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[PMID]: 27777505 [Au] Autor: Kosior-Jarecka E; Wróbel-Dudzinska D; Lukasik U; Aung T; Khor CC; Kocki J; Zarnowski T [Ad] Endereço: Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland. [Ti] Título: Plasma endothelin-1 and single nucleotide polymorphisms of as risk factors for normal tension glaucoma. [So] Source: Mol Vis;22:1256-1266, 2016. [Is] ISSN: 1090-0535 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PURPOSE: The purpose of this study was to determine whether four single nucleotide polymorphisms (SNPs) of can constitute a risk factor for normal tension glaucoma (NTG) and high tension glaucoma (HTG). METHODS: The study included 160 patients with NTG, 124 patients with HTG, and 165 healthy controls. To analyze the frequency of polymorphic variants of the (K198N) and the (C1222T, C70G, G231A), DNA was isolated from peripheral blood, and SNP genotyping was performed using the real-time PCR (RT-PCR) method. Plasma endothelin (ET) concentrations were detected using an enzyme immunoassay. Endothelin levels were compared with genotype and allele distributions, patients' clinical status, and various risk factors for NTG. RESULTS: There was a significant difference between the patients with NTG and HTG and the controls (p = 0.035, p = 0.008) regarding the genotype of the C1222T and C70G polymorphism. Plasma concentrations of ET did not differ between the NTG and HTG groups, and no significant correlation with intraocular pressure (IOP), best-corrected visual acuity (BCVA), and the cup to disc ratio (c/d ratio) was seen in patients with NTG. Plasma endothelin levels showed a noticeably positive correlation with age in the NTG group (R = 0.249, p = 0.042). Higher endothelin levels corresponded to more advanced visual field damage. No statistical difference was observed between variant genotypes of K198N and the ET-1 plasma concentration in patients with NTG, whereas a slightly higher ET level was observed in the patients with HTG with the GT genotype in comparison to those with the GG genotype (p = 0.001). The C1222T polymorphism significantly affected the plasma ET level in patients with NTG. The TT genotype carriers had the highest ET level, and the CC genotype carriers the lowest (p = 0.034). The AA variant genotype of the G231A polymorphism exhibited the highest ET level, while the GG variant genotype represented the lowest level (p = 0.033). No significant differences were observed regarding the endothelin levels and the frequency of notches, peripapillary atrophy, low blood pressure, cold extremities, or migraine in the two groups studied. Slightly lower endothelin plasma levels were observed in patients with optic disc hemorrhages in the NTG group (p = 0.05). CONCLUSIONS: Polymorphic variants of (K198N) and (C1222T, C70G, G231A) affected ET plasma concentrations. There was no association between the plasma endothelin levels and the risk factors for NTG. According to these results, plasma endothelin concentrations do not appear to be a marker for NTG. [Mh] Termos MeSH primário: Endotelina-1/sangue Endotelina-1/genética Glaucoma de Baixa Tensão/genética Polimorfismo de Nucleotídeo Único Receptor de Endotelina A/genética [Mh] Termos MeSH secundário: Idoso Ensaio de Imunoadsorção Enzimática Feminino Técnicas de Genotipagem Seres Humanos Pressão Intraocular Glaucoma de Baixa Tensão/sangue Masculino Reação em Cadeia da Polimerase em Tempo Real Fatores de Risco Acuidade Visual [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Endothelin-1); 0 (Receptor, Endothelin A) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180130 [Lr] Data última revisão: 180130 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161026 [St] Status: MEDLINE

