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[PMID]:27771442
[Au] Autor:Liu X; Wang J; Chu Y; Zhou X
[Ad] Endereço:School of Pharmaceutical Engineering and Life Science, Changzhou University, 213164, Jiangsu, China.
[Ti] Título:Serum based fluorescent assay for evaluating dipeptidyl peptidase I activity in collagen induced arthritis rat model.
[So] Source:Mol Cell Probes;32:5-12, 2017 04.
[Is] ISSN:1096-1194
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease and derived from immune granule cells. It has been suggested playing an important role in the development of rheumatoid arthritis. In this study, a coumarin based fluorescent probe (GF-AFC) was designed and synthesized to evaluate DPPI activity in serum or tissue homogenates of collagen-induced arthritis (CIA) rats, an inflammatory arthropathy model. It was revealed that the fluorescent intensity was significantly increased in a very short time after specific substrate GF-AFC reacted with the DPPI. The fluorophore (AFC) was released to shine after the cleavage reaction which was examined by F NMR spectroscopy. It has been shown that DPPI hydrolyzed the GF-AFC in a robust, linear, and time dependent manner at a significant high rate. A serum-based DPPI activity assay was validated by spiking and gradient dilution methods, there were no interferences or auto-fluorescence observed. The Coefficient of Variance calculated for serum-based DPPI activity assays indicates the good reproducibility. The good correlation has been seen between serum DPPI levels and the severity of arthritis during RA development in CIA rats. Our study has demonstrated a new serum based diagnostic assay for detecting DPPI activity using coumarin conjugated fluorescent (GF-AFC) as a substrate. The successful implementation of the case would provide beneficial experience in rheumatoid arthritis research.
[Mh] Termos MeSH primário: Artrite Experimental/sangue
Artrite Experimental/enzimologia
Bioensaio/métodos
Catepsina C/sangue
[Mh] Termos MeSH secundário: Animais
Artrite Experimental/diagnóstico
Modelos Animais de Doenças
Fluorescência
Corantes Fluorescentes/síntese química
Corantes Fluorescentes/química
Corantes Fluorescentes/metabolismo
Cinética
Espectroscopia de Ressonância Magnética
Masculino
Ratos Wistar
Reprodutibilidade dos Testes
Espectrofotometria Ultravioleta
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fluorescent Dyes); EC 3.4.14.1 (Cathepsin C)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:28528273
[Au] Autor:Lenartowicz P; Makowski M; Oszywa B; Haremza K; Latajka R; Pawelczak M; Kafarski P
[Ad] Endereço:Faculty of Chemistry, Opole University, Oleska 48, 45-052 Opole, Poland. Electronic address: pawel.lenartowicz@uni.opole.pl.
[Ti] Título:Addition of thiols to the double bond of dipeptide C-terminal dehydroalanine as a source of new inhibitors of cathepsin C.
[So] Source:Biochimie;139:46-55, 2017 Aug.
[Is] ISSN:1638-6183
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Addition of thiols to double bond of glycyl-dehydroalanine and phenyl-dehydroalanine esters provided micromolar inhibitors of cathepsin C. The structure-activity studies indicated that dipeptides containing N-terminal phenylalanine exhibit higher affinity towards the enzyme. A series of C-terminal S-substituted cysteines are responsible for varying interaction with S1 binding pocket of cathepsin C. Depending on diastereomer these compounds most likely act as slowly reacting substrates or competitive inhibitors. This was proved by TLC analysis of the medium in which interaction of methyl (S)-phenylalanyl-(R,S)-(S-adamantyl)cysteinate (7i) with the enzyme was studied. Molecular modeling enabled to establish their mode of binding showed that S2 pocket is long and narrow and accommodates phenyl group of phenylalanine while significantly spacious sites located at the surface of the enzyme (one of them being S1 pocket) bind the adamantyl moiety oriented in different direction for each stereoisomer. Finally replacement of carboxymethyl moiety of methyl (S)-phenylalanyl-(R,S)-(S-phenyl)cysteinate (7c) with nitrile group provided about 650-times more potent inhibitor of cathepsin C indicating that the studied C-terminal S-substituted cysteines are good activity probes for S1 binding pocket of this enzyme.
