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[PMID]:28456012
[Au] Autor:Alizadeh A; Dyck SM; Kataria H; Shahriary GM; Nguyen DH; Santhosh KT; Karimi-Abdolrezaee S
[Ad] Endereço:Regenerative Medicine Program, Department of Physiology and Pathophysiology, Spinal Cord Research Centre, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada.
[Ti] Título:Neuregulin-1 positively modulates glial response and improves neurological recovery following traumatic spinal cord injury.
[So] Source:Glia;65(7):1152-1175, 2017 Jul.
[Is] ISSN:1098-1136
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spinal cord injury (SCI) results in glial activation and neuroinflammation, which play pivotal roles in the secondary injury mechanisms with both pro- and antiregeneration effects. Presently, little is known about the endogenous molecular mechanisms that regulate glial functions in the injured spinal cord. We previously reported that the expression of neuregulin-1 (Nrg-1) is acutely and chronically declined following traumatic SCI. Here, we investigated the potential ramifications of Nrg-1 dysregulation on glial and immune cell reactivity following SCI. Using complementary in vitro approaches and a clinically-relevant model of severe compressive SCI in rats, we demonstrate that immediate delivery of Nrg-1 (500 ng/day) after injury enhances a neuroprotective phenotype in inflammatory cells associated with increased interleukin-10 and arginase-1 expression. We also found a decrease in proinflammatory factors including IL-1ß, TNF-α, matrix metalloproteinases (MMP-2 and 9) and nitric oxide after injury. In addition, Nrg-1 modulates astrogliosis and scar formation by reducing inhibitory chondroitin sulfate proteoglycans after SCI. Mechanistically, Nrg-1 effects on activated glia are mediated through ErbB2 tyrosine phosphorylation in an ErbB2/3 heterodimer complex. Furthermore, Nrg-1 exerts its effects through downregulation of MyD88, a downstream adaptor of Toll-like receptors, and increased phosphorylation of Erk1/2 and STAT3. Nrg-1 treatment with the therapeutic dosage of 1.5 µg/day significantly improves tissue preservation and functional recovery following SCI. Our findings for the first time provide novel insights into the role and mechanisms of Nrg-1 in acute SCI and suggest a positive immunomodulatory role for Nrg-1 that can harness the beneficial properties of activated glia and inflammatory cells in recovery following SCI.
[Mh] Termos MeSH primário: Doenças do Sistema Nervoso/tratamento farmacológico
Doenças do Sistema Nervoso/etiologia
Neuregulina-1/uso terapêutico
Neuroglia/fisiologia
Recuperação de Função Fisiológica/fisiologia
Traumatismos da Medula Espinal/complicações
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Arginase/metabolismo
Células Cultivadas
Meios de Cultivo Condicionados/farmacologia
Modelos Animais de Doenças
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/fisiologia
Proteína Glial Fibrilar Ácida/metabolismo
Interleucina-10/metabolismo
Lipopolissacarídeos/toxicidade
Locomoção/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos C57BL
Neuregulina-1/metabolismo
Neuregulina-1/farmacologia
Neuroglia/efeitos dos fármacos
Ratos
Recuperação de Função Fisiológica/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Traumatismos da Medula Espinal/patologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Culture Media, Conditioned); 0 (Glial Fibrillary Acidic Protein); 0 (Lipopolysaccharides); 0 (Neuregulin-1); 130068-27-8 (Interleukin-10); EC 3.5.3.1 (Arginase); EC 3.5.3.1 (arginase I, rat)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1002/glia.23150


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[PMID]:29307828
[Au] Autor:Wang X; Min S; Xie F; Yang J; Li L; Chen J
[Ad] Endereço:Department of Anesthesiology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
[Ti] Título:Glial cell-derived neurotrophic factor alleviates sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nicotinic acetylcholine receptors in an experimental rat model of neuromyopathy.