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[PMID]: 29203627 [Au] Autor: Schinzari F; Tesauro M; Veneziani A; Mores N; Di Daniele N; Cardillo C [Ad] Endereço: From the Policlinico A. Gemelli, Rome, Italy (F.S., A.V., N.M., C.C.); Department of Internal Medicine, University of Tor Vergata, Rome, Italy (M.T., N.D.D.); and Departments of Surgery (A.V.), Pharmacology (N.M.), and Internal Medicine (C.C.), Catholic University, Rome, Italy. [Ti] Título: Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity. [So] Source: Hypertension;71(1):185-191, 2018 01. [Is] ISSN: 1524-4563 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow ( =0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; >0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both >0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) ( =0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified ( =0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; <0.001); nitric oxide inhibition by l- -monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) ( =0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity. [Mh] Termos MeSH primário: Angiotensina I/metabolismo Endotelina-1/metabolismo Insulina Obesidade Fragmentos de Peptídeos/metabolismo Fluxo Sanguíneo Regional/efeitos dos fármacos Vasoconstrição Vasodilatação [Mh] Termos MeSH secundário: Adulto Feminino Antebraço/irrigação sanguínea Seres Humanos Insulina/metabolismo Insulina/farmacocinética Masculino Meia-Idade Obesidade/metabolismo Obesidade/fisiopatologia Receptor de Endotelina A/metabolismo Fluxo Sanguíneo Regional/fisiologia Estatística como Assunto Vasoconstrição/efeitos dos fármacos Vasoconstrição/fisiologia Vasoconstritores/farmacologia Vasodilatação/efeitos dos fármacos Vasodilatação/fisiologia Vasodilatadores/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Endothelin-1); 0 (Insulin); 0 (Peptide Fragments); 0 (Receptor, Endothelin A); 0 (Vasoconstrictor Agents); 0 (Vasodilator Agents); 9041-90-1 (Angiotensin I); IJ3FUK8MOF (angiotensin I (1-7)) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180113 [Lr] Data última revisão: 180113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171206 [St] Status: MEDLINE [do] DOI: 10.1161/HYPERTENSIONAHA.117.10280

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[PMID]: 28462837 [Au] Autor: Khadtare N; Stephani R; Korlipara V [Ad] Endereço: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States. [Ti] Título: Design, synthesis and evaluation of 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives as ET receptor selective antagonists using FRET assay. [So] Source: Bioorg Med Chem Lett;27(11):2281-2285, 2017 06 01. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The endothelin axis and in particular the two receptor subtypes, ET and ET , are under investigation for the treatment of various diseases such as pulmonary arterial hypertension, fibrosis, renal failure and cancer. Previous work in our lab has shown that 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives exhibit noteworthy endothelin receptor antagonist activity. A series of analogues with modifications centered around position 6 of the heterocyclic quinolone core and replacement of the aryl carboxylic acid group with an isosteric tetrazole ring was designed and synthesized to further optimize the structure activity relationship. The endothelin receptor antagonist activity was determined by in vitro Förster resonance energy transfer (FRET) using GeneBLAzer® assay technology. The most potent member of this series exhibited ET receptor antagonist activity in the subnanomolar range with an IC value of 0.8nM, and was 1000-fold selective for the ET receptor compared to the ET receptor. Its activity and selectivity profile resembles that of the most recently approved drug, macitentan. [Mh] Termos MeSH primário: Ácidos Carboxílicos/química Ácidos Carboxílicos/farmacologia Quinolinas/química Quinolinas/farmacologia Receptor de Endotelina A/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Ácidos Carboxílicos/síntese química Antagonistas dos Receptores de Endotelina/síntese química Antagonistas dos Receptores de Endotelina/química Antagonistas dos Receptores de Endotelina/farmacologia Transferência Ressonante de Energia de Fluorescência Seres Humanos Concentração Inibidora 50 Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (1,4-dihydroquinoline); 0 (Carboxylic Acids); 0 (Endothelin Receptor Antagonists); 0 (Quinolines); 0 (Receptor, Endothelin A) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171124 [Lr] Data última revisão: 171124 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE

