitochondria, the tissue-specific expression and co-expression patterns of hormone receptor subtypes may in part determine the resilience or vulnerability of different organ systems.
Assuntos
Glucocorticoides , Receptores Adrenérgicos , Humanos , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Transdução de Sinais , Receptores de Glucocorticoides/metabolismoRESUMO
The objective of study was to investigate the association between the Gln27Glu polymorphism in the ß2-ÐR gene and body mass index in patients with bronchial asthma with regard to the age of onset. Study included 553 patients with bronchial asthma (BA) and 95 apparently healthy individuals with no individual and family history of asthma symptoms. All of them had previously signed an informed consent form for study participation. The patients were divided into 2 clinical groups depending on the age of BA onset. Group I included 282 patients with late-onset asthma (late-onset asthma phenotype), and Group II included 271 patients with early-onset asthma (early-onset asthma phenotype). There was no significant difference in gender, age, severity, or control level between the groups (Ñ>0.05). BA diagnosis and BA severity were determined according to the GINA recommendations-2016 and its later version. Obesity was diagnosed in accordance with the Order of the Ministry of Health of Ukraine â 574 dated 05.08.2009 and the WHO recommendations (1999), the European Association for the Study of Obesity (EASO, 2016). The Gln27Glu polymorphism in the ß2-ÐR gene (rs1042714) was determined using polymerase chain reaction-restriction fragment length polymorphism analysis. The obtained results were statistically analyzed using SPSS-17 program. No significant difference was established in the distribution of alleles and genotypes for the Gln27Glu polymorphism in the ß2-adrenergic receptor gene depending on body mass index (BMI), p=0.1. Obesity relative risk estimation showed a statistically significant correlation related to the dominant (p=0.03) and additive (p=0.04) models of inheritance. The risk of obesity in minor allele carriers (Glu/Glu+Gln/Glu) was 1.75 times higher than that in the major allele homozygotes (Ñ=0.03). No association was observed between the Gln27Glu polymorphism in the ß2-AR gene and obesity risk in patients with early-onset bronchial asthma in any model of inheritance. Obesity relative risk estimation in late-onset BA patients showed a statistically significant correlation related to the dominant (p=0.03) and additive (p = 0.001) models of inheritance. The minor allele carriers (Gln/Glu and Glu/Glu genotypes) with late-onset BA had a 1.95 times higher risk of obesity in the dominant model and 1.65 times higher risk of obesity in the additive model vs. the major allele homozygotes. The obtained data indicated that the minor allele carriers of the Gln27Glu polymorphism in the ß2-ÐR gene (both homozygotes and heterozygotes) with late-onset BA had a higher risk of obesity.
Assuntos
Asma , Polimorfismo Genético , Humanos , Genótipo , Obesidade/genética , Asma/genética , Receptores Adrenérgicos/genéticaRESUMO
Adrenaline and noradrenaline, released as hormones and/or neurotransmitters, exert diverse physiological functions in vertebrates, and teleost fishes are widely used as model organisms to study adrenergic regulation; however, such investigations often rely on receptor subtype-specific pharmacological agents (agonists and antagonists; see Glossary) developed and validated in mammals. Meanwhile, evolutionary (phylogenetic and comparative genomic) studies have begun to unravel the diversification of adrenergic receptors (ARs) and reveal that whole-genome duplications and pseudogenization events in fishes results in notable distinctions from mammals in their genomic repertoire of ARs, while lineage-specific gene losses within teleosts have generated significant interspecific variability. In this Review, we visit the evolutionary history of ARs (including α1-, α2- and ß-ARs) to highlight the prominent interspecific differences in teleosts, as well as between teleosts and other vertebrates. We also show that structural modelling of teleost ARs predicts differences in ligand binding affinity compared with mammalian orthologs. To emphasize the difficulty of studying the roles of different AR subtypes in fish, we collate examples from the literature of fish ARs behaving atypically compared with standard mammalian pharmacology. Thereafter, we focus on specific case studies of the liver, heart and red blood cells, where our understanding of AR expression has benefited from combining pharmacological approaches with molecular genetics. Finally, we briefly discuss the ongoing advances in 'omics' technologies that, alongside classical pharmacology, will provide abundant opportunities to further explore adrenergic signalling in teleosts.