[So] Source:Biochem Biophys Res Commun;496(2):260-266, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sepsis-induced neuromuscular dysfunction results from up-regulation of the expression of γ- and α7-nicotinic acetylcholine receptors (nAChR). Although glial cell derived neurotrophic factor (GDNF) has been implicated in repairing and supporting neurons, little is known about the effects of GDNF on demyelination of nerves in sepsis. In this study, we tested the hypothesis that GDNF could alleviate sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nAChR in an experimental rat model of neuromyopathy. Rats were randomly divided into a sham group and a sepsis group. Levels of inflammatory factors, muscle function, and nicotinic acetylcholine receptors were tested in rats after cecal ligation and puncture (CLP). At 24 h after CLP, GDNF was injected around the sciatic nerve of sepsis rats, cytokines were detected by enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining was used to detect the expression of nAChRs. GDNF and its downstream effector (Erk1/2 and GFR-α), neuregulin-1 (NRG-1) and γ- and α7-nAChR were measured using Western blot analysis. The expression of GDNF reached a minimum at 24 h after CLP. Compared with the sham group, the release of cytokines and the expression of γ- and α7-nAChR were significantly increased in the sepsis group. The administration of GDNF significantly alleviated sepsis-induced neuromuscular dysfunction, as well as reducing the expression of γ- and α7-nAChR. In addition, the expression of Erk1/2, GFR-α, NRG-1 were significantly increased after GDNF treatment. GDNF administration may improve patient outcomes by reducing the demyelination of nerves and the expression of γ- and α7-nAChR.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Doenças Desmielinizantes/tratamento farmacológico
Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia
Doenças Musculares/tratamento farmacológico
Fármacos Neuroprotetores/farmacologia
Sepse/tratamento farmacológico
Receptor Nicotínico de Acetilcolina alfa7/genética
[Mh] Termos MeSH secundário: Animais
Citocinas/genética
Citocinas/metabolismo
Doenças Desmielinizantes/genética
Doenças Desmielinizantes/metabolismo
Doenças Desmielinizantes/patologia
Modelos Animais de Doenças
Regulação da Expressão Gênica
Fatores de Troca do Nucleotídeo Guanina/genética
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Masculino
Proteína Quinase 1 Ativada por Mitógeno/genética
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/genética
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Doenças Musculares/genética
Doenças Musculares/metabolismo
Doenças Musculares/patologia
Neuregulina-1/genética
Neuregulina-1/metabolismo
Junção Neuromuscular/efeitos dos fármacos
Junção Neuromuscular/metabolismo
Junção Neuromuscular/patologia
Isoformas de Proteínas/antagonistas & inibidores
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Ratos
Ratos Sprague-Dawley
Nervo Isquiático/efeitos dos fármacos
Nervo Isquiático/metabolismo
Nervo Isquiático/patologia
Sepse/genética
Sepse/metabolismo
Sepse/patologia
Transdução de Sinais
Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
Receptor Nicotínico de Acetilcolina alfa7/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Cytokines); 0 (Glial Cell Line-Derived Neurotrophic Factor); 0 (Guanine Nucleotide Exchange Factors); 0 (Neuregulin-1); 0 (Neuroprotective Agents); 0 (Nrg1 protein, rat); 0 (Protein Isoforms); 0 (alpha7 Nicotinic Acetylcholine Receptor); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


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[PMID]:27770508
[Au] Autor:Duruisseaux M; McLeer-Florin A; Antoine M; Alavizadeh S; Poulot V; Lacave R; Rabbe N; Cadranel J; Wislez M
[Ad] Endereço:Sorbonne Universités, UPMC University Paris 06, GRC n°04, Theranoscan, F-75252, Paris, France.
[Ti] Título:NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.
[So] Source:Cancer Med;5(12):3579-3585, 2016 Dec.
[Is] ISSN:2045-7634
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28-87% of the cases. NRG1 fusions were recently discovered in KRAS-negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed. In the IMA samples remaining negative for these driver oncogenes, an NRG1 rearrangement detection was performed by FISH. A driver oncogene was identified in 14/25 IMA, namely 12 KRAS mutations (48%), one ROS1 rearrangement (4%), and one ALK rearrangement (4%). The detection of NRG1 rearrangement by FISH was conducted in the 11 pan-negative IMA. One sample was NRG1FISH-positive and 100% of the tumor nuclei analyzed were positive. This NRG1-positive patient was a 61-year-old nonsmoking woman of Vietnamese ethnicity and was the sole patient of Asian ethnicity of the cohort. She died 6 months after the diagnosis with a pulmonary multifocal disease. NRG1FISH detection should be considered in patients with IMA pan-negative for known driver oncogenes. These results might suggest that NRG1 fusion is more frequent in IMA from Asian patient. Larger studies are needed.
