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1.
Eur J Clin Invest ; 50(3): e13206, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31999832

RESUMO

BACKGROUND AND AIMS: Neuregulin-4 (Nrg-4) is a new adipokine released from brown adipose tissue. It plays pivotal role in regulating systemic energy balance, glucose and lipid metabolism and in reducing chronic inflammation. We aimed to investigate the relation between diabetic microvascular complications (DMC) and serum (Nrg-4) levels in patients with type 2 diabetes mellitus. METHODS: Patients with type 2 diabetes mellitus were divided into DMC and diabetic patients without microvascular complications (non-DMC). Nrg-4 levels of the patients were compared. RESULTS: Fifty and 29 patients enrolled to the DMC and non-DMC groups, respectively. Nrg-4 was 1.23 (0.02-5.1) ng/mL and 2.5 (0.21-6.01) ng/mL in DMC and in non-DMC groups, respectively (P < .001). In patients with DMC, FPG was 189.5 (89-446) mg/ dL, whereas it was 128 (95-278) mg/dL in non-DMC diabetic patients (P < .001). HbA1c was also significantly higher in the DMC group than in the non-DMC group (P < .001). Negative correlation was found between Nrg-4 and FPG (r = -0.231, P = .03), HBA1c (r = -0.312, P = .003) and microalbuminuria (r = -0.277, P = .009). Logistic regression analysis showed a 1-unit decrease in Nrg-4 to increase the presence of DMC by 1.9 times. The best cut-off value of Nrg-4 was 1.56 ng/mL with 82.1% sensitivity and 64% specificity, in predicting DMC. CONCLUSION: In patients with diabetes, Nrg-4 levels may be a good predictor of early detection of one or more DMC, as microvascular dysfunction in an organ system is considered to be an initial onset of subclinical systemic damage.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Neurregulinas/sangue , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Microvasos , Pessoa de Meia-Idade
2.
Mol Pharmacol ; 97(2): 90-101, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31757861

RESUMO

Myocardial infarction is a frequent cardiovascular event and a major cause for cardiomyocyte loss. In adult mammals, cardiomyocytes are traditionally considered to be terminally differentiated cells, unable to proliferate. Therefore, the wound-healing response in the infarct area typically yields scar tissue rather than newly formed cardiomyocytes. In the last decade, several lines of evidence have challenged the lack of proliferative capacity of the differentiated cardiomyocyte: studies in zebrafish and neonatal mammals have convincingly demonstrated the regenerative capacity of cardiomyocytes. Moreover, multiple signaling pathways have been identified in these models that-when activated in adult mammalian cardiomyocytes-can reactivate the cell cycle in these cells. However, cardiomyocytes frequently exit the cell cycle before symmetric division into daughter cells, leading to polyploidy and multinucleation. Now that there is more insight into the reactivation of the cell cycle machinery, other prerequisites for successful symmetric division of cardiomyocytes, such as the control of sarcomere disassembly to allow cytokinesis, require more investigation. This review aims to discuss the signaling pathways involved in cardiomyocyte proliferation, with a specific focus on wingless/int-1 protein signaling. Comparing the conflicting results from in vitro and in vivo studies on this pathway illustrates that the interaction with other cells and structures around the infarct is likely to be essential to determine the outcome of these interventions. The extensive crosstalk with other pathways implicated in cardiomyocyte proliferation calls for the identification of nodal points in the cell signaling before cardiomyocyte proliferation can be moved forward toward clinical application as a cure of cardiac disease. SIGNIFICANCE STATEMENT: Evidence is mounting that proliferation of pre-existing cardiomyocytes can be stimulated to repair injury of the heart. In this review article, an overview is provided of the different signaling pathways implicated in cardiomyocyte proliferation with emphasis on wingless/int-1 protein signaling, crosstalk between the pathways, and controversial results obtained in vitro and in vivo.