Assuntos
Peixes , Vertebrados , Animais , Filogenia , Peixes/genética , Peixes/metabolismo , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Mamíferos/metabolismo , Adrenérgicos , Evolução MolecularRESUMO
Bacteria regulate virulence by using two-component systems (TCSs) composed of a histidine kinase (HK) and a response regulator (RR). TCSs respond to environmental signals and change gene-expression levels. The HK QseE and the RR QseF regulate the virulence of Enterobacteriaceae bacteria such as enterohemorrhagic Escherichia coli. The operon encoding QseE/QseF also contains a gene encoding an outer membrane lipoprotein, qseG. The protein product QseG interacts with QseE in the periplasmic space to control the activity of QseE and constitutes a unique QseE/F/G three-component system. However, the structural bases of their functions are unknown. Here, crystal structures of the periplasmic regions of QseE and QseG were determined with the help of AlphaFold models. The periplasmic region of QseE has a helix-bundle structure as found in some HKs. The QseG structure is composed of an N-terminal globular domain and a long C-terminal helix forming a coiled-coil-like structure that contributes to dimerization. Comparison of QseG structures obtained from several crystallization conditions shows that QseG has structural polymorphisms at the C-terminus of the coiled-coil structure, indicating that the C-terminus is flexible. The C-terminal flexibility is derived from conserved hydrophilic residues that reduce the hydrophobic interaction at the coiled-coil interface. Electrostatic surface analysis suggests that the C-terminal coiled-coil region can interact with QseE. The observed structural fluctuation of the C-terminus of QseG is probably important for interaction with QseE.
Assuntos
Escherichia coli Êntero-Hemorrágica , Proteínas de Escherichia coli , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Cristalografia por Raios X , Escherichia coli Êntero-Hemorrágica/genética , Escherichia coli Êntero-Hemorrágica/metabolismo , Expressão Gênica , Virulência , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Proteínas de Ligação a DNA/metabolismoRESUMO
Whole-genome duplications (WGDs) have been at the heart of the diversification of ß-adrenergic receptors (ß-ARs) in vertebrates. Non-teleost jawed vertebrates typically possess three ß-AR genes: adrb1 (ß1-AR), adrb2 (ß2-AR), and adrb3 (ß3-AR), originating from the ancient 2R (two rounds) WGDs. Teleost fishes, owing to the teleost-specific WGD, have five ancestral adrb paralogs (adrb1, adrb2a, adrb2b, adrb3a and adrb3b). Salmonids are particularly intriguing from an evolutionary perspective as they experienced an additional WGD after separating from other teleosts. Moreover, adrenergic regulation in salmonids, especially rainbow trout, has been intensively studied for decades. However, the repertoire of adrb genes in salmonids has not been yet characterized. An exhaustive genome survey of diverse salmonids, spanning five genera, complemented by phylogenetic sequence analysis, revealed each species has seven adrb paralogs: two adrb2a, two adrb2b, two adrb3a and one adrb3b. Surprisingly, salmonids emerge as the first known jawed vertebrate lineage to lack adrb1. adrb1 is nevertheless highly expressed in the hearts of non-salmonid teleosts, indicating that the wealth of data on adrenergic regulation in salmonids should be generalised to other teleost fishes with caution. It is hypothesised that the loss of adrb1 could have been viable because of the evolutionary radiation of adrb2 and adrb3 genes attributable to the salmonid WGD.
