Base de dados : MEDLINE
Pesquisa : D12.776.543.750.695.035 [Categoria DeCS]
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[PMID]:29254302
[Au] Autor:Wang Q; Wang J; Gao D; Li J
[Ad] Endereço:Tumor Center, The First Hospital of Jilin University, Changchun, Jilin, China.
[Ti] Título:Inhibition of PAR2 and TRPA1 signals alleviates neuropathic pain evoked by chemotherapeutic bortezomib.
[So] Source:J Biol Regul Homeost Agents;31(4):977-983, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:Bortezomib (BTZ) is generally used as a chemotherapeutic agent for the treatment of multiple myeloma; however, one of the significant limiting complications of BTZ is painful peripheral neuropathy observed during BTZ therapy. There is a lack of drugs which can prevent and/or treat the painful symptoms induced by BTZ, as the underlying molecular mechanism leading to neuropathic pain remains largely unclear. In the present study, we examined engagement of proteinase-activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) in neuropathic pain induced by BTZ in rats. Our results demonstrated that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals (P less than 0.05 vs control rats). Our data further showed that blocking respective PAR2 and TRPA1 attenuated mechanical pain and cold sensitivity observed in control rats and BTZ rats (P less than 0.05 vs vehicle control). Notably, the attenuating effect of blocking PAR2 and TRPA1 on mechanical pain and cold sensitivity was significantly less in BTZ rats than that in control rats. In addition, protein expression of PAR2 and TRPA1 was upregulated in the lumbar dorsal root ganglion of BTZ rats, and inhibition of PAR2 decreased the levels of TRPA1 and attenuated its downstream pathways (namely, PKCÉ› and PKA). Overall, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ and that blocking PAR2 and TRPA1 in sensory nerves is beneficial to improve neuropathic pain during BTZ intervention.
[Mh] Termos MeSH primário: Analgésicos/farmacologia
Antineoplásicos/efeitos adversos
Bortezomib/efeitos adversos
Neuralgia/prevenção & controle
Oligopeptídeos/farmacologia
Receptor PAR-2/antagonistas & inibidores
Canal de Cátion TRPA1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Gânglios Espinais/efeitos dos fármacos
Gânglios Espinais/metabolismo
Gânglios Espinais/fisiopatologia
Regulação da Expressão Gênica
Hiperalgesia/induzido quimicamente
Hiperalgesia/genética
Hiperalgesia/fisiopatologia
Hiperalgesia/prevenção & controle
Masculino
Neuralgia/induzido quimicamente
Neuralgia/genética
Neuralgia/fisiopatologia
Proteína Quinase C-épsilon/genética
Proteína Quinase C-épsilon/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Transdução de Sinais
Canal de Cátion TRPA1/genética
Canal de Cátion TRPA1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Antineoplastic Agents); 0 (H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2); 0 (Oligopeptides); 0 (Receptor, PAR-2); 0 (TRPA1 Cation Channel); 0 (Trpa1 protein, rat); 69G8BD63PP (Bortezomib); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.13 (Protein Kinase C-epsilon)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171220
[St] Status:MEDLINE


  2 / 1469 MEDLINE  
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[PMID]:27770804
[Au] Autor:Natarajan K; Gottipati KR; Berhane K; Samten B; Pendurthi U; Boggaram V
[Ad] Endereço:Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA.
[Ti] Título:Proteases and oxidant stress control organic dust induction of inflammatory gene expression in lung epithelial cells.
[So] Source:Respir Res;17(1):137, 2016 10 22.
[Is] ISSN:1465-993X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Persistant inflammatory responses to infectious agents and other components in organic dust underlie lung injury and development of respiratory diseases. Organic dust components responsible for eliciting inflammation and the mechanisms by which they cause lung inflammation are not fully understood. We studied the mechanisms by which protease activities in poultry dust extracts and intracellular oxidant stress induce inflammatory gene expression in A549 and Beas2B lung epithelial cells. METHODS: The effects of dust extracts on inflammatory gene expression were analyzed by quantitative polymerase chain reaction (qPCR), enzyme linked immunosorbent (ELISA) and western blot assays. Oxidant stress was probed by dihydroethidium (DHE) labeling, and immunostaining for 4-hydroxynonenal (4-HNE). Effects on interleukin-8 (IL-8) promoter regulation were determined by transient transfection assay. RESULTS: Dust extracts contained trypsin and elastase activities, and activated protease activated receptor (PAR)-1 and -2. Serine protease inhibitors and PAR-1 or PAR-2 knockdown suppressed inflammatory gene induction. Dust extract induction of IL-8 gene expression was associated with increased DHE-fluorescence and 4-HNE staining, and antioxidants suppressed inflammatory gene induction. Protease inhibitors and antioxidants suppressed protein kinase C and NF-κB activation and induction of IL-8 promoter activity in cells exposed to dust extract. CONCLUSIONS: Our studies demonstrate that proteases and intracellular oxidants control organic dust induction of inflammatory gene expression in lung epithelial cells. Targeting proteases and oxidant stress may serve as novel approaches for the treatment of organic dust induced lung diseases. This is the first report on the involvement of oxidant stress in the induction of inflammatory gene expression by organic dust.