Assuntos
Fármacos Cardiovasculares/farmacologia , Proliferação de Células/efeitos da radiação , Cicatriz/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Animais Recém-Nascidos , Fármacos Cardiovasculares/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular , Cicatriz/patologia , Proteínas Relacionadas à Folistatina/antagonistas & inibidores , Proteínas Relacionadas à Folistatina/metabolismo , Humanos , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , Neurregulinas/antagonistas & inibidores , Neurregulinas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo , Sarcômeros/efeitos dos fármacos , Sarcômeros/metabolismo , Transativadores/antagonistas & inibidores , Transativadores/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/fisiologia , Peixe-Zebra
3.
PLoS One ; 14(12): e0225705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815951

RESUMO

INTRODUCTION: Neuregulin 4 (Nrg4) was proven as a brown fat-enriched secreted factor that can regulate glucose and lipid metabolism. However, the association between circulating Nrg4 levels and diabetes mellitus (DM) in human remains unclear. We conducted a meta-analysis to investigate association of circulating Nrg4 with DM. METHODS: Observational studies comparing circulating Nrg4 levels in diabetes patients and health controls were included. Circulating Nrg4, correlation coefficients of clinical indices and circulating Nrg4 were pooled by meta-analysis. RESULTS: Seven studies were included. The pooled results indicated there were no significant difference in the circulating Nrg4 between diabetes patients and controls (SMD = 0.18, 95%CI = -0.06 to 0.42, P = 0.143). However, diabetes patients had higher circulating Nrg4 than their controls in cross-sectional studies (SMD = 0.55, 95%CI = 0.36 to 0.73, P<0.001). None of the renal function and metabolic syndrome markers were correlated with circulating Nrg4, whereas the HbA1c and BMI were positively correlated (rs = 0.09, 95%CI = 0.03 to 0.16, P = 0.005; rs = 0.20, 95%CI = 0.07 to 0.34, P = 0.003; respectively). CONCLUSION: Our findings suggested circulating Nrg4 may play a role in in the development of DM in cross-sectional studies and circulating Nrg4 might be associated with imbalance in glucose metabolism and obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Diabetes Mellitus/epidemiologia , Neurregulinas/sangue , Obesidade/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Humanos , Neurregulinas/metabolismo , Obesidade/sangue , Obesidade/metabolismo , Estudos Observacionais como Assunto
4.
Swiss Med Wkly ; 149: w20139, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31656034

RESUMO

BACKGROUND: Neuregulin-4 is a cytokine with many functions and is primarily produced by fat tissue. AIM OF THE STUDY: The aim of the study was to observe the relationship between serum neuregulin-4 levels and diabetes regulation in type 2 diabetes mellitus (T2DM), and to compare neuregulin-4 levels of diabetic subjects with those in healthy controls. METHODS: Patients with T2DM were included to the study. Healthy subjects were enrolled as controls. Subjects with T2DM with glycated haemoglobin (HbA1c) <7% were classed as well controlled and those with HbA1c >7% were classed as poorly controlled. Neuregulin-4 levels of the study and control groups were compared. RESULTS: The neuregulin-4 levels of the poorly controlled T2DM, well-controlled T2DM and control groups were significantly different (p = 0.005). Neuregulin-4 was significantly correlated with fasting plasma glucose (r = 0.247, p = 0.002) but not with HbA1c. In a regression analysis model, 0.1 point elevation in neuregulin-4 levels increased the rate of existence of T2DM 4.4-fold (odds ratio 4.4, 95% confidence interval 1.26-15.1; p = 0.02). CONCLUSION: Neuregulin-4 is significantly increased in patients with T2DM compared with control subjects, which means that it could be a marker of T2DM. Since neuregulin-4 was correlated with fasting glucose, we suggest that elevated neuregulin-4 could predict poor control in T2DM for short periods when HbA1c is not useful.  Moreover, one unit elevation in neuregulin-4 (0.1 ng/ml) increases the rate of existence of T2DM 4.4-fold, independently from other variables.


