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  1 / 11201 MEDLINE  
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[PMID]:29226984
[Au] Autor:Shah K; Nasir A; Irfanullah; Shahzad S; Khan S; Ahmad W
[Ad] Endereço:Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University (QAU), Islamabad, Pakistan.
[Ti] Título:A novel homozygous mutation disrupting the initiation codon in the SLURP1 gene underlies mal de Meleda in a consanguineous family.
[So] Source:Clin Exp Dermatol;41(6):675-679, 2016 Aug.
[Is] ISSN:1365-2230
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mal de Meleda (MDM) is a palmoplantar keratoderma (PPK), characterized by hyperkeratosis of the palms and soles, and keratotic skin lesions. Patients with MDM can develop perioral erythema, keratotic and lichenoid plaques over the joints (including the elbows and knees), nail abnormalities, joint contractures and stiffness, brachydactyly, sclerodactyly, pseudoainhum, and malodorous maceration. MDM is associated with mutations in the SLURP1 gene. We report a consanguineous family in which MDM was inherited in an autosomal recessive manner. Genotyping using microsatellite markers established linkage in the family to the SLURP1 gene, which has been mapped previously to chromosome 8q24.3. Sequence analysis revealed a homozygous missense mutation (c.2T>C, p.Met1Thr) in affected family members. Molecular docking studies using a ZDOCK server predicted disruption of binding of the mutant variant to its target α7-nAChR. This study further supports the previously reported findings that homozygous mutations in the SLURP1 gene cause MDM.
[Mh] Termos MeSH primário: Antígenos Ly/genética
Códon de Iniciação/genética
Ceratodermia Palmar e Plantar/genética
Mutação de Sentido Incorreto
Ativador de Plasminogênio Tipo Uroquinase/genética
[Mh] Termos MeSH secundário: Antígenos Ly/química
Consanguinidade
Seres Humanos
Linhagem
Estrutura Terciária de Proteína
Ativador de Plasminogênio Tipo Uroquinase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Ly); 0 (Codon, Initiator); 0 (SLURP1 protein, human); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180117
[Lr] Data última revisão:
180117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.1111/ced.12864


  2 / 11201 MEDLINE  
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[PMID]:29061810
[Au] Autor:Cho JH; Joo YH; Shin EY; Park EJ; Kim MS
[Ad] Endereço:Department of Otolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
[Ti] Título:Anticancer Effects of Colchicine on Hypopharyngeal Cancer.
[So] Source:Anticancer Res;37(11):6269-6280, 2017 11.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Colchicine is an alkaloid widely used for the treatment of inflammatory diseases, such as gout. It suppresses cell division by inhibiting mitosis. We investigated the anticancer effects of colchicine on human hypopharyngeal cancer cells and the mechanisms underlying its anticancer effects. XTT cell proliferation assay showed that colchicine inhibited the growth and proliferation of human hypopharyngeal cancer cells (FaDu and SNU1041) in a dose- and time-dependent manner. Colchicine also inhibited the migration, invasion, and adhesion of hypopharyngeal cancer cells in a dose-dependent manner. The levels of mRNA expression and activity of matrix metalloproteinase-9 (MMP9) and urokinase-type plasminogen activator (uPA) decreased after treatment with colchicine. Further investigation revealed that colchicine inhibited the phosphorylation of the FAK/SRC complex and paxillin. Tumor volume ratios in colchicine-treated mice (0.1 mg/kg, every 2 days for 14 days) increased less than in control mice. To our knowledge, this is the first report showing that colchicine can suppress cell invasion, migration, and adhesion through reduced expression of MMP9, the uPA system, and the FAK/SRC complex. Colchicine has the potential to prevent disease progression in hypopharyngeal cancer and may have application as an adjunctive treatment.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Colchicina/administração & dosagem
Neoplasias Hipofaríngeas/tratamento farmacológico
Metaloproteinase 9 da Matriz/genética
Ativador de Plasminogênio Tipo Uroquinase/genética
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Colchicina/farmacologia
Relação Dose-Resposta a Droga
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Neoplasias Hipofaríngeas/genética
Neoplasias Hipofaríngeas/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Camundongos
Invasividade Neoplásica
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9); SML2Y3J35T (Colchicine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE


  3 / 11201 MEDLINE  
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[PMID]:29019875
[Au] Autor:Hsu SY; Cheng HT; Manrique O; Hsu YC
[Ad] Endereço:Department of Plastic Surgery, China Medical University Hospital, Taichung, Taiwan.