[Mh] Termos MeSH primário: Alanina/análogos & derivados
Catepsina C/antagonistas & inibidores
Inibidores de Cisteína Proteinase/farmacologia
Dipeptídeos/farmacologia
Compostos de Sulfidrila/química
[Mh] Termos MeSH secundário: Alanina/química
Animais
Sítios de Ligação
Bovinos
Inibidores de Cisteína Proteinase/química
Dipeptídeos/química
Cinética
Modelos Moleculares
Relação Estrutura-Atividade
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cysteine Proteinase Inhibitors); 0 (Dipeptides); 0 (Sulfhydryl Compounds); 98RA387EKY (dehydroalanine); EC 3.4.14.1 (Cathepsin C); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170522
[St] Status:MEDLINE


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[PMID]:28251676
[Au] Autor:Shimizu T; Wisessmith W; Li J; Abe M; Sakimura K; Chetsawang B; Sahara Y; Tohyama K; Tanaka KF; Ikenaka K
[Ad] Endereço:Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.
[Ti] Título:The balance between cathepsin C and cystatin F controls remyelination in the brain of Plp1-overexpressing mouse, a chronic demyelinating disease model.
[So] Source:Glia;65(6):917-930, 2017 Jun.
[Is] ISSN:1098-1136
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In demyelinating diseases such as multiple sclerosis (MS), an imbalance between the demyelination and remyelination rates underlies the degenerative processes. Microglial activation is observed in demyelinating lesions; however, the molecular mechanism responsible for the homeostatic/environmental change remains elusive. We previously found that cystatin F (CysF), a cysteine protease inhibitor, is selectively expressed in microglia only in actively demyelinating/remyelinating lesions but ceases expression in chronic lesions, suggesting its role in remyelination. Here, we report the effects of manipulating the expression of CysF and cathepsin C (CatC), a key target of CysF, in a murine model of transgenic demyelinating disease, Plp . During the active remyelinating phase, both CysF knockdown (CysFKD) and microglial-selective CatC overexpression (CatCOE) showed a worsening of the demyelination in Plp transgenic mice. Conversely, during the chronic demyelinating phase, CatC knockdown (CatCKD) ameliorated the demyelination. Our results suggest that the balance between CatC and CysF expression controls the demyelination and remyelination process.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Catepsina C/metabolismo
Cistatinas/metabolismo
Doenças Desmielinizantes/metabolismo
Bainha de Mielina/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/patologia
Proteínas de Ligação ao Cálcio/metabolismo
Catepsina C/genética
Células Cultivadas
Cistatinas/genética
Doenças Desmielinizantes/patologia
Modelos Animais de Doenças
Progressão da Doença
Marcação de Genes
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Proteínas dos Microfilamentos/metabolismo
Microglia/metabolismo
Microglia/patologia
Proteína Proteolipídica de Mielina/genética
Proteína Proteolipídica de Mielina/metabolismo
Bainha de Mielina/patologia
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aif1 protein, mouse); 0 (Calcium-Binding Proteins); 0 (Cystatins); 0 (Microfilament Proteins); 0 (Myelin Proteolipid Protein); 0 (Plp1 protein, mouse); 0 (RNA, Messenger); 0 (cystatin F, mouse); EC 3.4.14.1 (Cathepsin C); EC 3.4.14.1 (Ctsc protein, mouse)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.1002/glia.23134


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[PMID]:28193451
[Au] Autor:Guarino C; Hamon Y; Croix C; Lamort AS; Dallet-Choisy S; Marchand-Adam S; Lesner A; Baranek T; Viaud-Massuard MC; Lauritzen C; Pedersen J; Heuzé-Vourc'h N; Si-Tahar M; Firatli E; Jenne DE; Gauthier F; Horwitz MS; Borregaard N; Korkmaz B
[Ad] Endereço:INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
[Ti] Título:Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases.