Assuntos
Biomarcadores , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Neurregulinas/análise , Glicemia/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Jejum , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade
5.
Obesity (Silver Spring) ; 27(10): 1555-1557, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31479202

RESUMO

The discovery that functional brown adipose tissue (BAT) in adult humans is inversely related to body fat mass and may reflect metabolic health has stimulated adipose tissue research to explore activation of BAT as a potential target for antiobesity treatments. In addition to the capacity of BAT to increase energy expenditure and glucose and lipid uptake, BAT secretes factors that may contribute to the regulation of whole-body metabolism. Among signals released from BAT, neuregulin 4 (NRG4) has been recently identified as an endocrine factor that may link the activation of BAT to protection against diet-induced obesity, insulin resistance, and hepatic steatosis. NRG4 was shown to directly reduce lipogenesis in hepatocytes, and it could indirectly activate BAT via sympathetic neurons or via inducing brown adipocyte-like signatures in white adipocytes in a paracrine manner. However, the potential relevance of NRG4 as a diagnostic tool or target for the treatment of obesity-related diseases remains to be explored.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fígado/metabolismo , Neurregulinas/fisiologia , Adipócitos Marrons/metabolismo , Adulto , Animais , Metabolismo Energético/fisiologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Glucose/metabolismo , Humanos , Resistência à Insulina/fisiologia , Lipogênese/fisiologia , Camundongos , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Transdução de Sinais/fisiologia , Termogênese/fisiologia
6.
Transl Psychiatry ; 9(1): 181, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371697

RESUMO

Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 µM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 µM clozapine and 30 µM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3-30 µM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Clozapina/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Neurregulinas/metabolismo , Proteínas Oncogênicas v-erbB/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
7.
Eur J Endocrinol ; 181(2): 151-159, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153139

RESUMO

Objective: Neuregulin 4 (NRG4) has recently been introduced as a novel brown adipose tissue (BAT)-secreted adipokine with beneficial metabolic effects in mice. However, regulation of Nrg4 in end-stage kidney disease (ESKD) and type 2 diabetes mellitus (T2DM) has not been elucidated, so far. Design/methods: Serum NRG4 levels were quantified by ELISA in 60 subjects with ESKD on chronic hemodialysis as compared to 60 subjects with an estimated glomerular filtration rate >50 mL/min/1.73 m2 in a cross-sectional cohort. Within both groups, about half of the patients had a T2DM. Furthermore, mRNA expression of Nrg4 was determined in two mouse models of diabetic kidney disease (DKD) as compared to two different groups of non-diabetic control mice. Moreover, mRNA expression of Nrg4 was investigated in cultured, differentiated mouse brown and white adipocytes, as well as hepatocytes, after treatment with the uremic toxin indoxyl sulfate. Results: Median serum NRG4 was significantly lower in patients with ESKD compared to controls and the adipokine was independently associated with a beneficial renal, glucose and lipid profile. In mice with DKD, Nrg4 mRNA expression was decreased in all adipose tissue depots compared to control mice. The uremic toxin indoxyl sulfate did not significantly alter Nrg4 mRNA expression in adipocytes and hepatocytes, in vitro. Conclusions: Circulating NRG4 is independently associated with a preserved renal function and mRNA expression of -Nrg4 is reduced in adipose tissue depots of mice with DKD. The BAT-secreted adipokine is further associated with a beneficial glucose and lipid profile supporting NRG4 as potential treatment target in metabolic and renal disease states.


Assuntos
Tecido Adiposo Marrom/metabolismo , Neurregulinas/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos Transversais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurregulinas/metabolismo
8.
J Obstet Gynaecol ; 39(7): 975-980, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31064233