[Ti] Título:Anterograde injection of low-dose urokinase salvages free anterolateral thigh flap: A case report of safe and effective treatment.
[So] Source:Medicine (Baltimore);96(41):e7932, 2017 Oct.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: A 54-year-old Taiwanese male came to our hospital presented with right retromolar mucoepidermoid carcinoma. Composite resection and right modified radical neck dissection were performed. We then use free anteral lateral thigh flap to reconstruct the defect. However, venous congestion was found 32 h after the surgery. PATIENT CONCERNS: The main concerns of the patient is complete salvage of the free flap, and avoiding the secondary free flap harvesting and reconstruction surgeries. DIAGNOSES: Right retromolar mucoepidermoid carcinoma. INTERVENTIONS: We report the case of a patient with an anterolateral thigh flap with venous perianastomosis thrombosis and intraflap microvascular thrombosis successfully salvaged using anterograde intra-arterial injection of low-dose urokinase (60,000 U), without administering intravenous anticoagulation heparin during the postoperative period. OUTCOMES: The flap was completely salvaged 3 days after treatment. No other flap-associated or bleeding complications were noted. The intra-oral wounds around the flap completely healed without any post-ischemic complications. LESSONS SUBSECTIONS: Although the ideal urokinase doses and delivery procedures for free flap salvage have not been developed thus far, our method maximizes the urokinase gradient in the flap, minimizes the total dose required for flap salvage, and ensures no systemic spread. Thus, compared with other thrombolytic agents, urokinase may be more effective and safe for free flap salvage. With more experience, a standardized dosage and procedure can be developed.
[Mh] Termos MeSH primário: Carcinoma Mucoepidermoide
Neoplasias Maxilomandibulares
Complicações Pós-Operatórias
Retalhos Cirúrgicos/irrigação sanguínea
Trombectomia/métodos
Trombose
Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem
Procedimentos Cirúrgicos Vasculares/efeitos adversos
[Mh] Termos MeSH secundário: Processo Alveolar/cirurgia
Carcinoma Mucoepidermoide/patologia
Carcinoma Mucoepidermoide/cirurgia
Fibrinolíticos/administração & dosagem
Neoplasias de Cabeça e Pescoço/patologia
Neoplasias de Cabeça e Pescoço/cirurgia
Seres Humanos
Neoplasias Maxilomandibulares/patologia
Neoplasias Maxilomandibulares/cirurgia
Masculino
Meia-Idade
Esvaziamento Cervical/métodos
Complicações Pós-Operatórias/etiologia
Complicações Pós-Operatórias/terapia
Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos
Procedimentos Cirúrgicos Reconstrutivos/métodos
Trombose/etiologia
Trombose/terapia
Resultado do Tratamento
Procedimentos Cirúrgicos Vasculares/métodos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fibrinolytic Agents); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007932


  4 / 11201 MEDLINE  
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[PMID]:28931568
[Au] Autor:Diaz A; Merino P; Manrique LG; Ospina JP; Cheng L; Wu F; Jeanneret V; Yepes M
[Ad] Endereço:Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
[Ti] Título:A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain.
[So] Source:J Neurosci;37(43):10310-10322, 2017 Oct 25.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin on the cell surface. Our previous studies indicate that uPA and uPAR expression increase in the ischemic brain during the recovery phase from an acute ischemic injury and that uPA binding to uPAR promotes neurological recovery after an acute ischemic stroke. Here, we used male mice genetically deficient on either uPA (uPA ) or uPAR (uPAR ) or with a four-amino acid substitution into the growth factor domain of uPA that abrogates its binding to uPAR ( ) to investigate the mechanism whereby uPA promotes neurorepair in the ischemic brain. We found that neurons release uPA and astrocytes recruit uPAR to their plasma membrane during the recovery phase from a hypoxic injury and that binding of neuronal uPA to astrocytic uPAR induces astrocytic activation by a mechanism that does not require plasmin generation, but instead is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-regulated phosphorylation of the signal transducer and activator of transcription 3 (STAT3). We report that uPA/uPAR binding is necessary and sufficient to induce astrocytic activation in the ischemic brain and that astrocytes activated by neuronal uPA promote synaptic recovery in neurons that have suffered an acute hypoxic injury via a mechanism mediated by astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). In summary, we show that uPA/uPAR-induced astrocytic activation mediates a cross talk between astrocytes and injured neurons that promotes synaptic recovery in the ischemic brain. To date, there is no therapeutic strategy to promote synaptic recovery in the injured brain. Here, we show that neurons release urokinase-type plasminogen activator (uPA) and astrocytes recruit the uPA receptor (uPAR) to their plasma membrane during the recovery phase from a hypoxic injury. We found that binding of neuronal uPA to astrocytic uPAR promotes astrocytic activation and that astrocytes activated by uPA-uPAR binding promote synaptic recovery in neurons that have suffered a hypoxic injury by a mechanism that does not require plasmin generation, but instead is mediated by ERK1/2-regulated STAT3 phosphorylation, astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). Our work unveils a new biological function for uPA-uPAR as mediator of a neuron-astrocyte cross talk that promotes synaptic recovery in the ischemic brain.