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[PMID]: 28455376 [Au] Autor: Tavares ALP; Cox TC; Maxson RM; Ford HL; Clouthier DE [Ad] Endereço: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. [Ti] Título: Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development. [So] Source: Development;144(11):2021-2031, 2017 06 01. [Is] ISSN: 1477-9129 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Jaw morphogenesis is a complex event mediated by inductive signals that establish and maintain the distinct developmental domains required for formation of hinged jaws, the defining feature of gnathostomes. The mandibular portion of pharyngeal arch 1 is patterned dorsally by Jagged-Notch signaling and ventrally by endothelin receptor A (EDNRA) signaling. Loss of EDNRA signaling disrupts normal ventral gene expression, the result of which is homeotic transformation of the mandible into a maxilla-like structure. However, loss of Jagged-Notch signaling does not result in significant changes in maxillary development. Here we show in mouse that the transcription factor SIX1 regulates dorsal arch development not only by inducing dorsal expression but also by inhibiting endothelin 1 ( ) expression in the pharyngeal endoderm of the dorsal arch, thus preventing dorsal EDNRA signaling. In the absence of SIX1, but not JAG1, aberrant EDNRA signaling in the dorsal domain results in partial duplication of the mandible. Together, our results illustrate that SIX1 is the central mediator of dorsal mandibular arch identity, thus ensuring separation of bone development between the upper and lower jaws. [Mh] Termos MeSH primário: Endotelina-1/metabolismo Proteínas de Homeodomínio/metabolismo Maxila/embriologia Maxila/metabolismo Transdução de Sinais [Mh] Termos MeSH secundário: Animais Padronização Corporal/genética Região Branquial/metabolismo Anormalidades Craniofaciais/embriologia Anormalidades Craniofaciais/genética Anormalidades Craniofaciais/patologia Embrião de Mamíferos/metabolismo Regulação da Expressão Gênica no Desenvolvimento Integrases/metabolismo Camundongos Modelos Biológicos Crista Neural/metabolismo Receptor de Endotelina A/metabolismo Receptores Notch/metabolismo Proteínas Serrate-Jagged/metabolismo Fator de Transcrição Sp7 Fatores de Transcrição/genética Fatores de Transcrição/metabolismo Regulação para Cima/genética Zigoma/embriologia Zigoma/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Endothelin-1); 0 (Homeodomain Proteins); 0 (Receptor, Endothelin A); 0 (Receptors, Notch); 0 (Serrate-Jagged Proteins); 0 (Six1 protein, mouse); 0 (Sp7 Transcription Factor); 0 (Sp7 protein, mouse); 0 (Transcription Factors); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171126 [Lr] Data última revisão: 171126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE [do] DOI: 10.1242/dev.145144

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[PMID]: 28802097 [Au] Autor: Zhao Y; Dang Z; Xu S; Chong S [Ad] Endereço: . [Ti] Título: Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice. [So] Source: Biol Chem;398(12):1357-1366, 2017 Nov 27. [Is] ISSN: 1437-4315 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: The study aimed to explore the regulation of heat shock protein 47 (HSP47) on expressions of receptors associated with hepatic stellate cell (HSC) in liver fibrosis mouse models induced by Schistosoma japonicum (S. japonicum). Mouse fibroblasts (NIH/3T3) were transfected with HSP47 shRNA plasmid by lipofectamine transfection, and experimental fibrosis in HSCs was studied in S. japonicum mouse models treated with HSP47 shRNA in vivo. HSP47 expression was assessed using Western blot and real-time PCR. Flow cytometry was adopted to determine the expression of cell membrane receptors. HSP47-shRNA could markedly down-regulate the expression of collagen (Col1a1 and Col3a1). The expressions of HSP47, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) significantly increased in the liver tissue of infected mice. However, the expressions of ETAR and HSP47 and ETBR remarkably decreased after the administration of HSP47 shRNA in vitro and in vivo. ETAR and ETBR levels were found to be positively correlated with HSP47 expression. HSP47 might exert influence on liver fibrosis via the regulation of ETAR and ETBR. [Mh] Termos MeSH primário: Proteínas de Choque Térmico HSP47/metabolismo Células Estreladas do Fígado/metabolismo Cirrose Hepática/metabolismo Receptor de Endotelina A/metabolismo Receptor de Endotelina B/metabolismo Schistosoma japonicum/metabolismo [Mh] Termos MeSH secundário: Animais Células Cultivadas Modelos Animais de Doenças Feminino Células Estreladas do Fígado/patologia Cirrose Hepática/patologia Camundongos Camundongos Endogâmicos BALB C Células NIH 3T3 Schistosoma japonicum/parasitologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (HSP47 Heat-Shock Proteins); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (Serpinh1 protein, mouse) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171113 [Lr] Data última revisão: 171113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170813 [St] Status: MEDLINE