RESUMO

Polycystic ovary syndrome (PCOS) is a metabolic disorder associated with obesity and energy metabolic system disturbances in adipose tissue. Neuregulin 4 (NRG4), which is secreted by adipose tissue, regulates energy metabolism. In the present study, we aimed to evaluate the association between serum NRG4 levels in obese and normal weight PCOS patients. This cross-sectional study was conducted at a tertiary hospital in Turkey from April to August 2017. We included 148 women who were divided into four groups as follows: 40 normal weight and 39 obese PCOS women diagnosed according to the Rotterdam criteria as well as 38 normal weight and 31 obese, age-matched, non-hyperandrogenemic women with a regular menstrual cycle (controls). Levels of serum NRG4, anti-Müllerian hormone (AMH), fasting blood glucose (FBG), insulin, and high-sensitivity C-reactive protein (hs-CRP); lipid and hormone profiles; insulin resistance indices [homeostasis model assessment of insulin resistance (HOMA-IR)];and anthropometric parameters were evaluated. Serum NRG4 levels were elevated in the normal weight PCOS group than in the control group. Moreover, serum NRG4 levels were higher in the obese PCOS group than in the normal weight PCOS and obese control groups (p < .01). Serum NRG4 levels were positively correlated with body mass index (BMI); waist/hip ratio; HOMA-IR; and levels of triglycerides, hs-CRP, FBG, insulin, AMH, and dehydroepiandrosterone sulphate. Multiple regression analyses revealed that serum NRG4 levels were independently associated with BMI. Obesity appears to be the most influential factor for NRG4 secretion in PCOS patients. Management of obesity may be a key factor for resolving PCOS-related metabolic abnormalities and fertility problems. Impact Sstatement What is already known on this subject? PCOS is a dynamic syndrome with different clinical and metabolic features during the reproductive age. PCOS is associated with various metabolic abnormalities, such as insulin resistance (IR), glucose intolerance, dyslipidemia, and obesity (particularly visceral obesity) as well as long-term complications, such as type 2 diabetes and cardiovascular diseases. Neuregulin 4 (NRG4), which is secreted by adipose tissue, regulates energy metabolism. What do the results of this study add? To the best of our knowledge, this was the first study investigating NRG4 levels in PCOS patients with different BMIs. Obesity appears to be the most influential factor for NRG4 secretion in these patients. Managing obesity may be a key factor for resolving PCOS-related metabolic abnormalities. What are the implications of these findings for clinical practice and/or further research? Further research in PCOS is warranted to ameliorate obesity, and our study can provide basis for future studies investigating NRG4 levels in PCOS patients with different phenotypes as well as studies of gene polymorphisms, AMH, and infertility and can contribute to the elucidation of problems related to the pathophysiology of PCOS.


Assuntos
Hormônio Antimülleriano/sangue , Neurregulinas/sangue , Síndrome do Ovário Policístico/sangue , Adolescente , Adulto , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Obesidade/sangue , Obesidade/complicações , Síndrome do Ovário Policístico/complicações , Relação Cintura-Quadril , Adulto Jovem
9.
Brain Behav Immun ; 79: 207-215, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30738182

RESUMO

Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g. schizophrenia and autism) in the offspring. In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alteration of the exposed MIA mice at juvenile and adulthood. We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material in fetal brain. At the behavioral levels, adult late-MIA-exposed female offspring, but not juvenile, display lack preference to a novel object. While working memory alteration observed only in adult male MIA-exposed offspring at late gestation day. In addition, we found that adult females MIA-exposed mice spent more time in the center of the open field than female-saline groups. On the other hand, juvenile male offspring exposed to MIA at early, but not late, gestation day displayed a significant alteration in social interaction. Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes, and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.


Assuntos
Neurregulinas/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Receptor ErbB-4/imunologia , Animais , Transtorno Autístico/imunologia , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Feto/metabolismo , Idade Gestacional , Masculino , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos , Neuregulina-1/genética , Neuregulina-1/metabolismo , Neurregulinas/metabolismo , Poli I-C/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor ErbB-4/metabolismo , Receptores de Dopamina D2/imunologia , Receptores de Dopamina D2/metabolismo , Esquizofrenia/imunologia , Fatores Sexuais , Transdução de Sinais/imunologia
10.
Dev Biol ; 446(2): 142-150, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611731

RESUMO

Ventricular trabeculation is one essential step for generating a functionally competent ventricular wall, while how the early trabeculae carneae forms and subsequently develops into mature chambers is poorly understood. We found that in zebrafish zfpm1-/- juvenile, cardiac function is significantly compromised, with hearts exhibiting deformed trabecular meshwork. To elucidate the mechanisms of Zfpm1 function in cardiac trabeculation, we analyzed zfpm1 mutant hearts more closely and found that loss of Zfpm1 activity resulted in over-activation of Neuregulin-ErbB signalling and abnormally elevated cardiomyocyte proliferation during cardiac trabeculae growth and modeling stages. These results implicate Zfpm1 plays a pivotal role in coordinating trabeculae patterning and growth.