[Mh] Termos MeSH primário: Astrócitos/metabolismo
Isquemia Encefálica/metabolismo
Receptor Cross-Talk/fisiologia
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Sinapses/fisiologia
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Astrócitos/patologia
Isquemia Encefálica/patologia
Células Cultivadas
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Neurônios/metabolismo
Neurônios/patologia
Recuperação de Função Fisiológica/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Urokinase Plasminogen Activator); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1630-17.2017


  5 / 11201 MEDLINE  
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[PMID]:28877230
[Au] Autor:Ettl J; Klein E; Hapfelmeier A; Grosse Lackmann K; Paepke S; Petry C; Specht K; Wolff L; Höfler H; Kiechle M
[Ad] Endereço:Klinik und Poliklinik für Frauenheilkunde, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
[Ti] Título:Decision impact and feasibility of different ASCO-recommended biomarkers in early breast cancer: Prospective comparison of molecular marker EndoPredict and protein marker uPA/PAI-1.
[So] Source:PLoS One;12(9):e0183917, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adjuvant therapy decisions in early breast cancer are based on accurate risk assessment. Urokinase plasminogen activator (uPA) and plaminogen activator inhibitor-1 (PAI-1) have been the first biomarkers in hormone receptor (HR) positive breast cancer to reach highest level of evidence. The EndoPredict test (EPclin) combines gene expression information with nodal status and tumor size. The aim of this prospective study was to compare uPA/PAI-1 and EPclin as prognostic biomarkers with regard to feasibility, risk stratification and impact on adjuvant therapy recommendation. MATERIALS AND METHOD: 395 patients with HR positive, HER2 negative, intermediate risk breast cancer were enrolled. Relations and concordance of histologic grading as well as EPclin and uPA/PAI-1 values were assessed by Spearman's rank correlation coefficient and Cohen's Kappa. To compare decision impact of EPclin and uPA/PAI-1 three independent case discussions were held: One with known uPA/PAI-1 and EPclin results, one blinded to EPclin alone and another one blinded to both EPclin and uPA/PAI-1. RESULTS: EPclin could be determined in all 395 (100%), uPA/PAI-1 in 190 (48%) of the tumor samples. EPclin allocated 250 patients (63%) to the low-risk group and 145 patients (37%) to the high-risk group, whereas uPA/PAI-1 allocated 88 patients (46%) to the low-risk group and 102 patients (54%) to the high-risk group. In 59% of cases, both tests showed concordant results. EPclin resulted more frequently in a change of therapy recommendation than the uPA/PAI-1 test (46% vs 24%). Recommendation of adjuvant chemotherapy (CTX) was abandoned twice as often by EPclin (45%) compared to uPA/PAI-1 (22%). CONCLUSION: In this first prospective comparison of EPclin and uPA/PAI-1 we found, that EPclin is superior to uPA/PAI-1 with respect to feasibility and decision impact. This leads to substantial avoidance of adjuvant CTX in endocrine-sensitive, HER2-negative breast cancer. Data collection for patients´ clinical outcome is ongoing.
[Mh] Termos MeSH primário: Neoplasias da Mama/diagnóstico
Inibidor 1 de Ativador de Plasminogênio/análise
Ativador de Plasminogênio Tipo Uroquinase/análise
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores/análise
Neoplasias da Mama/química
Neoplasias da Mama/patologia
Neoplasias da Mama/terapia
Quimioterapia Adjuvante
Estudos de Viabilidade
Feminino
Seres Humanos
Meia-Idade
Guias de Prática Clínica como Assunto
Prognóstico
Estudos Prospectivos
Medição de Risco
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Plasminogen Activator Inhibitor 1); 0 (SERPINE1 protein, human); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183917


  6 / 11201 MEDLINE  
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[PMID]:28854261
[Au] Autor:Wang L; Zhang Y; Wang W; Zhu Y; Chen Y; Tian B
[Ad] Endereço:Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, P.R. China.
