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Pesquisa : D12.644.822 [Categoria DeCS]
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  1 / 1181 MEDLINE  
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[PMID]:27779422
[Au] Autor:Kouzaki H; Matsumoto K; Kikuoka H; Kato T; Tojima I; Shimizu S; Kita H; Shimizu T
[Ad] Endereço:1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
[Ti] Título:Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis.
[So] Source:Am J Respir Crit Care Med;195(6):737-747, 2017 Mar 15.
[Is] ISSN:1535-4970
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function. OBJECTIVES: To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS). METHODS: We examined the expression of cystatin A and SPINK5 in the nasal epithelial cells of patients with CRS. Additionally, the in vitro effects of recombinant EPIs on the secretion of the epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin in airway epithelial cells, and the in vivo effects of recombinant EPIs in the nasal epithelium of mice exposed to multiple airborne allergens (MAA) were examined. MEASUREMENTS AND MAIN RESULTS: Compared with control subjects and patients with noneosinophilic CRS, patients with eosinophilic CRS showed significantly lower protein and mRNA expression of cystatin A and SPINK5 in the nasal epithelium. Allergen-induced production of IL-25, IL-33, and thymic stromal lymphopoietin in normal human bronchial epithelial cells was inhibited by treatment with recombinant cystatin A or SPINK5. Conversely, the production of these cytokines was increased when cystatin A or SPINK5 were knocked down with small interfering RNA. Chronic MAA exposure induced goblet cell metaplasia and epithelial disruption in mouse nasal epithelium and decreased the tissue expression and nasal lavage levels of cystatin A and SPINK5. Intranasal instillations of recombinant EPIs attenuated this MAA-induced pathology. CONCLUSIONS: Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS.
[Mh] Termos MeSH primário: Eosinofilia/metabolismo
Células Epiteliais/metabolismo
Inibidores de Proteases/metabolismo
Rinite/metabolismo
Sinusite/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Doença Crônica
Cistatina A/metabolismo
Eosinofilia/complicações
Feminino
Seres Humanos
Interleucina-17/metabolismo
Interleucina-33/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Meia-Idade
Mucosa Nasal/metabolismo
Proteínas Secretadas Inibidoras de Proteinases/metabolismo
Rinite/complicações
Inibidor de Serinopeptidase do Tipo Kazal 5
Sinusite/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cystatin A); 0 (Interleukin-17); 0 (Interleukin-33); 0 (Protease Inhibitors); 0 (Proteinase Inhibitory Proteins, Secretory); 0 (SPINK5 protein, human); 0 (Serine Peptidase Inhibitor Kazal-Type 5)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1164/rccm.201603-0529OC


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[PMID]:28710277
[Au] Autor:Murray AS; Varela FA; Hyland TE; Schoenbeck AJ; White JM; Tanabe LM; Todi SV; List K
[Ad] Endereço:From the Departments of Pharmacology.
[Ti] Título:Phosphorylation of the type II transmembrane serine protease, TMPRSS13, in hepatocyte growth factor activator inhibitor-1 and -2-mediated cell-surface localization.
[So] Source:J Biol Chem;292(36):14867-14884, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Although various TTSPs have been characterized in detail biochemically and functionally, the basic properties of TMPRSS13 remain unclear. Here, we investigate the activation, inhibition, post-translational modification, and localization of TMPRSS13. We show that TMPRSS13 is a glycosylated, active protease and that its own proteolytic activity mediates zymogen cleavage. Full-length, active TMPRSS13 exhibits impaired cell-surface expression in the absence of the cognate Kunitz-type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 or HAI-2. Concomitant presence of TMPRSS13 with either HAI-1 or -2 mediates phosphorylation of residues in the intracellular domain of the protease, and it coincides with efficient transport of the protease to the cell surface and its subsequent shedding. Cell-surface labeling experiments indicate that the dominant form of TMPRSS13 on the cell surface is phosphorylated, whereas intracellular TMPRSS13 is predominantly non-phosphorylated. These data provide novel insight into the cellular properties of TMPRSS13 and highlight phosphorylation of TMPRSS13 as a novel post-translational modification of this TTSP family member and potentially other members of this family of proteases.