[So] Source:Biochem Pharmacol;131:52-67, 2017 May 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cathepsin C (CatC) is a tetrameric cysteine dipeptidyl aminopeptidase that plays a key role in activation of pro-inflammatory serine protease zymogens by removal of a N-terminal pro-dipeptide sequence. Loss of function mutations in the CatC gene is associated with lack of immune cell serine protease activities and cause Papillon-Lefèvre syndrome (PLS). Also, only very low levels of elastase-like protease zymogens are detected by proteome analysis of neutrophils from PLS patients. Thus, CatC inhibitors represent new alternatives for the treatment of neutrophil protease-driven inflammatory or autoimmune diseases. We aimed to experimentally inactivate and lower neutrophil elastase-like proteases by pharmacological blocking of CatC-dependent maturation in cell-based assays and in vivo. Isolated, immature bone marrow cells from healthy donors pulse-chased in the presence of a new cell permeable cyclopropyl nitrile CatC inhibitor almost totally lack elastase. We confirmed the elimination of neutrophil elastase-like proteases by prolonged inhibition of CatC in a non-human primate. We also showed that neutrophils lacking elastase-like protease activities were still recruited to inflammatory sites. These preclinical results demonstrate that the disappearance of neutrophil elastase-like proteases as observed in PLS patients can be achieved by pharmacological inhibition of bone marrow CatC. Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans.
[Mh] Termos MeSH primário: Catepsina C/antagonistas & inibidores
Inibidores de Cisteína Proteinase/farmacologia
Neutrófilos/enzimologia
Serina Proteases/metabolismo
[Mh] Termos MeSH secundário: Animais
Líquido da Lavagem Broncoalveolar
Estudos de Casos e Controles
Feminino
Seres Humanos
Elastase de Leucócito/sangue
Macaca fascicularis
Doença de Papillon-Lefevre/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cysteine Proteinase Inhibitors); EC 3.4.- (Serine Proteases); EC 3.4.14.1 (Cathepsin C); EC 3.4.21.37 (Leukocyte Elastase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE


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[PMID]:28131168
[Au] Autor:Yang X; Zheng J; Tian S; Chen Y; An R; Zhao Q; Xu Y
[Ad] Endereço:Department of Neurology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan Province 610041, PR China.
[Ti] Título:HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort.
[So] Source:J Neurol Sci;373:124-128, 2017 Feb 15.
[Is] ISSN:1878-5883
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are neurodegenerative diseases that share common genetic risk factors. A recent genome-wide association study has linked risk of FTD with polymorphisms in the HLA-DRA/HLA-DRB5 gene (rs9268877, rs9268856), BTNL2 gene (rs1980493), and RAB38/CTSC gene (rs302668). METHODS: We used the SNPscan™ Kit to genotype these variants in 400 Chinese patients with sporadic ALS, 554 with sporadic PD and 634 healthy controls. RESULTS: The AA genotype at rs9268856 increased risk of ALS (P=0.005). Mean survival time was significantly shorter in patients with the AA genotype (24.8±16.2months) than in patients with other genotypes (36.9±19.9months; P<0.001). Kaplan-Meier curves and Cox analysis indicated significantly lower survival probability for patients carrying the AA genotype (P<0.001). CONCLUSION: Our results suggest that the AA genotype at rs9268856 is an independent risk factor and prognostic factor for ALS in Han Chinese from southwest China.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Predisposição Genética para Doença
Cadeias alfa de HLA-DR/genética
Cadeias HLA-DRB5/genética
Doença de Parkinson/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Grupo com Ancestrais do Continente Asiático/genética
Butirofilinas/genética
Estudos de Casos e Controles
Catepsina C/genética
China
Feminino
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Modelos de Riscos Proporcionais
Estudos Retrospectivos
Proteínas rab de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BTNL2 protein, human); 0 (Butyrophilins); 0 (HLA-DR alpha-Chains); 0 (HLA-DRB5 Chains); EC 3.4.14.1 (CTSC protein, human); EC 3.4.14.1 (Cathepsin C); EC 3.6.1.- (RAB38 protein, human); EC 3.6.5.2 (rab GTP-Binding Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170130
[St] Status:MEDLINE


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[PMID]:28317349
[Au] Autor:Yuanjiao C; Chen-Jun L
[Ad] Endereço:Dept. of Stomatology, Chengdu Military General Hospital, Chengdu 610017, China.
[Ti] Título:[Gene mutational analyses of the cathepsin C gene in families with Papillon-Lefèvre syndrome].
[So] Source:Hua Xi Kou Qiang Yi Xue Za Zhi;34(4):346-349, 2016 Aug 01.