Assuntos
Duplicação Gênica , Oncorhynchus mykiss , Animais , Filogenia , Evolução Molecular , Vertebrados/genética , Receptores Adrenérgicos/genéticaRESUMO
Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for ADRB1 Arg389Gly and Ser49Gly, ADRB2 Gln27Glu and Gly16Arg, and ADRA2C Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (P<0.05) reduced association with incident VF, and none was associated with increased VF risk except for ADRB1 Gly389 homozygotes in the subset of patients not receiving ß-blockers. ADRB1 Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the ADRA2C 322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both ADRB1 Gly49 carriers (OR, 0.67 [0.56-0.80]) and ADRA2C Del carriers (OR, 0.57 [0.45- 0.71]) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles ADRB1 Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and ß-arrestin interactions leading to cardioprotective biased signaling, and ADRA2C Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.
Assuntos
Infarto do Miocárdio com Supradesnível do Segmento ST , Fibrilação Ventricular , Humanos , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/epidemiologia , Fibrilação Ventricular/genética , Estudos de Casos e Controles , Polimorfismo Genético , Receptores Adrenérgicos/genética , NorepinefrinaRESUMO
ß-adrenergic receptors regulate cardiac function in both the healthy and failing heart. Their expression is decreased in heart failure due to chronic overactivation of the sympathetic nervous system, contributing to declines in cardiac function and disease progression. Furthermore, therapies that prevent ß-adrenergic receptor downregulation or restore ß-adrenergic receptor levels are beneficial, making the determination of cardiac ß-adrenergic receptor expression in the heart an important consideration. Although quantitative RT-PCR can provide an indication of ß-adrenergic receptor density and subtype expression, mRNA levels do not always correlate with functional protein levels. Additionally, antibodies to ß-adrenergic receptors lack specificity, making immunoblotting and other antibody-based techniques unreliable. Radioligand binding assays were developed over 50 years ago and remain the gold standard for quantifying ß-adrenergic receptor densities in biological samples. This technique capitalizes on the binding of high-affinity, highly specific ligands to receptors and can give quantifiable levels of receptor expression. Furthermore, competition assays using subtype-selective antagonists generate binding profiles and can differentiate ß-adrenergic receptor subtype expression in cardiac tissue. This article focuses on the quantification of ß-adrenergic receptors in the heart using saturation and competition radioligand binding techniques to quantify ß-adrenergic receptor density and ligand affinities in cardiac membranes. © 2023 Wiley Periodicals LLC. Basic Protocol: Radioligand binding to quantify adrenergic receptor expression in the heart.
Assuntos
Adrenérgicos , Insuficiência Cardíaca , Humanos , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Coração , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Insuficiência Cardíaca/genéticaRESUMO
Thermoregulation is a process by which core body temperature is maintained in mammals. Males typically have a lower body temperature than females. However, the effects of androgens, which show higher levels in males, on adrenergic receptor-mediated thermogenesis remain unclear. Here, we demonstrate that androgen-androgen receptor (AR) signaling suppresses the ß-adrenergic agonist-induced rise of core body temperature using castrated and AR knockout (ARKO) male mice. Furthermore, in vitro mechanistic studies show that activated AR inhibits cAMP response element (CRE)-mediated transcription by suppressing cAMP response element-binding protein (CREB) phosphorylation. The elevation of body temperature induced by the ß-adrenergic agonist CL316243 was higher in ARKO and castrated mice than in the control mice. Similarly, CL316243 induced a greater increase in Uncoupling protein 1 (Ucp1) expression and CREB phosphorylation in the brown adipose tissue of ARKO mice than in that of controls. We determined that activation of AR by dihydrotestosterone suppressed ß3-agonist- or forskolin-induced CRE-mediated transcription, which was prevented by AR antagonist. AR activation also suppressed CREB phosphorylation induced by forskolin. Moreover, we found AR nuclear localization, but not transcriptional activity, was necessary for the suppression of CRE-mediated transcription. Finally, modified mammalian two-hybrid and immunoprecipitation analyses suggest nuclear AR and CREB form a protein complex both in the presence and absence of dihydrotestosterone and forskolin. These results suggest androgen-AR signaling suppresses ß-adrenoceptor-induced UCP1-mediated brown adipose tissue thermogenesis by suppressing CREB phosphorylation, presumably owing to a protein complex with AR and CREB. This mechanism explains sexual differences in body temperature, at least partially.