[Ti] Título:Gemcitabine treatment induces endoplasmic reticular (ER) stress and subsequently upregulates urokinase plasminogen activator (uPA) to block mitochondrial-dependent apoptosis in Panc-1 cancer stem-like cells (CSCs).
[So] Source:PLoS One;12(8):e0184110, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates. The presence of cancer stem-like cells (CSCs) is believed to be among the underlying reasons for the aggressiveness of PDAC, which contributes to chemoresistance and recurrence. However, the mechanisms that induce chemoresistance and inhibit apoptosis remain largely unknown. METHODS: We used serum-free medium to enrich CSCs from panc-1 human pancreatic cancer cells and performed sphere formation testing, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and semi-quantitative western blotting to confirm the stemness of panc-1 CSCs. Hallmarks of endoplasmic reticulum (ER) stress, including IRE1, PERK, ATF4, ATF6α, GRP78 and uPA expression, were detected after gemcitabine treatment. Effects of gemcitabine-induced uPA expression on cell invasion, sphere formation, colony formation and gemcitabine sensitivity were detected. Electrophoretic mobility shift assays (EMSAs) and RNA-immunoprecipitation (RIP) were performed to detect interaction between the uPA mRNA 3'-UTR and mutant p53-R273H expressed by panc-1 CSCs. The effects of upregulated uPA by gemcitabine on apoptosis were detected by Annexin V-FITC/PI staining, and the impact of uPA on small molecule CP-31398-restored mutant p53 transcriptional activity was measured by a luciferase reporter assay. RESULTS: Enriched panc-1 CSCs expressing high levels of CD44 and CD133 also produced significantly higher amounts of Oct4 and Nanog. Compared with panc-1 cells, panc-1 CSCs presented chemoresistance to gemcitabine. ER stress gene detections demonstrated effects of gemcitabine-induced ER stress on both the pro-apoptotic and pro-survival branches. ER stress-induced ATF6α upregulated level of uPA by transcriptionally activating GRP78. Gemcitabine-induced uPA promoted invasion, sphere formation and colony formation and attenuated apoptosis induced by gemcitabine in panc-1 CSCs, depending on interaction with mutant p53-R273H. Upregulation of uPA abolished CP-31398-mediated restoration of mutant p53 transcriptional activity in panc-1 CSCs. CONCLUSION: Gemcitabine treatment induced ER stress and promoted mutant p53-R273H stabilization via transcriptionally activated uPA which may contribute to chemoresistance to gemcitabine. Notably, upregulation of uPA by gemcitabine treatment may lead to the failure of CP-31398; thus, a novel strategy for modulating mutant p53 function needs to be developed.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/farmacologia
Desoxicitidina/análogos & derivados
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Células-Tronco Neoplásicas/efeitos dos fármacos
Neoplasias Pancreáticas/tratamento farmacológico
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Desoxicitidina/farmacologia
Proteínas de Choque Térmico/metabolismo
Seres Humanos
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Células-Tronco Neoplásicas/metabolismo
Células-Tronco Neoplásicas/patologia
Pâncreas/efeitos dos fármacos
Pâncreas/metabolismo
Pâncreas/patologia
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Pirimidinas/farmacologia
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Heat-Shock Proteins); 0 (Pyrimidines); 0 (Tumor Suppressor Protein p53); 0 (molecular chaperone GRP78); 0W860991D6 (Deoxycytidine); B76N6SBZ8R (gemcitabine); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator); IN3WH41H3A (CP 31398)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184110


  7 / 11201 MEDLINE  
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[PMID]:28818858
[Au] Autor:Hohensinner PJ; Baumgartner J; Kral-Pointner JB; Uhrin P; Ebenbauer B; Thaler B; Doberer K; Stojkovic S; Demyanets S; Fischer MB; Huber K; Schabbauer G; Speidl WS; Wojta J
[Ad] Endereço:From the Department of Internal Medicine II, Division of Cardiology (P.J.H., J.B., B.E., B.T., K.D., S.S., S.D., W.S.S., J.W.), Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research (J.B.K.-P., P.U., G.S.), Department of Laboratory Medicine (S.D.), Clinic for
[Ti] Título:PAI-1 (Plasminogen Activator Inhibitor-1) Expression Renders Alternatively Activated Human Macrophages Proteolytically Quiescent.