[Mh] Termos MeSH primário: Glicoproteínas de Membrana/metabolismo
Proteínas de Membrana/química
Proteínas de Membrana/metabolismo
Proteínas Secretadas Inibidoras de Proteinases/metabolismo
Serina Endopeptidases/química
Serina Endopeptidases/metabolismo
[Mh] Termos MeSH secundário: Células HEK293
Seres Humanos
Proteínas de Membrana/genética
Fosforilação
Serina Endopeptidases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Glycoproteins); 0 (Membrane Proteins); 0 (Proteinase Inhibitory Proteins, Secretory); 0 (SPINT1 protein, human); 0 (SPINT2 protein, human); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.- (TMPRSS13 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170716
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.775999


  3 / 1181 MEDLINE  
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[PMID]:28618968
[Au] Autor:Ning T; Zhang H; Wang X; Li S; Zhang L; Deng T; Zhou L; Wang X; Liu R; Bai M; Ge S; Li H; Huang D; Ying G; Ba Y
[Ad] Endereço:Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
[Ti] Título:miR-221 and miR-222 synergistically regulate hepatocyte growth factor activator inhibitor type 1 to promote cell proliferation and migration in gastric cancer.
[So] Source:Tumour Biol;39(6):1010428317701636, 2017 Jun.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gastric cancer is a common malignancy with limited treatment options and poor prognosis. Introduction of novel pathways of gastric cancer will provide candidates for target therapy. Hepatocyte growth factor activator inhibitor type 1 is an integral-membrane proteinase inhibitor. Hepatocyte growth factor activator inhibitor type 1 abnormality is found in various cancers and correlates with tumor progression and metastasis. However, the mechanisms underlying the dysregulation of hepatocyte growth factor activator inhibitor type 1 expression in gastric cancer remain unclear. Although microRNAs have been reported to be involved in the development of cancer, the roles of miR-221 and miR-222 in gastric cancer have not been reported yet. In this study, we showed that hepatocyte growth factor activator inhibitor type 1 protein was downregulated, while miR-221 and miR-222 were significantly increased in gastric cancer tissues. Bioinformatic predictions and luciferase assay verified that the 3'-untranslated region of the HAI-1 gene is a direct target site for miR-221 and miR-222. Overexpression of miR-221 and miR-222 in MGC-803 cells leads to the inhibition of hepatocyte growth factor activator inhibitor type 1 protein expression, thus promoting cell proliferation and migration; whereas knockdown of miR-221 and miR-222 showed opposite effects. Moreover, we found that the expression level of hepatocyte growth factor activator protein was increased when hepatocyte growth factor activator inhibitor type 1 was knocked down in MGC-803 cells. Thus, gastric cancer is probably an autocrine tumor, and the antitumor mechanism of hepatocyte growth factor activator inhibitor type 1 in vitro might be mediated by regulating the expression of hepatocyte growth factor activator protein. Therefore, our data illustrated a novel pathway comprising miR-221and miR-222 and hepatocyte growth factor activator inhibitor type 1 in gastric cancer, which is a potential target for future clinical use.
[Mh] Termos MeSH primário: MicroRNAs/genética
Proteínas Secretadas Inibidoras de Proteinases/biossíntese
Neoplasias Gástricas/genética
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/genética
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
MicroRNAs/biossíntese
Proteínas Secretadas Inibidoras de Proteinases/genética
Neoplasias Gástricas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN221 microRNA, human); 0 (MIRN222 microRNA, human); 0 (MicroRNAs); 0 (Proteinase Inhibitory Proteins, Secretory); 0 (SPINT1 protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170705
[Lr] Data última revisão:
170705
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317701636


  4 / 1181 MEDLINE  
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[PMID]:28442313
[Au] Autor:Polverino E; Rosales-Mayor E; Dale GE; Dembowsky K; Torres A
[Ad] Endereço:Institut Clínic Respiratori, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Ciber de Enfermedades Respiratorias, Barcelona, Spain.