Assuntos
Tecido Adiposo Marrom , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Receptores Androgênicos , Termogênese , Animais , Feminino , Masculino , Camundongos , Tecido Adiposo Marrom/metabolismo , Androgênios/metabolismo , Colforsina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Di-Hidrotestosterona/farmacologia , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteína Desacopladora 1/genética , Temperatura CorporalRESUMO
BACKGROUND: FAM132b (myonectin) has been identified as a muscle-derived myokine with exercise and has hormone activity in circulation to regulate iron homeostasis and lipid metabolism via unknown receptors. Here, we aim to explore the potential of adeno-associated virus to deliver FAM132b in vivo to develop a gene therapy against obesity. METHODS: Adeno-associated virus AAV9 were engineered to induce overexpression of FAM132b with two mutations, A136T and P159A. Then, AAV9 was delivered into high-fat diet mice through tail vein, and glucose homeostasis and obesity development of mice were observed. Methods of structural biology were used to predict the action site or receptor of the FAM132b mutant. RESULTS: Treatment of high-fat diet-fed mice with AAV9 improved glucose intolerance and insulin resistance, and resulted in reductions in body weight, fat depot, and adipocyte size. Codon-optimized FAM132b (coFAM132b) reduced the glycemic response to epinephrine (EPI) in the whole body and increased the lipolytic response to EPI in adipose tissues. However, FAM132b knockdown by shRNA significantly increased the glycemic response to EPI in vivo and reduced adipocyte response to EPI and adipose tissue browning. Structural analysis predicted that the FAM132b mutant with A136T and P159A may form a weak bond with ß2 adrenergic receptor (ADRB2) and may have more affinity for insulin and insulin-receptor complexes. CONCLUSIONS: Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating the adrenergic response and insulin action. Both structural biological analysis and in vivo experiments suggest that the adrenergic response and insulin action are most likely blockaded by FAM132b mutants.
Assuntos
Adrenérgicos , Resistência à Insulina , Camundongos , Animais , RNA Interferente Pequeno , Obesidade/genética , Obesidade/terapia , Obesidade/metabolismo , Resistência à Insulina/genética , Dieta Hiperlipídica , Insulina/metabolismo , Glicemia/metabolismo , Terapia Genética , Códon , Epinefrina , Receptores Adrenérgicos/genética , Ferro , Camundongos Endogâmicos C57BLRESUMO
Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.
Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/metabolismo , Receptores Adrenérgicos/química , Receptores Adrenérgicos/metabolismo , Sequência de Aminoácidos , Animais , Cristalografia por Raios X/métodos , Epinefrina/química , Epinefrina/metabolismo , Humanos , Ligantes , Norepinefrina/química , Norepinefrina/metabolismo , Ligação Proteica/fisiologia , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Adrenérgicos/genéticaRESUMO
Reperfusion therapy, the standard treatment for acute myocardial infarction, can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, signaling pathways that regulate cardiomyocyte necrosis remain largely unknown. Our recent genome-wide RNAi screen has identified a potential necrosis suppressor gene PRKAR1A, which encodes PKA regulatory subunit 1α (R1α). R1α is primarily known for regulating PKA activity by sequestering PKA catalytic subunits in the absence of cAMP. Here, we showed that depletion of R1α augmented cardiomyocyte necrosis in vitro and in vivo, resulting in exaggerated myocardial I/R injury and contractile dysfunction. Mechanistically, R1α loss downregulated the Nrf2 antioxidant transcription factor and aggravated oxidative stress following I/R. Degradation of the endogenous Nrf2 inhibitor Keap1 through p62-dependent selective autophagy was blocked by R1α depletion. Phosphorylation of p62 at Ser349 by mammalian target of rapamycin complex 1 (mTORC1), a critical step in p62-Keap1 interaction, was induced by I/R, but diminished by R1α loss. Activation of PKA by forskolin or isoproterenol almost completely abolished hydrogen-peroxide-induced p62 phosphorylation. In conclusion, R1α loss induces unrestrained PKA activation and impairs the mTORC1-p62-Keap1-Nrf2 antioxidant defense system, leading to aggravated oxidative stress, necrosis, and myocardial I/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis, which may be exploited to develop new cardioprotective therapies.