[Mh] Termos MeSH primário: Adenocarcinoma Mucinoso/genética
Adenocarcinoma Mucinoso/patologia
Adenocarcinoma/genética
Adenocarcinoma/patologia
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Neuregulina-1/genética
Proteínas de Fusão Oncogênicas/genética
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais
Estudos de Coortes
Feminino
Seres Humanos
Imuno-Histoquímica
Hibridização in Situ Fluorescente
Masculino
Meia-Idade
Mutação
Invasividade Neoplásica
Neuregulina-1/metabolismo
Proteínas de Fusão Oncogênicas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (NRG1 protein, human); 0 (Neuregulin-1); 0 (Oncogene Proteins, Fusion)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1002/cam4.838


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[PMID]:28938399
[Au] Autor:Chowdhury I; Branch A; Mehrabi S; Ford BD; Thompson WE
[Ad] Endereço:Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, Georgia 30310.
[Ti] Título:Gonadotropin-Dependent Neuregulin-1 Signaling Regulates Female Rat Ovarian Granulosa Cell Survival.
[So] Source:Endocrinology;158(10):3647-3660, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mammalian ovarian follicular development and maturation of an oocyte competent to be fertilized and develop into an embryo depends on tightly regulated, spatiotemporally orchestrated crosstalk among cell death, survival, and differentiation signals through extra- and intraovarian signals, as well as on a permissive ovarian follicular microenvironment. Neuregulin-1 (NRG1) is a member of the epidermal growth factor-like factor family that mediates its effects by binding to a member of the erythroblastoma (ErbB) family. Our experimental results suggest gonadotropins promote differential expression of NRG1 and erbB receptors in granulosa cells (GCs), and NRG1 in theca cells during follicular development, and promote NRG1 secretions in the follicular fluid (FF) of rat ovaries. During the estrous cycle of rat, NRG1 and erbB receptors are differentially expressed in GCs and correlate positively with serum gonadotropins and steroid hormones. Moreover, in vitro experimental studies suggest that the protein kinase C inhibitor staurosporine (STS) causes the physical destruction of GCs by the activation of caspase-3. Exogenous NRG1 treatment of GCs delayed onset of STS-induced apoptosis and inhibited cleaved caspase-3 expressions. Moreover, exogenous NRG1 treatment of GCs alters STS-induced death by maintaining the expression of ErbB2, ErbB3, pAkt, Bcl2, and BclxL proteins. Taken together, these studies demonstrate that NRG1 is gonadotropin dependent, differentially regulated in GCs and theca cells, and secreted in ovarian FF as an intracellular survival factor that may govern follicular maturation.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Sobrevivência Celular
Receptores ErbB/efeitos dos fármacos
Gonadotropinas/farmacologia
Células da Granulosa/efeitos dos fármacos
Neuregulina-1/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Caspase 3/efeitos dos fármacos
Caspase 3/metabolismo
Receptores ErbB/metabolismo
Feminino
Líquido Folicular
Células da Granulosa/metabolismo
Técnicas In Vitro
Neuregulina-1/metabolismo
Neuregulina-1/farmacologia
Folículo Ovariano/crescimento & desenvolvimento
Ovário/citologia
Ovário/efeitos dos fármacos
Ovário/metabolismo
Fosfoproteínas/efeitos dos fármacos
Fosfoproteínas/metabolismo
Proteína Quinase C/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor ErbB-2/efeitos dos fármacos
Receptor ErbB-2/metabolismo
Receptor ErbB-3/efeitos dos fármacos
Receptor ErbB-3/metabolismo
Estaurosporina/farmacologia
Células Tecais
Proteína bcl-X/efeitos dos fármacos
Proteína bcl-X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bcl2 protein, rat); 0 (Bcl2l1 protein, rat); 0 (Gonadotropins); 0 (Neuregulin-1); 0 (Nrg1 protein, rat); 0 (Phosphoproteins); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (bcl-X Protein); EC 2.7.10.1 (ErbB Receptors); EC 2.7.10.1 (Erbb2 protein, rat); EC 2.7.10.1 (Erbb3 protein, rat); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Receptor, ErbB-3); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.13 (Protein Kinase C); EC 3.4.22.- (Casp3 protein, rat); EC 3.4.22.- (Caspase 3); H88EPA0A3N (Staurosporine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00065


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[PMID]:28860329
[Au] Autor:Fledrich R; Mannil M; Leha A; Ehbrecht C; Solari A; Pelayo-Negro AL; Berciano J; Schlotter-Weigel B; Schnizer TJ; Prukop T; Garcia-Angarita N; Czesnik D; Haberlová J; Mazanec R; Paulus W; Beissbarth T; Walter MC; Triaal C; Hogrel JY; Dubourg O; Schenone A; Baets J; De Jonghe P; Shy ME; Horvath R; Pareyson D; Seeman P; Young P; Sereda MW
[Ad] Endereço:Department of Clinical Neurophysiology, University Medical Center Göttingen (UMG), Göttingen, Germany.