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[PMID]: 28758529 [Au] Autor: Rosanò L; Cianfrocca R; Sestito R; Tocci P; Di Castro V; Bagnato A [Ad] Endereço: a Preclinical Models and New Therapeutic Agents Unit, Translational Research Functional Departmental Area , Regina Elena National Cancer Institute , Rome , Italy. [Ti] Título: Targeting endothelin-1 receptor/ß-arrestin1 network for the treatment of ovarian cancer. [So] Source: Expert Opin Ther Targets;21(10):925-932, 2017 Oct. [Is] ISSN: 1744-7631 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Endothelin-1 receptor (ET-1R)/ß-arrestin1 (ß-arr1) signaling is dysregulated in ovarian cancer. This signaling circuit enables cancer cells to engage several signaling and transcriptional networks that are pervasively intertwined, and represent a potential therapeutic target for developing novel agents for ovarian cancer treatment. Areas covered: In this article, we discuss the role of the signaling network between ET-1R and key pathways mediated by the scaffold protein ß-arr1, as part of signaling complex, or as a transcription co-activator, promoting precise control of transcription of different genes, including ET-1. Therefore ET-1R/ß-arr1 is an actionable node involved in the activation of a persistent feedback loop that contributes to bypass signaling. Targeting ET-1R empowering this circuit can represent a necessary measure to reach clinical efficacy. Preclinical studies demonstrate that blocking ET-1R by FDA approved dual ET R/ET R antagonist prevents ß-arr1 network formation, offering a novel therapeutic strategy in ovarian cancer patients. Expert opinion: The information provided in this review about the ET-1R/ß-arr1 hub represents an invaluable tool for both identifying the interconnected pathways involved in ovarian cancer and targeting them more effectively. The new perspective arising from ET-1R therapeutics will likely prompt a valuable frame for the design of new promising combinatorial therapy, blocking compensatory networks. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Terapia de Alvo Molecular Neoplasias Ovarianas/tratamento farmacológico [Mh] Termos MeSH secundário: Desenho de Drogas Feminino Seres Humanos Neoplasias Ovarianas/patologia Receptor de Endotelina A/efeitos dos fármacos Receptor de Endotelina A/metabolismo Receptor de Endotelina B/efeitos dos fármacos Receptor de Endotelina B/metabolismo Transdução de Sinais beta-Arrestina 1/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (beta-Arrestin 1) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170801 [St] Status: MEDLINE [do] DOI: 10.1080/14728222.2017.1361930

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[PMID]: 28720331 [Au] Autor: Park BG; Shin WS; Oh S; Park GM; Kim NI; Lee S [Ad] Endereço: Department of Physiology, Catholic Kwandong University College of Medicine, Gangneung 25601, Republic of Korea; Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 25601, Republic of Korea. [Ti] Título: A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca channel blocker and endothelin A/B receptor antagonist. [So] Source: Bioorg Med Chem;25(17):4649-4655, 2017 Sep 01. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK )-induced basilar artery contraction with EC values of 3.52±0.42 and 1.62±0.63µM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC =9.8±0.6µM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca channel and endothelin A/B receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension. [Mh] Termos MeSH primário: Anti-Hipertensivos/química Benzopiranos/química Bloqueadores dos Canais de Cálcio/química Antagonistas do Receptor de Endotelina A/química Antagonistas do Receptor de Endotelina B/química Feófitas/química [Mh] Termos MeSH secundário: Administração Oral Animais Anti-Hipertensivos/isolamento & purificação Anti-Hipertensivos/farmacologia Artéria Basilar/efeitos dos fármacos Artéria Basilar/fisiologia Benzopiranos/isolamento & purificação Benzopiranos/farmacologia Pressão Sanguínea/efeitos dos fármacos Bloqueadores dos Canais de Cálcio/isolamento & purificação Bloqueadores dos Canais de Cálcio/farmacologia Canais de Cálcio Tipo L/química Canais de Cálcio Tipo L/metabolismo Antagonistas do Receptor de Endotelina A/isolamento & purificação Antagonistas do Receptor de Endotelina A/farmacologia Antagonistas do Receptor de Endotelina B/isolamento & purificação Antagonistas do Receptor de Endotelina B/farmacologia Masculino Feófitas/metabolismo Coelhos Ratos Ratos Endogâmicos SHR Receptor de Endotelina A/química Receptor de Endotelina A/metabolismo Receptor de Endotelina B/química Receptor de Endotelina B/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antihypertensive Agents); 0 (Benzopyrans); 0 (Calcium Channel Blockers); 0 (Calcium Channels, L-Type); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (sargachromenol) [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: 170720 [St] Status: MEDLINE