[Ti] Título:The Role of Neutrophil Elastase Inhibitors in Lung Diseases.
[So] Source:Chest;152(2):249-262, 2017 Aug.
[Is] ISSN:1931-3543
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In many respiratory diseases characterized by an intense inflammatory response, the balance between proteolytic enzymes (proteases, including elastases) and their inhibitors (proteinases inhibitors) is not neutral. Excess activity of neutrophil elastase (NE) and similar proteases has been reported to cause tissue damage and to alter the remodeling process in many clinical conditions such as pneumonia, respiratory distress, and acute lung injury (ALI). Several experimental NE inhibitors have been tested in preclinical and clinical studies of different conditions of inflammatory lung injury such as ALI and pneumonia, with contrasting results. This study reviews the literature regarding NE inhibitors in the field of respiratory diseases and reflects on possible future developments. In particular, we highlight potential gaps in the scientific evidence and discuss potential strategies for focusing investigation on antielastases in clinical practice through the selection of targeted populations and proper outcomes.
[Mh] Termos MeSH primário: Pneumopatias/tratamento farmacológico
Proteínas Secretadas Inibidoras de Proteinases/farmacologia
[Mh] Termos MeSH secundário: Lesão Pulmonar Aguda/tratamento farmacológico
Lesão Pulmonar Aguda/enzimologia
Animais
Bronquiectasia/tratamento farmacológico
Bronquiectasia/enzimologia
Fibrose Cística/tratamento farmacológico
Fibrose Cística/enzimologia
Modelos Animais de Doenças
Seres Humanos
Elastase de Leucócito/fisiologia
Pneumopatias/enzimologia
Proteínas Secretadas Inibidoras de Proteinases/fisiologia
Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
Doença Pulmonar Obstrutiva Crônica/enzimologia
Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico
Síndrome do Desconforto Respiratório do Adulto/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Proteinase Inhibitory Proteins, Secretory); EC 3.4.21.37 (Leukocyte Elastase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE


  5 / 1181 MEDLINE  
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[PMID]:28348485
[Au] Autor:Hou XF; Xu LP; Song HY; Li S; Wu C; Wang JF
[Ad] Endereço:Xin-Fang Hou, Shuai Li, Chen Wu, Ju-Feng Wang, Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, Henan Province, China.
[Ti] Título: enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells upregulation of and downregulation of .
[So] Source:World J Gastroenterol;23(10):1796-1803, 2017 Mar 14.
[Is] ISSN:2219-2840
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIM: To explore the anti-tumor effects of esophageal cancer-related gene 2 (ECRG2) in combination with cisplatin (DDP) in DDP-resistant esophageal cancer cells (EC9706/DDP). METHODS: A drug-resistant cell model was established, with EC9706/DDP cells being treated with ECRG2 and/or DDP. Cell viability was examined by MTT assay. The rate of cell apoptosis was determined by flow cytometry. The mRNA expression levels of proliferating cell nuclear antigen (PCNA), metallothionein (MT), and p53 were determined by RT-PCR and PCNA, while MT and p53 protein expression levels were determined by western blotting. RESULTS: The anti-proliferative effect of ECRG2 in combination with DDP was superior when compared to ECRG2 or DDP alone. The inhibition rate for the combination reached its peak (51.33%) at 96 h. The early apoptotic rates of the control, ECRG2 alone, DDP alone, and ECRG2 plus DDP groups were 5.71% ± 0.27%, 12.68% ± 0.61%, 14.15% ± 0.87%, and 27.96% ± 0.36%, respectively. Although all treatment groups were significantly different from the control group ( < 0.05), the combination treatment of ECRG2 plus DDP performed significantly better when compared to either ECRG2 or DDP alone ( < 0.05). The combination of ECRG2 and DDP significantly upregulated p53 mRNA and protein levels and downregulated PCNA mRNA and protein levels compared to ECRG2 or DDP alone ( < 0.05). However, no changes were seen in the expression of MT mRNA or protein. CONCLUSION: in combination with DDP can inhibit viability and induce apoptosis in esophageal cancer DDP-resistant cells, possibly upregulation of expression and downregulation of expression. These findings suggest that the combination of ECRG2 and DDP may be a promising strategy for the clinical treatment of esophageal cancers that are resistant to DDP.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Cisplatino/farmacologia