Assuntos
Complexo de Carney/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Traumatismo por Reperfusão Miocárdica/genética , Fator 2 Relacionado a NF-E2/genética , Adenilil Ciclases/genética , Animais , Complexo de Carney/patologia , Complexo de Carney/terapia , Catecolaminas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/terapia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/genética , Fosforilação/genética , Proteínas de Ligação a RNA/genética , Ratos , Receptores Adrenérgicos/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the relationship between the cardiotonic activity of Fuzi (Radix Aconiti Lateralis Preparata, RALP) and its fingerprint determined by liquid chromatography-mass spectrometry (LC-MS). METHODS: First, the fingerprints of six processed products of RALP were established by high performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS) followed by analysis of the principal component of the relative peak area of its common peaks. Next, the scores of the first five principal components were used as input for an artificial neural network (ANN). Additionally, the therapeutic effect of RALP was assessed by measuring the hemodynamic indexes of heart failure model rats. Subsequently, fluorescence semi-quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay kit were used to determine the effects of RALP-processed products on the serum levels of noradrenaline (NA), angiotensin-â (Ang-â ), and the expression of ß-norepinephrine receptor mRNA (ß-NRm) in the rat cardiac tissues. P < 0.05 was used as the output of the ANN. Finally, a network was constructed to display the relationship between the LC-MS fingerprints and the cardiotonic activity of the RALP-processed products. RESULTS: Several types of RALPs can improve diastolic function, systolic function and heart rate. On the basis of the findings from the principal component analysis (PCA) of 16 common peaks of fingerprints of six RALP-processed products, it was revealed that the first five principal components may include 100% of the information of the original data. As observed from the multilayer perceptron neural network analysis, principal component 4 presented with the strongest effects on serum levels of NA and Ang-â in rats, while principal component 1 exerted the greatest effect on ß-NRm expression in cardiac tissue. CONCLUSION: The key findings obtained from this study indicated that the network constructed by the PCA-ANN may predict pharmacodynamic effects of the main ingredients of Traditional Chinese Medicine (TCM). This method may serve as a new approach to identify the relationship between LC-MS fingerprints and the pharmacodynamic effects of TCM ingredients.
Assuntos
Aconitum/química , Cardiotônicos/química , Medicamentos de Ervas Chinesas/química , Insuficiência Cardíaca/tratamento farmacológico , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Cardiotônicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/administração & dosagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Espectrometria de Massas , Norepinefrina/genética , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismoRESUMO
The catecholamine norepinephrine (NE) links hindbrain metabolic-sensory neurons with key glucostatic control structures in the brain, including the ventromedial hypothalamic nucleus (VMN). In the brain, the glycogen reserve is maintained within the astrocyte cell compartment as an alternative energy source to blood-derived glucose. VMN astrocytes are direct targets for metabolic stimulus-driven noradrenergic signaling due to their adrenergic receptor expression (AR). The current review discusses recent affirmative evidence that neuro-metabolic stability in the VMN may be shaped by NE influence on astrocyte glycogen metabolism and glycogen-derived substrate fuel supply. Noradrenergic modulation of estrogen receptor (ER) control of VMN glycogen phosphorylase (GP) isoform expression supports the interaction of catecholamine and estradiol signals in shaping the physiological stimulus-specific control of astrocyte glycogen mobilization. Sex-dimorphic NE control of glycogen synthase and GP brain versus muscle type proteins may be due, in part, to the dissimilar noradrenergic governance of astrocyte AR and ER variant profiles in males versus females. Forthcoming advances in the understanding of the molecular mechanistic framework for catecholamine stimulus integration with other regulatory inputs to VMN astrocytes will undoubtedly reveal useful new molecular targets in each sex for glycogen mediated defense of neuronal metabolic equilibrium during neuro-glucopenia.