[Ti] Título:Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A.
[So] Source:J Neurol Neurosurg Psychiatry;88(11):941-952, 2017 Nov.
[Is] ISSN:1468-330X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.
[Mh] Termos MeSH primário: Doença de Charcot-Marie-Tooth/terapia
Progressão da Doença
Marcadores Genéticos/genética
Pele/patologia
Resultado do Tratamento
[Mh] Termos MeSH secundário: Adulto
Idoso
Biópsia
Catepsina A/genética
Doença de Charcot-Marie-Tooth/sangue
Doença de Charcot-Marie-Tooth/genética
Feminino
Glutationa Transferase/genética
Glicoproteínas/genética
Seres Humanos
Masculino
Meia-Idade
Neuregulina-1/genética
PPAR gama/genética
Diester Fosfórico Hidrolases/genética
Prognóstico
Pirofosfatases/genética
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
Transcrição Genética/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDAN1 protein, human); 0 (Genetic Markers); 0 (Glycoproteins); 0 (NRG1 protein, human); 0 (Neuregulin-1); 0 (PPAR gamma); 0 (RNA, Messenger); EC 2.5.1.- (GSTT2 protein, human); EC 2.5.1.18 (Glutathione Transferase); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.1 (ectonucleotide pyrophosphatase phosphodiesterase 1); EC 3.4.16.5 (CTSA protein, human); EC 3.4.16.5 (Cathepsin A); EC 3.6.1.- (Pyrophosphatases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170902
[St] Status:MEDLINE
[do] DOI:10.1136/jnnp-2017-315721


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[PMID]:28796037
[Au] Autor:Ruan L; Yang Y; Huang Y; Ding L; Zhang C; Wu X
[Ad] Endereço:Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
[Ti] Título:Functional prediction of miR-3144-5p in human cardiac myocytes based on transcriptome sequencing and bioinformatics.
[So] Source:Medicine (Baltimore);96(32):e7539, 2017 Aug.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: RAN guanine nucleotide release factor (RANGRF) encoding protein MOG1 plays an important role in cardiac arrhythmia, so we intended to investigate the regulatory miRNA of RANGRF and explore its potential regulatory mechanism in arrhythmogenesis. METHODS: Based on bioinformatic analysis, miR-3144-5p was predicted to be a regulatory miRNA of RANGRF, which were then validated through a dual-luciferase reporter plasmid assay. Subsequently, the expression level of miR-3144-5p in human cardiac myocytes (HCMs) was detected, followed by cell transfection with miR-3144-5p mimics. Transcriptome sequencing was then performed in HCMs with or without transfection. The sequencing results were subjected to bioinformatic analyses, including differentially expressed gene (DEG) analysis, functional enrichment analysis, protein-protein interaction (PPI) network analysis, miRNA-target gene analysis, and miRNA-transcription factor (TF)-target gene coregulatory network analysis. RESULTS: There really existed a regulatory relation between miR-3144-5p and RANGRF. The expression level of miR-3144-5p was low in HCMs. After cell transfection, miR-3144-5p expression level significantly increased in HCMs. Bioinformatic analyses of the transcriptome sequencing results identified 300 upregulated and 271 downregulated DEGs between miR-3144-5p mimic and control group. The upregulated genes ISL1 and neuregulin 1 (NRG1) were significantly enriched in cardiac muscle cell myoblast differentiation (GO:0060379). CCL21 was one of the hub genes in the PPI network and also a target gene of miR-3144-5p. Moreover, the TF of v-Myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN) was involved in the miR-3144-5p-TF-target gene coregulatory network and interacted with the target genes of miR-3144-5p. CONCLUSION: ISL1, NRG1, CCL21, and MYCN were differentially expressed in the miR-3144-5p mimic group, suggesting that miR-3144-5p overexpression plays a role in HCMs by regulating these genes and TF. This study may provide new insight into the mechanisms behind the progression of cardiac arrhythmia.