[So] Source:Arterioscler Thromb Vasc Biol;37(10):1913-1922, 2017 Oct.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine-polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages. APPROACH AND RESULTS: We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine-polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1 bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss. CONCLUSIONS: We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence in alternatively polarized macrophages by the expression of PAI-1.
[Mh] Termos MeSH primário: Macrófagos/metabolismo
Inibidor 1 de Ativador de Plasminogênio/metabolismo
Proteólise
[Mh] Termos MeSH secundário: Fibrose
Seres Humanos
Pulmão/enzimologia
Pulmão/patologia
Metaloproteinase 14 da Matriz/metabolismo
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plasminogen Activator Inhibitor 1); 0 (Receptors, Urokinase Plasminogen Activator); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator); EC 3.4.24.80 (MMP14 protein, human); EC 3.4.24.80 (Matrix Metalloproteinase 14)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309383


  8 / 11201 MEDLINE  
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[PMID]:28803936
[Au] Autor:Swamynathan S; Loughner CL; Swamynathan SK
[Ad] Endereço:Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
[Ti] Título:Inhibition of HUVEC tube formation via suppression of NFκB suggests an anti-angiogenic role for SLURP1 in the transparent cornea.
[So] Source:Exp Eye Res;164:118-128, 2017 Nov.
[Is] ISSN:1096-0007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Previously, we have reported that the Secreted Ly6/uPAR related protein-1 (SLURP1) serves an important immunomodulatory function in the ocular surface. Here, we examine the involvement of SLURP1 in regulating corneal angiogenic privilege. Slurp1 expression detected by QPCR, immunoblots and immunofluorescent stain, was significantly decreased in mouse corneas subjected to alkali burn-induced corneal neovascularization (CNV). Addition of exogenous SLURP1 (6XHis-tagged, E. coli expressed and partially purified using Ni-ion columns) significantly suppressed the tumor necrosis factor-α (TNF-α)-stimulated human umbilical cord vascular endothelial cell (HUVEC) tube formation. SLURP1 suppressed the HUVEC tube length, tube area and number of branch points, without affecting their viability and/or proliferation. Exogenous SLURP1 in HUVEC also suppressed the TNF-α-induced (i) interleukin-8 (IL-8) and TNF-α production, (ii) adhesion to different components of the extracellular matrix, (iii) migration, and (iv) nuclear localization of NFκB. Together, these results demonstrate that SLURP1 suppresses HUVEC tube formation by blocking nuclear translocation of NFκB, and suggest a potential role for SLURP1 in promoting corneal angiogenic privilege.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia
Antígenos Ly/farmacologia
Neovascularização da Córnea/metabolismo
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
NF-kappa B/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/farmacologia
[Mh] Termos MeSH secundário: Animais
Antígenos Ly/fisiologia
Queimaduras Químicas/metabolismo
Adesão Celular/efeitos dos fármacos
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Lesões da Córnea/metabolismo
Modelos Animais de Doenças
Queimaduras Oculares/metabolismo
Seres Humanos
Interleucina-8/metabolismo
Camundongos
Fator de Necrose Tumoral alfa/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Antigens, Ly); 0 (Interleukin-8); 0 (NF-kappa B); 0 (SLURP-1 protein, mouse); 0 (Tumor Necrosis Factor-alpha); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28722103
[Au] Autor:Missault S; Peeters L; Amhaoul H; Thomae D; Van Eetveldt A; Favier B; Thakur A; Van Soom J; Pitkänen A; Augustyns K; Joossens J; Staelens S; Dedeurwaerdere S
[Ad] Endereço:Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
[Ti] Título:Decreased levels of active uPA and KLK8 assessed by [ In]MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy.