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[PMID]: 28665894 [Au] Autor: OʼLeary JG; Demetris AJ; Philippe A; Freeman R; Cai J; Heidecke H; Smith C; Hart B; Jennings LW; Catar R; Everly M; Klintmalm GB; Dragun D [Ad] Endereço: 1 Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX. 2 Department of Pathology, University of Pittsburgh, Pittsburg, PA. 3 Department of Nephrology and Critical Care Medicine, Charité, Berlin, Germany. 4 Terasaki Foundation Laboratory, Los Angeles, CA. 5 Celltrend, Luckenwalde, Germany. [Ti] Título: Non-HLA Antibodies Impact on C4d Staining, Stellate Cell Activation and Fibrosis in Liver Allografts. [So] Source: Transplantation;101(10):2399-2409, 2017 Oct. [Is] ISSN: 1534-6080 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Recent data have shown an increased risk for rejection, fibrosis progression, and death in liver transplantation (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1 of 2000 to 4 of 2009 with known HLA DSA status for angiotensin II type-1 receptor and endothelin-1 type A receptor autoantibodies pre-LT, and year 1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death (hazard ratio [HR], 1.66; P = 0.02) especially if the HLA DSA was of the IgG3 subclass (HR, 2.28; P = 0.01). A single de novo non-HLA autoantibody was associated with an increased risk for T cell-mediated rejection or antibody-mediated rejection (68% vs 41%, P = 0.01) and fibrosis progression (HR, 1.84; P = 0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared with HLA DSA (71% vs 3%; P < 0.001). Liver sinusoidal endothelial cell activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-angiotensin II type-1 receptor and anti-endothelin-1 type A receptor autoantibodies are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to liver sinusoidal endothelial cell capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding. [Mh] Termos MeSH primário: Autoanticorpos/sangue Complemento C4b/imunologia Rejeição de Enxerto/imunologia Antígenos HLA/imunologia Células Estreladas do Fígado/imunologia Isoanticorpos/sangue Cirrose Hepática/imunologia Transplante de Fígado/efeitos adversos Fragmentos de Peptídeos/imunologia Receptor Tipo 1 de Angiotensina/imunologia Receptor de Endotelina A/imunologia [Mh] Termos MeSH secundário: Adulto Aloenxertos Biópsia Feminino Rejeição de Enxerto/diagnóstico Células Estreladas do Fígado/patologia Seres Humanos Estimativa de Kaplan-Meier Cirrose Hepática/diagnóstico Cirrose Hepática/mortalidade Transplante de Fígado/mortalidade Masculino Meia-Idade Estudos Retrospectivos Fatores de Risco Fatores de Tempo Resultado do Tratamento [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (AGTR1 protein, human); 0 (Autoantibodies); 0 (HLA Antigens); 0 (Isoantibodies); 0 (Peptide Fragments); 0 (Receptor, Angiotensin, Type 1); 0 (Receptor, Endothelin A); 80295-50-7 (Complement C4b); 80295-52-9 (complement C4d) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170701 [St] Status: MEDLINE [do] DOI: 10.1097/TP.0000000000001853