[Mh] Termos MeSH primário: Biologia Computacional/métodos
MicroRNAs/biossíntese
Miócitos Cardíacos/metabolismo
Proteína ran de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Quimiocina CCL21/biossíntese
Perfilação da Expressão Gênica
Seres Humanos
Proteínas com Homeodomínio LIM/biossíntese
Proteína Proto-Oncogênica N-Myc/biossíntese
Neuregulina-1/biossíntese
Fatores de Transcrição/biossíntese
Transcriptoma
Regulação para Cima
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCL21 protein, human); 0 (Chemokine CCL21); 0 (LIM-Homeodomain Proteins); 0 (MYCN protein, human); 0 (MicroRNAs); 0 (N-Myc Proto-Oncogene Protein); 0 (NRG1 protein, human); 0 (Neuregulin-1); 0 (Transcription Factors); 0 (insulin gene enhancer binding protein Isl-1); EC 3.6.1.- (RANGNRF protein, human); EC 3.6.5.2 (ran GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170827
[Lr] Data última revisão:
170827
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007539


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[PMID]:28780372
[Au] Autor:Huang Z; Sawyer DB; Troy EL; McEwen C; Cleator JH; Murphy A; Caggiano AO; Eisen A; Parry TJ
[Ad] Endereço:Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: huang5994@yahoo.com.
[Ti] Título:Species-specific effects of neuregulin-1ß (cimaglermin alfa) on glucose handling in animal models and humans with heart failure.
[So] Source:Toxicol Appl Pharmacol;332:92-99, 2017 Oct 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neuregulin-1ß is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1ß, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1ß stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8mg/kg and 2.6mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2h after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2h after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects.
[Mh] Termos MeSH primário: Glicemia/metabolismo
Insuficiência Cardíaca/sangue
Neuregulina-1/farmacologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Animais
Diabetes Mellitus Experimental/tratamento farmacológico
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Insulina/sangue
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Meia-Idade
Modelos Animais
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/metabolismo
Especificidade da Espécie
Suínos
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Insulin); 0 (Neuregulin-1); 0 (neuregulin beta)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170807
[St] Status:MEDLINE


  8 / 1791 MEDLINE  
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[PMID]:28723928
[Au] Autor:Alvarado D; Ligon GF; Lillquist JS; Seibel SB; Wallweber G; Neumeister VM; Rimm DL; McMahon G; LaVallee TM
[Ad] Endereço:Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
[Ti] Título:ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC.
[So] Source:PLoS One;12(7):e0181356, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma de Células Escamosas/metabolismo
Cetuximab/farmacologia
Neoplasias de Cabeça e Pescoço/metabolismo
Receptor do Fator de Crescimento Epidérmico/metabolismo
Receptor ErbB-3/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Biomarcadores Tumorais/metabolismo
Carcinoma de Células Escamosas/tratamento farmacológico
Carcinoma de Células Escamosas/patologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Cetuximab/uso terapêutico
Neoplasias de Cabeça e Pescoço/tratamento farmacológico
Neoplasias de Cabeça e Pescoço/patologia
Seres Humanos
Neuregulina-1/metabolismo
Receptor ErbB-2/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Neuregulin-1); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Receptor, ErbB-3); PQX0D8J21J (Cetuximab)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181356


  9 / 1791 MEDLINE  
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[PMID]:28698179
[Au] Autor:Sun Y; Yang Z; Zheng B; Zhang XH; Zhang ML; Zhao XS; Zhao HY; Suzuki T; Wen JK
[Ad] Endereço:From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University (Y.S., Z.Y., B.Z., X.-h.Z., M.-l.Z., X.-s.Z., H.-y.Z., J.-k.W.); Department of Urology, The Second Hospital of Hebei Medical Universi
[Ti] Título:A Novel Regulatory Mechanism of Smooth Muscle α-Actin Expression by NRG-1/circACTA2/miR-548f-5p Axis.