Assuntos
Astrócitos/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Glicogênio/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Neurônios/metabolismo , Norepinefrina/farmacologia , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Rombencéfalo/efeitos dos fármacos , Rombencéfalo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
Adrenergic receptors (ARs) are the primary targets of catecholamines released from the sympathetic nerve endings during their activation. ARs play a central role in autonomic nervous system and serve as important targets of widely used drugs. Several ARs gene polymorphisms were found to be associated with cardiovascular disease in previous clinical studies. Although more precise mechanism of the polymorphisms influence on autonomic control of cardiovascular system was studied in many previous physiological studies, their results are not unequivocal. This paper reviews the results of clinical and physiological studies focused on the impact of selected common single nucleotide polymorphisms of ARs genes involved in sympathetic control on cardiovascular system and its control. In summary, many studies assessed only a very limited range of cardiovascular control related parameters providing only very limited view on the complex cardiovascular control. The overview of partially contradicting results underlines a need to examine wider range of cardiovascular measures including their reactivity under various stress conditions requiring further study. It is expected that an effect of one given polymorphism is not very prominent, but it is suggested that even subtle differences in cardiovascular control could - on a longer time scale - lead to the development of severe pathological consequences.
Assuntos
Sistema Cardiovascular , Coração , Sistema Nervoso Autônomo/fisiologia , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos/genética , Sistema Nervoso SimpáticoRESUMO
The RNA-binding protein RapZ cooperates with small RNAs (sRNAs) GlmY and GlmZ to regulate the glmS mRNA in Escherichia coli. Enzyme GlmS synthesizes glucosamine-6-phosphate (GlcN6P), initiating cell envelope biosynthesis. GlmZ activates glmS expression by base-pairing. When GlcN6P is ample, GlmZ is bound by RapZ and degraded through ribonuclease recruitment. Upon GlcN6P depletion, the decoy sRNA GlmY accumulates through a previously unknown mechanism and sequesters RapZ, suppressing GlmZ decay. This circuit ensures GlcN6P homeostasis and thereby envelope integrity. In this work, we identify RapZ as GlcN6P receptor. GlcN6P-free RapZ stimulates phosphorylation of the two-component system QseE/QseF by interaction, which in turn activates glmY expression. Elevated GlmY levels sequester RapZ into stable complexes, which prevents GlmZ decay, promoting glmS expression. Binding of GlmY also prevents RapZ from activating QseE/QseF, generating a negative feedback loop limiting the response. When GlcN6P is replenished, GlmY is released from RapZ and rapidly degraded. We reveal a multifunctional sRNA-binding protein that dynamically engages into higher-order complexes for metabolite signaling.
Assuntos
Proteínas de Escherichia coli/metabolismo , Escherichia coli/genética , Glucosamina/análogos & derivados , Glucose-6-Fosfato/análogos & derivados , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/fisiologia , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Glucosamina/metabolismo , Glucose-6-Fosfato/metabolismo , RNA Bacteriano/genética , RNA Mensageiro/genética , Pequeno RNA não Traduzido/genética , Proteínas de Ligação a RNA/genética , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismoRESUMO
Our understanding of the relationship between stress-derived epinephrine and early pregnancy failure remains incomplete. Here, we explored the effect of epinephrine exposure on early pregnancy and pseudopregnancy in mice. Increased expression of adrenergic receptors Adra1b, Adra2b and Adrb2 was observed during decidualization and post-implantation embryogenesis was delayed or survival impaired. Epinephrine treatment also impaired decidualization in both the gravid and pseudopregnant uterus, suggesting the effect on decidualization was independent of the conceptus. This included a suppression of endometrial stroma cell proliferation and of key decidualization regulators, including COX2, BMP2 and WNT4. Collectively, these data demonstrate that maternal epinephrine exposure during early pregnancy impairs uterine decidualization and embryo development, underlying early pregnancy failure.