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[PMID]: 28606962 [Au] Autor: Planas-Rigol E; Terrades-Garcia N; Corbera-Bellalta M; Lozano E; Alba MA; Segarra M; Espígol-Frigolé G; Prieto-González S; Hernández-Rodríguez J; Preciado S; Lavilla R; Cid MC [Ad] Endereço: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CRB-CELLEX, Barcelona, Spain. [Ti] Título: Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis. [So] Source: Ann Rheum Dis;76(9):1624-1634, 2017 Sep. [Is] ISSN: 1468-2060 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Giant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function. OBJECTIVE: To investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA. METHODS AND RESULTS: Immunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ET R), were expressed by both mononuclear cells and VSMC. ET-1 increased TA-derived VSMC migration in vitro and α-smooth muscle actin (αSMA) expression and migration from the media to the intima in cultured TA explants. ET-1 promoted VSMC motility by increasing activation of focal adhesion kinase (FAK), a crucial molecule in the turnover of focal adhesions during cell migration. FAK activation resulted in Y397 autophosphorylation creating binding sites for Src kinases and the p85 subunit of PI3kinases which, upon ET-1 exposure, colocalised with FAK at the focal adhesions of migrating VSMC. Accordingly, FAK or PI3K inhibition abrogated ET-1-induced migration in vitro. Consistently, ET-1 receptor A and ET R antagonists reduced αSMA expression and delayed VSMC outgrowth from cultured GCA-involved artery explants. CONCLUSIONS: ET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA. [Mh] Termos MeSH primário: Movimento Celular/genética Endotelina-1/genética Arterite de Células Gigantes/genética Músculo Liso Vascular/metabolismo Miócitos de Músculo Liso/metabolismo Remodelação Vascular/genética [Mh] Termos MeSH secundário: Actinas/efeitos dos fármacos Actinas/genética Actinas/metabolismo Idoso Western Blotting Estudos de Casos e Controles Movimento Celular/efeitos dos fármacos Antagonistas dos Receptores de Endotelina/farmacologia Endotelina-1/metabolismo Endotelina-1/farmacologia Feminino Imunofluorescência Quinase 1 de Adesão Focal/antagonistas & inibidores Quinase 1 de Adesão Focal/metabolismo Arterite de Células Gigantes/metabolismo Arterite de Células Gigantes/patologia Seres Humanos Hiperplasia Técnicas In Vitro Leucócitos Mononucleares Masculino Microscopia Confocal Músculo Liso Vascular/citologia Miócitos de Músculo Liso/citologia Miócitos de Músculo Liso/efeitos dos fármacos Fosfatidilinositol 3-Quinases/antagonistas & inibidores Fosfatidilinositol 3-Quinases/metabolismo Fosforilação Receptor de Endotelina A/efeitos dos fármacos Receptor de Endotelina A/metabolismo Receptor de Endotelina B/metabolismo Reação em Cadeia da Polimerase Via Transcriptase Reversa Túnica Íntima/patologia Remodelação Vascular/efeitos dos fármacos Quinases da Família src/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ACTA2 protein, human); 0 (Actins); 0 (Endothelin Receptor Antagonists); 0 (Endothelin-1); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (PTK2 protein, human); EC 2.7.10.2 (src-Family Kinases) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170821 [Lr] Data última revisão: 170821 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170614 [St] Status: MEDLINE [do] DOI: 10.1136/annrheumdis-2016-210792

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MEDLINE

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[PMID]: 28597546 [Au] Autor: Russignan A; Spina C; Tamassia N; Cassaro A; Rigo A; Bagnato A; Rosanò L; Bonalumi A; Gottardi M; Zanatta L; Giacomazzi A; Scupoli MT; Tinelli M; Salvadori U; Mosna F; Zamò A; Cassatella MA; Vinante F; Tecchio C [Ad] Endereço: Haematology and Bone-Marrow Transplant Unit, Department of Medicine, Verona University, Verona, Italy. [Ti] Título: Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma. [So] Source: Br J Haematol;178(5):781-793, 2017 Sep. [Is] ISSN: 1365-2141 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM. [Mh] Termos MeSH primário: Antagonistas do Receptor de Endotelina A/farmacologia Mieloma Múltiplo/sangue Receptor de Endotelina A/sangue [Mh] Termos MeSH secundário: Adulto Idoso Idoso de 80 Anos ou mais Comunicação Autócrina/fisiologia Bortezomib/farmacologia Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Sobrevivência Celular/fisiologia Metilação de DNA DNA de Neoplasias/genética Sinergismo Farmacológico Endotelina-1/sangue Endotelina-1/fisiologia Feminino Regulação Neoplásica da Expressão Gênica Seres Humanos Masculino Meia-Idade Terapia de Alvo Molecular/métodos Mieloma Múltiplo/genética Mieloma Múltiplo/patologia Plasmócitos/metabolismo Regiões Promotoras Genéticas Receptor de Endotelina A/genética Sulfonamidas/farmacologia Células Tumorais Cultivadas/efeitos dos fármacos Células Tumorais Cultivadas/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA, Neoplasm); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin-1); 0 (Receptor, Endothelin A); 0 (Sulfonamides); 69G8BD63PP (Bortezomib); Q326023R30 (bosentan) [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: 170610 [St] Status: MEDLINE [do] DOI: 10.1111/bjh.14771

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