Assuntos
Miocárdio/metabolismo , Neurregulinas/genética , Receptor ErbB-2/genética , Transdução de Sinais/genética , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Proliferação de Células/genética , Células Cultivadas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Coração/embriologia , Microscopia Confocal , Miocárdio/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Neurregulinas/metabolismo , Receptor ErbB-2/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
12.
Peptides ; 111: 33-41, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29807087

RESUMO

Heart failure with preserved ejection fraction (HFpEF) represents an important cardiac condition because of its increasing prevalence, resistance to treatment and high associated morbidity and mortality. Two of the major mechanisms responsible for HFpEF are impaired cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a), which is responsible for calcium reuptake into the SR, and cardiac fibroblasts/myofibroblasts that produce collagen or myocardial fibrosis. Phospholamban (PLB), in the SR and endoplasmic reticulum, is the primary regulator of SERCA2a in the heart and acts as a reversible inhibitor of SERCA2a. Glucagon-like peptide-1, a 30 amino acid peptide, improves diastolic function through increasing SERCA2a expression and activity as well as by decreasing phosphorylation of Ryanodine receptors. It also enhances collagen production through enhanced procollagen IalphaI/IIIalphaI, connective tissue growth factor, fibronectin, TGF-ß3 as well as Interleukin -10, -1beta, and -6 gene expression. Relaxin-2, a two chain, 53 amino acid peptide, increases Ser16- and Thr17-phosphorylation levels of PLB, thereby relieving SERCA2a of its inhibition. H3 Relaxin inhibits TGF-ß1-stimulated collagen deposition through H3 relaxin-induced increases in pSmad2. Neuregulin-1, an epidermal growth factor, induces nitric oxide and PI-3 kinase activation that enhance SERCA2 activity. Neuregulin-1 was associated with less myocardial macrophage infiltration and cytokine expression reducing collagen deposition. Ghrelin, a 28 amino acid peptide, improves SERCA2a function by inducing PLB phosphorylation. Ghrelin also reduces cardiac fibrosis. In summary, Glucagon-like peptide-1, Relaxin-2, Neuregulin-1, and Ghrelin each modify calcium dynamics, collagen expression, and myocardial fibrosis through attenuation of deleterious signaling cascades, and induction of adaptive pathways, representing potential therapeutic targets for HFpEF.


Assuntos
Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insuficiência Cardíaca/metabolismo , Neurregulinas/metabolismo , Relaxina/metabolismo , Animais , Humanos , Miócitos Cardíacos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
13.
Clin Obes ; 9(1): e12289, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30411515