[So] Source:Epilepsia;58(9):1615-1625, 2017 Sep.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Urokinase-type plasminogen activator (uPA) and kallikrein-related peptidase 8 (KLK8) are serine proteases that contribute to extracellular matrix (ECM) remodeling after brain injury. They can be labelled with the novel radiotracer [ In]MICA-401. As the first step in exploring the applicability of [ In]MICA-401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [ In]MICA-401 distribution in the brain in two animal models: kainic acid-induced status epilepticus (KASE) and controlled cortical impact (CCI)-induced traumatic brain injury (TBI). METHODS: In the KASE model, in vitro autoradiography with [ In]MICA-401 was performed at 7 days and 12 weeks post-SE. To assess seizure burden, rats were monitored using video-electroencephalography (EEG) for 1 month before the 12-week time point. In the CCI model, in vitro autoradiography was performed at 4 days and ex vivo autoradiography at 7 days post-TBI. RESULTS: At 7 days post-SE, in vitro autoradiography revealed significantly decreased [ In]MICA-401 binding in hippocampal CA3 subfield and extrahippocampal temporal lobe (ETL). In the chronic phase, when animals had developed spontaneous seizures, specific binding was decreased in CA3 and CA1/CA2 subfields of hippocampus, dentate gyrus, ETL, and parietal cortex. Of interest, KASE rats with the highest frequency of seizures had the lowest hippocampal [ In]MICA-401 binding (r = -0.76, p ≤ 0.05). Similarly, at 4 days post-TBI, in vitro [ In]MICA-401 binding was significantly decreased in medial and lateral perilesional cortex and ipsilateral dentate gyrus. Ex vivo autoradiography at 7 days post-TBI, however, revealed increased tracer uptake in perilesional cortex and hippocampus, which was likely related to tracer leakage due to blood-brain barrier (BBB) disruption. SIGNIFICANCE: Strong association of reduced [ In]MICA-401 binding with seizure burden in the KASE model suggests that analysis of reduced levels of active uPA/KLK8 represents a novel biomarker candidate to be explored as a biomarker for epilepsy severity. However, limited BBB permeability of [ In]MICA-401 currently limits its application in vivo.
[Mh] Termos MeSH primário: Epilepsia do Lobo Temporal/metabolismo
Calicreínas/metabolismo
Convulsões/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Eletroencefalografia
Masculino
Ratos
Ratos Sprague-Dawley
Estado Epiléptico/metabolismo
Gravação em Vídeo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.21.- (Kallikreins); EC 3.4.21.- (Prss19 protein, mouse); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13845


  10 / 11201 MEDLINE  
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[PMID]:28686711
[Au] Autor:Zhalyalov AS; Panteleev MA; Gracheva MA; Ataullakhanov FI; Shibeko AM
[Ad] Endereço:Center for Theoretical Problems of Physicochemical Pharmacology RAS, Moscow, Russia.
[Ti] Título:Co-ordinated spatial propagation of blood plasma clotting and fibrinolytic fronts.
[So] Source:PLoS One;12(7):e0180668, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibrinolysis is a cascade of proteolytic reactions occurring in blood and soft tissues, which functions to disintegrate fibrin clots when they are no more needed. In order to elucidate its regulation in space and time, fibrinolysis was investigated using an in vitro reaction-diffusion experimental model of blood clot formation and dissolution. Clotting was activated by a surface with immobilized tissue factor in a thin layer of recalcified blood plasma supplemented with tissue plasminogen activator (TPA), urokinase plasminogen activator or streptokinase. Formation and dissolution of fibrin clot was monitored by videomicroscopy. Computer systems biology model of clot formation and lysis was developed for data analysis and experimental planning. Fibrin clot front propagated in space from tissue factor, followed by a front of clot dissolution propagating from the same source. Velocity of lysis front propagation linearly depended on the velocity clotting front propagation (correlation r2 = 0.91). Computer model revealed that fibrin formation was indeed the rate-limiting step in the fibrinolysis front propagation. The phenomenon of two fronts which switched the state of blood plasma from liquid to solid and then back to liquid did not depend on the fibrinolysis activator. Interestingly, TPA at high concentrations began to increase lysis onset time and to decrease lysis propagation velocity, presumably due to plasminogen depletion. Spatially non-uniform lysis occurred simultaneously with clot formation and detached the clot from the procoagulant surface. These patterns of spatial fibrinolysis provide insights into its regulation and might explain clinical phenomena associated with thrombolytic therapy.
[Mh] Termos MeSH primário: Coagulação Sanguínea/genética
Fibrinólise/genética
Terapia Trombolítica
[Mh] Termos MeSH secundário: Simulação por Computador
Fibrina/genética
Fibrina/metabolismo
Seres Humanos
Plasminogênio/metabolismo
Estreptoquinase/sangue
Tromboplastina/metabolismo
Ativador de Plasminogênio Tecidual/sangue
Ativador de Plasminogênio Tipo Uroquinase/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9001-31-4 (Fibrin); 9001-91-6 (Plasminogen); 9035-58-9 (Thromboplastin); EC 3.4.- (Streptokinase); EC 3.4.21.68 (PLAT protein, human); EC 3.4.21.68 (Tissue Plasminogen Activator); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180668



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