Assuntos
Agonistas Adrenérgicos/toxicidade , Epinefrina/toxicidade , Receptores Adrenérgicos/genética , Útero/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 2/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Camundongos , Gravidez , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Útero/metabolismo , Útero/patologia , Proteína Wnt4/metabolismoRESUMO
Advanced age is an independent risk factor for natural death and common diseases, such as cardiovascular diseases, dementia, and cancers, which are life-threatening and cause disabilities. On the other hand, individual with healthy longevity is a plausible model for successful aging. Thus, search for longevity-associated genes and pathways likely provides a unique approach to understand the genetic mechanisms underlying aging and healthspan, and emerging evidence from model organisms has highlighted the significance of genetic components in longevity. Here we reviewed the uses of model organisms including yeast, ciliate, nematode, arthropod, fish, rodent, and primate as well as human to identify the genetic determinants of longevity and discussed the genetic contributions of conserved longevity pathways, such as adrenergic system, AMPK, insulin/IGF-1, and mTOR signaling pathways.
Assuntos
Longevidade , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Humanos , Insulina/genética , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Associations between human leukocyte antigen (HLA) and postural orthostatic tachycardia syndrome (POTS) have not been investigated. We included patients diagnosed with POTS and showing orthostatic heart rate increases ≥ 50 during orthostatic vital sign measurement or experiencing syncope/near-syncope while standing (prominent POTS; n = 17). DQB1*06:09 was present in seven (41%) patients, a significantly higher percentage than in healthy Koreans (7%; odds ratio [OR] 8.7, 95% confidence interval [CI] 3.1-24.3, corrected P = 3.2 × 10-4) and epilepsy controls (8%; OR 7.9, 95% CI 2.7-23.5, corrected P = 3.2 × 10-4). Six (35.3%) carried the A*33:03-B*58:01-C*03:02-DRB1*13:02-DQB1*06:09 haplotype. The results signify an autoimmune etiology in prominent POTS.
Assuntos
Antígenos HLA/fisiologia , Síndrome da Taquicardia Postural Ortostática/genética , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Adolescente , Adulto , Pressão Sanguínea , Feminino , Frequência Cardíaca , Humanos , Masculino , Receptor Tipo 1 de Angiotensina/genética , Receptores Adrenérgicos/genética , SíncopeRESUMO
As part of the pathogenesis of osteoarthritis (OA), chondrocytes lose their phenotype and become hypertrophic, or dedifferentiate, mainly driven by interleukin-1ß (IL-1ß). The contribution of other factors to the dedifferentiation process is not completely understood. Recent studies suggested a dose-dependent role for the sympathetic neurotransmitter norepinephrine (NE) in OA chondrocyte metabolism. Therefore, the aim of this study was to analyze the contribution of NE (10-8 M, 10-6 M) to human articular OA chondrocyte dedifferentiation in the absence or presence of IL-1ß (0.5 ng/mL). Here, we demonstrate that OA chondrocytes express α2A-, α2C- and ß2-adrenoceptors (AR) and show the characteristic shift towards a fibroblast-like shape at day 7 in physioxic monolayer culture. NE alone did not affect morphology but, in combination with IL-1ß, markedly accelerated this shift. Moderate glycosaminoglycan (GAG) staining was observed in untreated and NE-treated cells, while IL-1ß strongly decreased GAG deposition. IL-1ß alone or in combination with NE decreased SOX9, type II collagen, COMP, and aggrecan, and induced MMP13 and ADAMTS4 gene expression, indicating an accelerated dedifferentiation. NE alone did not influence gene expression and did not modulate IL-1ß-mediated effects. In conclusion, these results indicate that low-grade inflammation exerts a dominant effect on chondrocyte dedifferentiation and should be targeted early in OA therapy.