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Neoplasias Esofágicas/tratamento farmacológico
Antígeno Nuclear de Célula em Proliferação/metabolismo
Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cisplatino/uso terapêutico
Regulação para Baixo
Quimioterapia Combinada
Neoplasias Esofágicas/fisiopatologia
Citometria de Fluxo
Seres Humanos
Metalotioneína/metabolismo
Proteínas Secretadas Inibidoras de Proteinases/farmacologia
RNA Mensageiro/metabolismo
Proteínas Recombinantes/farmacologia
Proteínas Recombinantes/uso terapêutico
Inibidores de Serinopeptidase do Tipo Kazal
Ativação Transcricional
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Proliferating Cell Nuclear Antigen); 0 (Proteinase Inhibitory Proteins, Secretory); 0 (RNA, Messenger); 0 (Recombinant Proteins); 0 (SPINK7 protein, human); 0 (Serine Peptidase Inhibitors, Kazal Type); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 9038-94-2 (Metallothionein); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE
[do] DOI:10.3748/wjg.v23.i10.1796


  6 / 1181 MEDLINE  
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[PMID]:28348076
[Au] Autor:Liu M; Yuan C; Jensen JK; Zhao B; Jiang Y; Jiang L; Huang M
[Ad] Endereço:From the State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.
[Ti] Título:The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition.
[So] Source:J Biol Chem;292(20):8412-8423, 2017 May 19.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hepatocyte growth factor activator inhibitor 1 (HAI-1) is a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development and is also important in maintaining postnatal homeostasis in many tissues. HAI-1 is a Kunitz-type serine protease inhibitor, and soluble fragments of HAI-1 with variable lengths have been identified The full-length extracellular portion of HAI-1 (sHAI-1) shows weaker inhibitory activity toward target proteases than the smaller fragments, suggesting auto-inhibition of HAI-1. However, this possible regulatory mechanism has not yet been evaluated. Here, we solved the crystal structure of sHAI-1 and determined the solution structure by small-angle X-ray scattering. These structural analyses revealed that, despite the presence of long linkers, sHAI-1 exists in a compact conformation in which sHAI-1 active sites in Kunitz domain 1 are sterically blocked by neighboring structural elements. We also found that in the presence of target proteases, sHAI-1 adopts an extended conformation that disables the auto-inhibition effect. Our results also reveal the roles of non-inhibitory domains of this multidomain protein and explain the low activity of the full-length protein. The structural insights gained here improve our understanding of the regulation of HAI-1 inhibitory activities and point to new approaches for better controlling these activities.
[Mh] Termos MeSH primário: Proteínas Secretadas Inibidoras de Proteinases/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Domínios Proteicos
Proteínas Secretadas Inibidoras de Proteinases/genética
Proteínas Secretadas Inibidoras de Proteinases/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proteinase Inhibitory Proteins, Secretory); 0 (SPINT1 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170624
[Lr] Data última revisão:
170624
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.779256


  7 / 1181 MEDLINE  
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[PMID]:28347540
[Au] Autor:Fukui M; Takamochi K; Oh S; Matsunaga T; Suzuki K; Ando K; Suzuki K
[Ad] Endereço:Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
[Ti] Título:Study on Perioperative Administration of a Neutrophil Elastase Inhibitor for Interstitial Pneumonias.
[So] Source:Ann Thorac Surg;103(6):1781-1787, 2017 Jun.