RESUMO

Neuregulin 4 (Nrg4), a newly identified adipokine secreted by brown adipose tissue, is hypothesised to play a crucial role in metabolism. The present study aimed to evaluate the association between serum Nrg4 levels and non-alcoholic fatty liver disease (NAFLD) in children with obesity in China. A total of 123 children with obesity were included in this study. Anthropometric and biochemical parameters were measured in all subjects. NAFLD was diagnosed using ultrasonography. The serum levels of Nrg4, leptin and adiponectin were measured by enzyme-linked immunosorbent assay. NAFLD was identified in 58 children with obesity (47.2%). Serum Nrg4 levels were significantly lower in the NAFLD group (2.24 [1.20, 3.22] ng/mL) than in the control group (5.50 [2.45, 10.85] ng/mL) (p < 0.001). Serum Nrg4 levels were negatively correlated with most of the anthropometric and biochemical parameters (p < 0.05) but were positively correlated with high-density lipoprotein cholesterol (p < 0.05). In multiple stepwise regression analyses, serum Nrg4 levels were independently related with WHtR (ß = -2.009, p = 0.048) and homeostasis model assessment of insulin resistance (ß = -0.524, p = 0.005). Furthermore, a multivariable logistic regression analysis of NAFLD prediction by Nrg4 revealed an odds ratio of 0.129 (95% confidence interval: 0.028-0.587, p < 0.01). The receiver operating characteristic curve analysis of the diagnostic value of using serum Nrg4 levels to differentiate NAFLD in children with obesity showed that the area under the curve was 0.723; the cutoff for serum Nrg4 levels to have diagnostic value for predicting NAFLD in children with obesity was 3.39 ng/mL. Elevated Nrg4 is associated with a decreased risk of NAFLD in children with obesity.


Assuntos
Neurregulinas/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade Pediátrica/complicações , Adolescente , Glicemia/análise , Índice de Massa Corporal , Criança , China , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Leptina/sangue , Lipídeos/sangue , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade Pediátrica/sangue , Curva ROC , Fatores de Risco , Circunferência da Cintura , Razão Cintura-Estatura
14.
Life Sci ; 217: 185-192, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528184

RESUMO

AIMS: Enhanced hepatic gluconeogenesis is an important cause of hyperglycemia in type 2 diabetes. However, the regulatory mechanisms underlying disordered hepatic gluconeogenesis remains largely unclear. In the present study, we investigated the potential role of hepatic neuregulin 4 (Nrg4) in the regulation of gluconeogenesis in mice. MAIN METHODS: Microarray analysis was performed in primary mouse hepatocytes treated with or without 8-Br-cAMP. Primary mouse hepatocytes transfected with Nrg4 overexpressing or shRNA adenovirus were used to detect the expressions of the key gluconeogenic genes and glucose output. Hepatic Nrg4 expression levels were measured in fasted C57/BL6 mice, obese ob/ob mice, diabetic db/db mice and Goto-Kakisaki (GK) rats. Pyruvate tolerance test was performed and gluconeogenic gene expressions were detected 7 days after Nrg4 shRNA adenovirus was injected into male C57BL/6 and db/db mice. KEY FINDINGS: Microarray analysis revealed that Nrg4 expression was significantly induced by 8-Br-cAMP in primary mouse hepatocytes, along with the upregulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Adenovirus-mediated overexpression or knockdown of Nrg4 in primary mouse hepatocytes increased or decreased PEPCK and G6Pase expressions as well as hepatic glucose production. Hepatic Nrg4 expression was induced by fasting in normal C57/BL6 mice, and markedly upregulated in obese ob/ob mice, diabetic db/db mice and GK rats. Hepatic Nrg4 knockdown in C57BL/6 and db/db mice improved pyruvate tolerance, with the downregulation of PEPCK, G6Pase, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). SIGNIFICANCE: Hepatic Nrg4 plays a crucial role in the regulation of gluconeogenesis and may be a therapeutic target of type 2 diabetes.


Assuntos
Gluconeogênese , Fígado/metabolismo , Neurregulinas/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Jejum , Técnicas de Silenciamento de Genes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neurregulinas/genética , Obesidade/genética , Obesidade/metabolismo , Ratos
15.
Glia ; 67(2): 309-320, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30485552