[Is] ISSN:1000-1182
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: This study aims to investigate the gene mutational characteristics of cathepsin C (CTSC) gene in a Chinese patient with Papillon-Lefèvre syndrome (PLS), then further confirm the genetic basis for the phenotype of PLS, and obtain genetic information that can be used as guide in the diagnosis and treatment of PLS. METHODS: With their consent, peripheral blood samples were obtained from the proband and his family members (his parents and older sister) for genomic DNA extraction. The coding region and exon/intron boundaries of the CTSC gene were amplified and sequenced using poly-merase chain reaction and direct sequencing of DNA. RESULTS: Compound heterozygous mutations of CTSC gene were iden-tified in the patient. The proband carries one heterozygous nonsense mutation c.754C>T in exon 5 and one heterozygous missense mutation c.1040A>G in exon 7. Both parents were heterozygous carriers without the clinical symptoms of PLS. None of the mutations were detected in the proband's sister. CONCLUSIONS: The study proves that mutations of CTSC gene are responsible for the phenotype of Papillon-Lefèvre syndrome.
.
[Mh] Termos MeSH primário: Mutação
Doença de Papillon-Lefevre
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Asiático
Sequência de Bases
Catepsina C
DNA
Análise Mutacional de DNA
Éxons
Seres Humanos
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.4.14.1 (Cathepsin C)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170403
[Lr] Data última revisão:
170403
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:170321
[St] Status:MEDLINE
[do] DOI:10.7518/hxkq.2016.04.005


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[PMID]:27746119
[Au] Autor:Legowska M; Hamon Y; Wojtysiak A; Grzywa R; Sienczyk M; Burster T; Korkmaz B; Lesner A
[Ad] Endereço:Faculty of Chemistry, University of Gdansk, 80-308, Gdansk, Poland.
[Ti] Título:Development of the first internally-quenched fluorescent substrates of human cathepsin C: The application in the enzyme detection in biological samples.
[So] Source:Arch Biochem Biophys;612:91-102, 2016 Dec 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cathepsin C is a widely expressed cysteine exopeptidase that is mostly recognized for the activation of the granule-associated proinflammatory serine proteases in neutrophils, cytotoxic T lymphocytes and mast cells. It has been shown that the enzyme can be secreted extracellularly; however, its occurrence in human bodily fluids/physiological samples has not been thoroughly studied. In the course of this study, the first fluorescence resonance energy transfer peptides for the measurement of the activity of human cathepsin C were designed and synthesized. Two series of tetra- and pentapeptide substrates enabled the detailed S' specificity study of cathepsin C, which has been examined for the first time. The extensive enzymatic studies of the obtained compounds resulted in the selection of the highly specific and selective substrate Thi-Ala(Mca)-Ser-Gly-Tyr(3-NO )-NH , which was successfully employed for the detection of cathepsin C activity in complex biological samples such as cell lysates, urine and bronchoalveolar lavage fluids. Molecular docking of the selected substrate was performed in order to better understand the binding mode of the substrates in the active site of cathepsin C.
[Mh] Termos MeSH primário: Catepsina C/química
Microscopia de Fluorescência/métodos
[Mh] Termos MeSH secundário: Domínio Catalítico
Catepsina L/química
Transferência Ressonante de Energia de Fluorescência
Seres Humanos
Concentração de Íons de Hidrogênio
Inflamação
Cinética
Mastócitos/citologia
Conformação Molecular
Simulação de Acoplamento Molecular
Neutrófilos/metabolismo
Peptídeos/química
Ligação Proteica
Proteínas Recombinantes/química
Especificidade por Substrato
Linfócitos T Citotóxicos/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 0 (Recombinant Proteins); EC 3.4.14.1 (Cathepsin C); EC 3.4.22.15 (Cathepsin L)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171008
[Lr] Data última revisão:
171008
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161018
[St] Status:MEDLINE


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[PMID]:27690432
[Au] Autor:Doyle K; Lönn H; Käck H; Van de Poël A; Swallow S; Gardiner P; Connolly S; Root J; Wikell C; Dahl G; Stenvall K; Johannesson P
[Ad] Endereço:Discovery, Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, U.K.
[Ti] Título:Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986).