[Is] ISSN:1552-6259
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although acute exacerbation of idiopathic interstitial pneumonias (IIPs) is a lethal complication after pulmonary resection for lung cancer with IIPs, there are no established methods to prevent its occurrence. This prospective randomized study was conducted to evaluate whether perioperative administration of the neutrophil elastase inhibitor sivelestat prevents acute exacerbation after surgery. METHODS: The IIP patients with suspected lung cancers were randomly assigned to two groups before surgery: in group A (n = 65), sivelestat was perioperatively administered for 5 days; in group B (n = 65), no medications were administered. The primary endpoint was the frequency of acute exacerbation of IIPs. The secondary endpoints were perioperative changes in the lactate dehydrogenase, C-reactive protein, sialylated carbohydrate antigen, surfactant protein D and surfactant protein A values, and the safety of preoperative administration of sivelestat. Multivariate analyses were performed using a logistic regression model to identify the factors that predicted acute exacerbation. RESULTS: Acute exacerbation developed in 2 patients in group A and 1 patient in group B (p = 0.559). Administration of sivelestat did not contribute to decreasing the acute exacerbation as well as short- and long-term mortality. The differences were not statistically significant in perioperative lactate dehydrogenase, C-reactive protein, sialylated carbohydrate antigen, and surfactant protein D and A levels. No subjective adverse events were observed. A preoperative partial pressure oxygen level of less than 70 mm Hg was the only predictive factor identified in the logistic analysis (p = 0.019, hazard ratio 19.2). CONCLUSIONS: Perioperative administration of neutrophil elastase inhibitor appeared to be safe; however, it could not prevent the development of acute exacerbation after surgery in lung cancer patients with IIPs.
[Mh] Termos MeSH primário: Glicina/análogos & derivados
Pneumonias Intersticiais Idiopáticas/prevenção & controle
Neoplasias Pulmonares/cirurgia
Pneumonectomia/efeitos adversos
Complicações Pós-Operatórias/prevenção & controle
Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico
Sulfonamidas/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Biomarcadores/metabolismo
Feminino
Glicina/efeitos adversos
Glicina/uso terapêutico
Seres Humanos
Pneumonias Intersticiais Idiopáticas/mortalidade
Neoplasias Pulmonares/mortalidade
Masculino
Meia-Idade
Análise Multivariada
Assistência Perioperatória
Estudos Prospectivos
Proteínas Secretadas Inibidoras de Proteinases/efeitos adversos
Prevenção Secundária
Sulfonamidas/efeitos adversos
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Biomarkers); 0 (Proteinase Inhibitory Proteins, Secretory); 0 (Sulfonamides); DWI62G0P59 (sivelestat); TE7660XO1C (Glycine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170815
[Lr] Data última revisão:
170815
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE


  8 / 1181 MEDLINE  
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[PMID]:28289921
[Au] Autor:Sasaki K; Kurahara H; Young ED; Natsugoe S; Ijichi A; Iwakuma T; Welch DR
[Ad] Endereço:Department of Cancer Biology, The University of Kansas Medical Center, 3901 Rainbow Blvd, Mail Stop 1071, Kansas City, KS, 66160, USA.
[Ti] Título:Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer.
[So] Source:Clin Exp Metastasis;34(3-4):229-239, 2017 Apr.
[Is] ISSN:1573-7276
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The overwhelming majority of pancreatic ductal adenocarcinoma (PDAC) is not diagnosed until the cancer has metastasized, leading to an abysmal average life expectancy (3-6 months post-diagnosis). Earlier detection and more effective treatments have been hampered by inadequate understanding of the underlying molecular mechanisms controlling metastasis. We hypothesized that metastasis suppressors are involved in controlling metastasis in pancreatic cancer. Using an unbiased genome-wide shRNA screen, an shRNA library was transduced into the non-metastatic PDAC line S2-028 followed by intrasplenic injection. Resulting liver metastases were individually isolated from these mice. One liver metastatic nodule contained shRNA for ITIH5 (Inter-alpha-trypsin inhibitor heavy chain 5), suggesting that ITIH5 may act as a metastasis suppressor. Consistent with this notion, metastatic PDAC cell lines had significantly lower protein expression of ITIH5 compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines. By manipulating expression of ITIH5 in different PDAC cell lines (over-expression in metastatic, knockdown in non-metastatic) functional and selective regulation of metastasis was observed for ITIH5. Orthotopic tumor growth of PDAC cells was not blocked following orthotopic injection. In vitro ITIH5 over-expression inhibited motility and invasion. Immunohistochemical analysis of a human PDAC tissue microarray revealed that ITIH5 expression inversely correlated with both survival and invasion/metastasis. ITIH5 is, therefore, functionally validated as a PDAC metastasis suppressor and shows promise as a prognostic biomarker.