RESUMO

Gonadotropin releasing hormone (GnRH)-secretion is not only regulated by neuronal factors but also by astroglia cells via growth factors and ErbB receptors of the epidermal growth factor family. Studies in transgenic mice carrying mutations in the ErbB receptor system experience impaired reproductive capacity. In addition, some of these animals show a typical skin phenotype with wavy hair and curly whiskers. The rat strain SPRD-CU3 (CU3), examined in this study, displays a similar skin phenotype and a significant impairment of the timing of puberty onset and reproductive performance, suggesting a disruption in the astrocytic to GnRH neuronal communication. To address this issue, we analyzed astrocytic prostaglandin E2 (PGE2 ) release from primary hypothalamic astrocytic cell cultures after stimulation with transforming growth factor α (TGFα), ligand for ErbB1/ErbB2, or Neuregulin 1 beta 2 (NRG1ß2 ), ligand for ErbB4/ErbB2 signaling pathway. Compared to cultures from wild type animals, astrocytic cultures from CU3 rats were unable to respond to NRG stimulation, suggesting a disruption of the ErbB4/ErbB2 signaling pathway. This is confirmed by mutational analysis of ErbB4 that revealed a single point mutation at 3125 bp resulting in an amino acid change from proline to glutamine located at the carboxy-terminal region. As a consequence, substantial conformational changes occur in the transmembrane and intracellular domain of the protein, affecting the ability to form a receptor dimer with a partner and the ability to function as a transcriptional regulator. Thus, astroglia to GnRH neuronal signaling via ErbB4 is essential of timely onset of puberty and reproductive function.


Assuntos
Astrócitos/efeitos dos fármacos , Dinoprostona/metabolismo , Transtornos do Desenvolvimento Sexual/patologia , Hormônio Liberador de Gonadotropina/metabolismo , Neurregulinas/farmacologia , Neurônios/metabolismo , Receptor ErbB-4/genética , Animais , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Transtornos do Desenvolvimento Sexual/tratamento farmacológico , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/efeitos da radiação , Hipotálamo/citologia , Modelos Moleculares , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Mutação Puntual/genética , Ratos , Ratos Transgênicos , Receptor ErbB-4/metabolismo , Fator de Crescimento Transformador alfa/metabolismo
16.
Int Heart J ; 60(1): 45-49, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30393265

RESUMO

Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD.We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD.Nrg4 levels were negatively associated with the SYNTAX score (r = -0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions.Nrg4 levels were found to be inversely associated with the presence and severity of CAD.


Assuntos
Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Neurregulinas/sangue , Idoso , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença
17.
Pharmacogenomics J ; 19(1): 25-32, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30287910

RESUMO

The identification of predictive biomarkers for the first-line treatment of epithelial ovarian cancer (EOC) remains a challenge. Although genome-wide association studies (GWAS) have identified several genetic polymorphisms as predictors of EOC clinical outcome, the subsequent validation has not yet been performed. This study aims to validate the influence of Neuregulin 3 (NRG3) rs1649942 and Brain and reproductive organ-expressed (TNFRSF1A modulator) (BRE) rs7572644 GWAS-identified variants in an independent cohort of EOC patients from the North region of Portugal (n = 339) submitted to first-line treatment. Polymorphism genotypes were determined by real-time PCR using validated assays. Patients carrying the NRG3 rs1649942 A allele presented a significantly longer overall survival (OS) when compared to GG-genotype patients (log-rank test, P = 0.011) in the FIGO IV stage subgroup. No impact was observed for early-stage patients or considering disease-free survival (DFS) as an outcome. For FIGO I/II stage patients, BRE rs7572644 C allele carriers exhibit a decreased OS (P = 0.014) and DFS (P = 0.032) when compared to TT-homozygous patients. Furthermore, a Multivariate Cox regression analysis revealed a three-fold increase in the risk of death (HR, 3.09; P = 0.015) and recurrence (HR, 3.33; P = 0.009) for FIGO I/II C allele carriers. No significant impact was observed for late-stage patients. The BRE rs7572644 and NRG3 rs1649942 genetic variants were validated in an independent cohort of EOC Portuguese patients, particularly in specific subgroups considering FIGO staging. Further functional post-GWAS analyses are indispensable to understand the biological mechanisms underlying the observed results.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas do Tecido Nervoso/genética , Neurregulinas/genética , Polimorfismo de Nucleotídeo Único/genética , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Farmacogenética/métodos , Estudos Retrospectivos , Resultado do Tratamento
18.
Cytokine ; 113: 356-364, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30322810