[So] Source:Circ Res;121(6):628-635, 2017 Sep 01.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Neuregulin-1 (NRG-1) includes an extracellular epidermal growth factor-like domain and an intracellular domain (NRG-1-ICD). In response to transforming growth factor-ß1, its cleavage by proteolytic enzymes releases a bioactive fragment, which suppresses the vascular smooth muscle cell (VSMC) proliferation by activating ErbB (erythroblastic leukemia viral oncogene homolog) receptor. However, NRG-1-ICD function in VSMCs remains unknown. OBJECTIVE: Here, we characterize the function of NRG-1-ICD and underlying mechanisms in VSMCs. METHODS AND RESULTS: Immunofluorescence staining, Western blotting, and quantitative real-time polymerase chain reaction showed that NRG-1 was expressed in rat, mouse, and human VSMCs and was upregulated and cleaved in response to transforming growth factor-ß1. In the cytoplasm of HASMCs (human aortic smooth muscle cells), the NRG-1-ICD participated in filamentous actin formation by interacting with α-SMA (smooth muscle α-actin). In the nucleus, the Nrg-1-ICD induced circular ACTA2 (alpha-actin-2; circACTA2) formation by recruitment of the zinc-finger transcription factor IKZF1 (IKAROS family zinc finger 1) to the first intron of α-SMA gene. We further confirmed that circACTA2, acting as a sponge binding microRNA (miR)-548f-5p, interacted with miR-548f-5p targeting 3' untranslated region of α-SMA mRNA, which in turn relieves miR-548f-5p repression of the α-SMA expression and thus upregulates α-SMA expression, thereby facilitating stress fiber formation and cell contraction in HASMCs. Accordingly, in vivo studies demonstrated that the localization of the interaction of circACTA2 with miR-548f-5p is significantly decreased in human intimal hyperplastic arteries compared with normal arteries, implicating that dysregulation of circACTA2 and miR-548f-5p expression is involved in intimal hyperplasia. CONCLUSIONS: These results suggest that circACTA2 mediates NRG-1-ICD regulation of α-SMA expression in HASMCs via the NRG-1-ICD/circACTA2/miR-548f-5p axis. Our data provide a molecular basis for fine-tuning α-SMA expression and VSMC contraction by transcription factor, circular RNA, and microRNA.
[Mh] Termos MeSH primário: Actinas/metabolismo
MicroRNAs/genética
Músculo Liso Vascular/metabolismo
Miócitos de Músculo Liso/metabolismo
Neuregulina-1/metabolismo
[Mh] Termos MeSH secundário: Actinas/genética
Animais
Células Cultivadas
Células HEK293
Seres Humanos
Fator de Transcrição Ikaros/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
MicroRNAs/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (MicroRNAs); 0 (Neuregulin-1); 148971-36-2 (Ikaros Transcription Factor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.117.311441


  10 / 1791 MEDLINE  
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[PMID]:28636612
[Au] Autor:Ghidinelli M; Poitelon Y; Shin YK; Ameroso D; Williamson C; Ferri C; Pellegatta M; Espino K; Mogha A; Monk K; Podini P; Taveggia C; Nave KA; Wrabetz L; Park HT; Feltri ML
[Ad] Endereço:Hunter James Kelly Research Institute, Department of Biochemistry and Neurology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
[Ti] Título:Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination.
[So] Source:PLoS Biol;15(6):e2001408, 2017 Jun.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2ß1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Laminina/metabolismo
Bainha de Mielina/metabolismo
Neuregulina-1/metabolismo
Células de Schwann/metabolismo
[Mh] Termos MeSH secundário: Animais
Axônios/metabolismo
Western Blotting
Células Cultivadas
Laminina/genética
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Microscopia Eletrônica de Transmissão
Modelos Neurológicos
Neuregulina-1/genética
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Nervo Isquiático/citologia
Nervo Isquiático/metabolismo
Nervo Isquiático/ultraestrutura
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lamb1-1 protein, mouse); 0 (Laminin); 0 (Neuregulin-1); 0 (laminin alpha 2); 0 (laminin gamma 1); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2001408



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