[So] Source:J Med Chem;59(20):9457-9472, 2016 Oct 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found for earlier compound series was discovered. This work culminated in the identification of compound 30 (AZD7986) as a highly potent, reversible, and selective clinical candidate for COPD, with predicted human PK properties suitable for once daily human dosing.
[Mh] Termos MeSH primário: Benzoxazóis/farmacologia
Catepsina C/antagonistas & inibidores
Descoberta de Drogas
Oxazepinas/farmacologia
Inibidores de Proteases/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Animais
Benzoxazóis/administração & dosagem
Benzoxazóis/química
Catepsina C/metabolismo
Cães
Relação Dose-Resposta a Droga
Seres Humanos
Camundongos
Estrutura Molecular
Oxazepinas/administração & dosagem
Oxazepinas/química
Inibidores de Proteases/administração & dosagem
Inibidores de Proteases/química
Coelhos
Ratos
Relação Estrutura-Atividade
Células U937
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AZD7986); 0 (Benzoxazoles); 0 (Oxazepines); 0 (Protease Inhibitors); EC 3.4.14.1 (CTSC protein, human); EC 3.4.14.1 (Cathepsin C)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161004
[St] Status:MEDLINE


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[PMID]:27689189
[Au] Autor:Verbeek RE; Siersema PD; Vleggaar FP; Ten Kate FJ; Posthuma G; Souza RF; de Haan J; van Baal JW
[Ad] Endereço:Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands. r.verbeek@antoniusziekenhuis.nl.
[Ti] Título:Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett's Esophagus.
[So] Source:J Gastrointestin Liver Dis;25(3):273-82, 2016 Sep.
[Is] ISSN:1842-1121
[Cp] País de publicação:Romania
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIMS: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett's esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett's esophagus epithelium cell line. METHODS: TLR2 expression in normal squamous esophagus, reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma biopsies was assessed with Q-RT-PCR, in situ hybridization and immunohistochemistry. Barrett's esophagus epithelium cells (BAR-T) were incubated with acid and bile salts in the presence or absence of the TLR2 agonist Pam3CSK4 for a period up to 4 weeks. Morphological changes were assessed with electron microscopy, while Q-RT-PCR was used to determine the expression of lysosomal enzymes (Cathepsin B and C) and factors involved in endocytosis (LAMP-1 and M6PR) and autophagy (LC3 and Rab7). RESULTS: TLR2 was expressed in normal squamous esophagus, reflux esophagitis, Barrett's esophagus but was most prominent in esophageal adenocarcinoma. Long-term TLR2 activation in acid and bile salts exposed BAR-T cells resulted in more and larger lysosomes, more mitochondria and increased expression of LAMP-1, M6PR, Cathepsin B and C when compared to BAR-T cells incubated with acid and bile salts but no TLR2 agonist. Factors associated with autophagy (LC3 and Rab7) expression remained largely unchanged. CONCLUSION: Activation of TLR2 in acid and bile salts exposed Barrett epithelium cells resulted in an increased number of mitochondria and lysosomes and increased expression of lysosomal enzymes and factors involved in endocytosis.
[Mh] Termos MeSH primário: Adenocarcinoma/metabolismo
Esôfago de Barrett/metabolismo
Células Epiteliais/metabolismo
Neoplasias Esofágicas/metabolismo
Esofagite Péptica/metabolismo
Esôfago/metabolismo
Lisossomos/metabolismo
Transdução de Sinais
Receptor 2 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Adenocarcinoma/genética
Adenocarcinoma/patologia
Idoso
Idoso de 80 Anos ou mais
Esôfago de Barrett/genética
Esôfago de Barrett/patologia
Ácidos e Sais Biliares/farmacologia
Estudos de Casos e Controles
Catepsina B/metabolismo
Catepsina C/metabolismo
Linhagem Celular
Relação Dose-Resposta a Droga
Endocitose
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/patologia
Neoplasias Esofágicas/genética
Neoplasias Esofágicas/patologia
Esofagite Péptica/genética
Esofagite Péptica/patologia
Esôfago/efeitos dos fármacos
Esôfago/patologia
Feminino
Seres Humanos
Lipopeptídeos/farmacologia
Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo
Lisossomos/efeitos dos fármacos
Masculino
Meia-Idade
Mitocôndrias/metabolismo
Receptor IGF Tipo 2/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Receptor 2 Toll-Like/agonistas
Receptor 2 Toll-Like/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (LAMP1 protein, human); 0 (Lipopeptides); 0 (Lysosome-Associated Membrane Glycoproteins); 0 (Pam(3)CSK(4) peptide); 0 (Receptor, IGF Type 2); 0 (TLR2 protein, human); 0 (Toll-Like Receptor 2); 0 (cation-dependent mannose-6-phosphate receptor); EC 3.4.14.1 (CTSC protein, human); EC 3.4.14.1 (Cathepsin C); EC 3.4.22.1 (CTSB protein, human); EC 3.4.22.1 (Cathepsin B)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170228
[Lr] Data última revisão:
170228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161001
[St] Status:MEDLINE
[do] DOI:10.15403/jgld.2014.1121.253.rc2


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[PMID]:27283739
[Au] Autor:Yan H; Zhou HF; Akk A; Hu Y; Springer LE; Ennis TL; Pham CTN
[Ad] Endereço:John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
[Ti] Título:Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation.