[Mh] Termos MeSH primário: Genoma Humano
Neoplasias Hepáticas/prevenção & controle
Neoplasias Pancreáticas/prevenção & controle
Proteínas Secretadas Inibidoras de Proteinases/genética
RNA Interferente Pequeno/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Apoptose
Biomarcadores Tumorais/genética
Proliferação Celular
Feminino
Seguimentos
Regulação Neoplásica da Expressão Gênica
Ensaios de Triagem em Larga Escala
Seres Humanos
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/secundário
Neoplasias Hepáticas/cirurgia
Masculino
Camundongos
Camundongos Nus
Meia-Idade
Gradação de Tumores
Estadiamento de Neoplasias
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Neoplasias Pancreáticas/cirurgia
Prognóstico
Regiões Promotoras Genéticas
Proteínas Secretadas Inibidoras de Proteinases/antagonistas & inibidores
Taxa de Sobrevida
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (ITIH5 protein, human); 0 (Proteinase Inhibitory Proteins, Secretory); 0 (RNA, Small Interfering)
[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:170315
[St] Status:MEDLINE
[do] DOI:10.1007/s10585-017-9840-3


  9 / 1181 MEDLINE  
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[PMID]:28139439
[Au] Autor:Tati R; Kristoffersson AC; Manea Hedström M; Mörgelin M; Wieslander J; van Kooten C; Karpman D
[Ad] Endereço:Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
[Ti] Título:Neutrophil Protease Cleavage of Von Willebrand Factor in Glomeruli - An Anti-thrombotic Mechanism in the Kidney.
[So] Source:EBioMedicine;16:302-311, 2017 Feb.
[Is] ISSN:2352-3964
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Adequate cleavage of von Willebrand factor (VWF) prevents formation of thrombi. ADAMTS13 is the main VWF-cleaving protease and its deficiency results in development of thrombotic microangiopathy. Besides ADAMTS13 other proteases may also possess VWF-cleaving activity, but their physiological importance in preventing thrombus formation is unknown. This study investigated if, and which, proteases could cleave VWF in the glomerulus. The content of the glomerular basement membrane (GBM) was studied as a reflection of processes occurring in the subendothelial glomerular space. VWF was incubated with human GBMs and VWF cleavage was assessed by multimer structure analysis, immunoblotting and mass spectrometry. VWF was cleaved into the smallest multimers by the GBM, which contained ADAMTS13 as well as neutrophil proteases, elastase, proteinase 3 (PR3), cathepsin-G and matrix-metalloproteinase 9. The most potent components of the GBM capable of VWF cleavage were in the serine protease or metalloprotease category, but not ADAMTS13. Neutralization of neutrophil serine proteases inhibited GBM-mediated VWF-cleaving activity, demonstrating a marked contribution of elastase and/or PR3. VWF-platelet strings formed on the surface of primary glomerular endothelial cells, in a perfusion system, were cleaved by both elastase and the GBM, a process blocked by elastase inhibitor. Ultramorphological studies of the human kidney demonstrated neutrophils releasing elastase into the GBM. Neutrophil proteases may contribute to VWF cleavage within the subendothelium, adjacent to the GBM, and thus regulate thrombus size. This anti-thrombotic mechanism would protect the normal kidney during inflammation and could also explain why most patients with ADAMTS13 deficiency do not develop severe kidney failure.