RESUMO

Neuregulin-4 (Nrg4) is a novel adipokine associated with obesity, hyperglycemia, insulin resistance, dislipidemia, inflammation, and oxidative stress in mice and humans. However, no report has demonstrated the relationship of circulating Nrg4 with diabetic peripheral neuropathy (DPN). The objective of our study was to investigate the relationship between circulating Nrg4 and DPN in a cross-sectional study. Circulating Nrg4 levels were determined with an enzyme-linked immunosorbent assays kit in 132 newly diagnosed type 2 diabetes mellitus (nT2DM) patients and 41 normal controls (NC group). The associations of circulating Nrg4 with other parameters were also analyzed. Circulating Nrg4 levels were significantly lower in nT2DM patients with no DPN than in NC subjects, and were further markedly decreased in nT2DM patients with DPN (P < 0.01 or P < 0.05). Circulating Nrg4 levels were progressively decreased with an increasing number of abnormal DPN screening (P for trend < 0.01). Circulating Nrg4 levels correlated negatively with 8-iso-prostaglandin F2α (8-iso-PGF2α), high-sensitivity C-reactive protein (hs-CRP) and vibration perception threshold (VPT) (all P < 0.01), and 8-iso-PGF2α, hs-CRP, glycated hemoglobin A1c and VPT were independently related factors to circulating Nrg4 in nT2DM patients (P < 0.01 or P < 0.05). Moreover, circulating Nrg4 was significantly associated with the development of DPN even after controlling for anthropometric, biochemical and clinical parameters. Additionally, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Nrg4 to predict DPN was 1.58 ng/mL (sensitivity 90.91%, specificity 54.55%, and area under the curve 0.716). These findings together suggested that circulating Nrg4 levels were reduced in DPN patients and Nrg4 may be a novel adipokine associated with inflammation, oxidative stress, and long-term glycemic control in nT2DM patients.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/sangue , Neurregulinas/sangue , Doenças do Sistema Nervoso Periférico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , China , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Neuropatias Diabéticas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/diagnóstico
19.
Int J Mol Sci ; 21(1)2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31906113

RESUMO

Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain's pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3-CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.


Assuntos
Transtornos Mentais/metabolismo , Doenças do Sistema Nervoso/metabolismo , Neurregulinas/metabolismo , Plasticidade Neuronal , Transmissão Sináptica , Animais , Receptores ErbB , Hipocampo/metabolismo , Humanos , Transtornos Mentais/patologia , Mesencéfalo/metabolismo , Doenças do Sistema Nervoso/patologia
20.
PLoS Biol ; 16(10): e3000027, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30379844

RESUMO

Extensive apoptosis is often seen in patterning mutants, suggesting that tissues can detect and eliminate potentially harmful mis-specified cells. Here, we show that the pattern of apoptosis in the embryonic epidermis of Drosophila is not a response to fate mis-specification but can instead be explained by the limiting availability of prosurvival signaling molecules released from locations determined by patterning information. In wild-type embryos, the segmentation cascade elicits the segmental production of several epidermal growth factor receptor (EGFR) ligands, including the transforming growth factor Spitz (TGFα), and the neuregulin, Vein. This leads to an undulating pattern of signaling activity, which prevents expression of the proapoptotic gene head involution defective (hid) throughout the epidermis. In segmentation mutants, where specific peaks of EGFR ligands fail to form, gaps in signaling activity appear, leading to coincident hid up-regulation and subsequent cell death. These data provide a mechanistic understanding of how cell survival, and thus appropriate tissue size, is made contingent on correct patterning.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Receptores ErbB/metabolismo , Receptores de Peptídeos de Invertebrados/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/genética , Apoptose/fisiologia , Padronização Corporal/genética , Padronização Corporal/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Epiderme/embriologia , Epiderme/metabolismo , Receptores ErbB/genética , Feminino , Genes de Insetos , Ligantes , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Neurregulinas/genética , Neurregulinas/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Receptores de Peptídeos de Invertebrados/genética , Transdução de Sinais
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