[So] Source:Arterioscler Thromb Vasc Biol;36(8):1660-1669, 2016 Aug.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We previously established that neutrophil-derived dipeptidyl peptidase I (DPPI) is essential for experimental abdominal aortic aneurysm (AAA) development. Because DPPI activates several neutrophil serine proteases, it remains to be determined whether the AAA-promoting effect of DPPI is mediated by neutrophil serine proteases. APPROACH AND RESULTS: Using an elastase-induced AAA model, we demonstrate that the absence of 2 neutrophil serine proteases, neutrophil elastase and proteinase-3, recapitulates the AAA-resistant phenotype of DPPI-deficient mice. DPPI and neutrophil serine proteases direct the in vitro and in vivo release of extracellular structures termed neutrophil extracellular traps (NETs). Administration of DNase1, which dismantles NETs, suppresses elastase-induced AAA in wild-type animals and in DPPI-deficient mice reconstituted with wild-type neutrophils. NETs also contain the cathelicidin-related antimicrobial peptide that complexes with self-DNA in recruiting plasmacytoid dendritic cells (pDCs), inducing type I interferons (IFNs) and promoting AAA in DPPI-deficient mice. Conversely, depletion of pDCs or blockade of type I IFNs suppresses experimental AAA. Moreover, we find an abundance of human cathelicidin peptide, a 37 amino acid sequence starting with 2 leucines and the human orthologue of cathelicidin-related antimicrobial peptide, in the vicinity of pDCs in human AAA tissues. Increased type I IFN mRNA expression is observed in human AAA tissues and circulating IFN-α is detected in ≈50% of the AAA sera examined. CONCLUSIONS: These results suggest that neutrophil protease-mediated NET release contributes to elastase-induced AAA through pDC activation and type I IFN production. These findings increase our understanding of the pathways underlying AAA inflammatory responses and suggest that limiting NET, pDC, and type I IFN activities may suppress aneurysm progression.
[Mh] Termos MeSH primário: Aorta Abdominal/enzimologia
Aneurisma da Aorta Abdominal/enzimologia
Catepsina C/metabolismo
Células Dendríticas/enzimologia
Armadilhas Extracelulares/enzimologia
Elastase de Leucócito/metabolismo
Mieloblastina/metabolismo
Neutrófilos/enzimologia
[Mh] Termos MeSH secundário: Animais
Aorta Abdominal/patologia
Aneurisma da Aorta Abdominal/genética
Aneurisma da Aorta Abdominal/patologia
Aneurisma da Aorta Abdominal/prevenção & controle
Catepsina C/genética
Células Cultivadas
Modelos Animais de Doenças
Genótipo
Seres Humanos
Interferon Tipo I/metabolismo
Elastase de Leucócito/deficiência
Elastase de Leucócito/genética
Camundongos Endogâmicos C57BL
Camundongos Knockout
Mieloblastina/deficiência
Mieloblastina/genética
Neutrófilos/patologia
Fenótipo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interferon Type I); EC 3.4.14.1 (Cathepsin C); EC 3.4.14.1 (Ctsc protein, mouse); EC 3.4.21.37 (Leukocyte Elastase); EC 3.4.21.76 (Myeloblastin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160611
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.307786



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