[Mh] Termos MeSH primário: Glomérulos Renais/metabolismo
Rim/metabolismo
Neutrófilos/enzimologia
Peptídeo Hidrolases/metabolismo
Trombose/metabolismo
Fator de von Willebrand/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS13/metabolismo
Adulto
Plaquetas/metabolismo
Catepsina G/metabolismo
Células Endoteliais/metabolismo
Membrana Basal Glomerular/efeitos dos fármacos
Membrana Basal Glomerular/metabolismo
Seres Humanos
Immunoblotting
Rim/irrigação sanguínea
Rim/ultraestrutura
Glomérulos Renais/efeitos dos fármacos
Glomérulos Renais/ultraestrutura
Elastase de Leucócito/antagonistas & inibidores
Elastase de Leucócito/metabolismo
Masculino
Metaloproteinase 9 da Matriz/metabolismo
Microscopia Eletrônica de Transmissão
Mieloblastina/metabolismo
Proteínas Secretadas Inibidoras de Proteinases/farmacologia
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
Trombose/prevenção & controle
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proteinase Inhibitory Proteins, Secretory); 0 (von Willebrand Factor); EC 3.4.- (Peptide Hydrolases); EC 3.4.21.20 (Cathepsin G); EC 3.4.21.37 (Leukocyte Elastase); EC 3.4.21.76 (Myeloblastin); EC 3.4.24.35 (Matrix Metalloproteinase 9); EC 3.4.24.87 (ADAMTS13 Protein); EC 3.4.24.87 (ADAMTS13 protein, human)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE


  10 / 1181 MEDLINE  
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[PMID]:28059468
[Au] Autor:Dittmann J; Ziegfeld A; Jansen L; Gajda M; Kloten V; Dahl E; Runnebaum IB; Dürst M; Backsch C
[Ad] Endereço:Department of Gynecology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
[Ti] Título:Gene expression analysis combined with functional genomics approach identifies ITIH5 as tumor suppressor gene in cervical carcinogenesis.
[So] Source:Mol Carcinog;56(6):1578-1589, 2017 Jun.
[Is] ISSN:1098-2744
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Progression from human papillomavirus-induced premalignant cervical intraepithelial neoplasia (CIN) to cervical cancer (CC) is driven by genetic and epigenetic events. Our microarray-based expression study has previously shown that inter-α-trypsin-inhibitor heavy chain 5 (ITIH5) mRNA levels in CCs were significantly lower than in high-grade precursor lesions (CIN3s). Therefore, we aimed to analyze in depth ITIH5 expression during cervical carcinogenesis in biopsy material and cell culture. Moreover, functional analyses were performed by ectopic expression of ITIH5 in different cell lines. We were able to confirm the validity of our microarray differential expression data by qPCR, demonstrating a clear ITIH5 downregulation in CC as compared with CIN2/3 or normal cervix. ITIH5 protein loss, evaluated by immunohistochemistry, was evident in 81% of CCs, whereas ITIH5 showed weak to moderate cytoplasmic staining in 91% of CIN2/3 cases. In addition, ITIH5 was strongly reduced or absent in seven CC cell lines and in three immortalized keratinocyte cell lines. Moreover, ITIH5 mRNA loss was associated with ITIH5 promoter methylation. ITIH5 expression could be restored in CC cell lines by pharmacological induction of DNA demethylation and histone acetylation. Functionally, ITIH5 overexpression significantly suppressed proliferation of SW756 cells and further resulted in a significant reduction of colony formation and cell migration in both CaSki and SW756 tumor models, but had no effect on invasion. Remarkably, ITIH5 overexpression did not influence the phenotype of HeLa cells. Taken together, ITIH5 gene silencing is a frequent event during disease progression, thereby providing evidence for a tumor suppressive role in cervical carcinogenesis.
[Mh] Termos MeSH primário: Carcinogênese/genética
Regulação Neoplásica da Expressão Gênica
Genes Supressores de Tumor
Ovário/patologia
Proteínas Secretadas Inibidoras de Proteinases/genética
Neoplasias do Colo do Útero/genética
[Mh] Termos MeSH secundário: Carcinogênese/patologia
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Células Cultivadas
Metilação de DNA
Regulação para Baixo
Feminino
Genômica
Seres Humanos
Ovário/metabolismo
Regiões Promotoras Genéticas
Proteínas Secretadas Inibidoras de Proteinases/análise
Neoplasias do Colo do Útero/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ITIH5 protein, human); 0 (Proteinase Inhibitory Proteins, Secretory)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE
[do] DOI:10.1002/mc.22613



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