[Mh] Termos MeSH primário: Poeira
Células Epiteliais/efeitos dos fármacos
Mediadores da Inflamação/metabolismo
Pulmão/efeitos dos fármacos
Compostos Orgânicos/toxicidade
Estresse Oxidativo/efeitos dos fármacos
Peptídeo Hidrolases/metabolismo
Pneumonia/induzido quimicamente
[Mh] Termos MeSH secundário: Células A549
Animais
Anti-Inflamatórios/farmacologia
Antioxidantes/farmacologia
Células Epiteliais/enzimologia
Regulação da Expressão Gênica
Abrigo para Animais
Seres Humanos
Exposição por Inalação/efeitos adversos
Interleucina-8/genética
Interleucina-8/metabolismo
Pulmão/enzimologia
Metaloproteinases da Matriz/genética
Metaloproteinases da Matriz/metabolismo
Pneumonia/enzimologia
Pneumonia/genética
Pneumonia/prevenção & controle
Aves Domésticas
Receptor PAR-1/genética
Receptor PAR-1/metabolismo
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Inibidores de Serino Proteinase/farmacologia
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Antioxidants); 0 (Dust); 0 (IL8 protein, human); 0 (Inflammation Mediators); 0 (Interleukin-8); 0 (Organic Chemicals); 0 (Receptor, PAR-1); 0 (Receptor, PAR-2); 0 (Serine Proteinase Inhibitors); EC 3.4.- (Peptide Hydrolases); EC 3.4.24.- (Matrix Metalloproteinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:28694352
[Au] Autor:Du C; Zhang T; Xiao X; Shi Y; Duan H; Ren Y
[Ad] Endereço:Department of Pathology, Hebei Medical University, Shijiazhuang, China.
[Ti] Título:Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway.
[So] Source:Biochem J;474(16):2733-2747, 2017 Aug 02.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protease-activated receptor-2 (PAR2), which belongs to a specific class of the G-protein-coupled receptors, is central to several inflammation processes. However, the precise molecular mechanism involved remains undefined. Autophagy has been previously shown to affect inflammation. In the present study, we examine the effect of PAR2 on kidney tubular epithelial autophagy and on autophagy-related inflammation and reveal the underlying mechanism involved. Autophagic activity and levels of autophagic marker LC3 were examined in human kidney tubular epithelial cells with PAR2 knockdown or overexpression. We administered the mammalian target of rapamycin (mTOR) inhibitor (rapamycin) or activator (MHY1485) to investigate the function of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. We also used transforming growth factor-ß1 (TGF-ß1)-induced HK-2 cell inflammation models to investigate the role of PAR2-associated autophagy in kidney tubular epithelial inflammation. PAR2 antagonist and rapamycin were administered to mice after unilateral ureteral obstruction to detect the correlations between PAR2, autophagy, and inflammation. Our results show that PAR2 overexpression in HK-2 cells led to a greater reduction in autophagy via the PI3K/Akt/mTOR pathway activation and induces autophagy-related inflammation. Meanwhile, a knockdown of PAR2 via PAR2 RNAi transfection greatly increased autophagy and alleviated autophagy-associated inflammation. In unilateral ureteral obstruction (UUO) kidneys, PAR2 antagonist treatment greatly attenuated renal inflammation and interstitial injury by enhancing autophagy. Moreover, inhibition of mTOR, rapa, markedly increased autophagy and inhibited the UUO-induced inflammation. We conclude that PAR2 induces kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Our results are suggestive that PAR2 inhibition may play a role in the treatment of diseases with increased inflammatory responses in renal systems.
[Mh] Termos MeSH primário: Autofagia/genética
Inflamação/genética
Receptor PAR-2/metabolismo
Serina-Treonina Quinases TOR/genética
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Seres Humanos
Inflamação/patologia
Rim/metabolismo
Rim/patologia
Fosfatidilinositol 3-Quinases/genética
Fosforilação
Proteínas Proto-Oncogênicas c-akt/genética
Receptor PAR-2/genética
Transdução de Sinais
Sirolimo/metabolismo
Fator de Crescimento Transformador beta1/genética
Fator de Crescimento Transformador beta1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, PAR-2); 0 (Transforming Growth Factor beta1); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170272


  4 / 1469 MEDLINE  
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[PMID]:28613153
[Au] Autor:Hanusova Z; Mosko T; Matej R; Holada K
[Ad] Endereço:1​Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, Studnickova 7, Prague 2, 128 00, Czech Republic.
[Ti] Título:Precision in the design of an experimental study deflects the significance of proteinase-activated receptor 2 expression in scrapie-inoculated mice.
[So] Source:J Gen Virol;98(6):1563-1569, 2017 Jun.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Proteinase-activated receptor 2 (PAR2) is suspected to modulate the pathogenesis of various neurodegenerative conditions. We previously described delayed onset of clinical symptoms and prolonged survival of PAR2-deficient mice after intracerebral inoculation with prions. Here we report the results from a refined blinded study that aimed to investigate the effects of PAR2 deletion on scrapie pathogenesis after peripheral infection. This study failed to confirm that PAR2 deficiency impacts on the length of the incubation period, with PAR2-/- and PAR2+/+ littermates developing scrapie at the same time. To clarify the discrepancy between the two observations, we repeated the intracerebral inoculation study while utilizing our refined protocol, which aimed to limit possible sources of experimental bias. The study again failed to confirm the significant effect of PAR2 expression on the course of prion infection. Our report emphasizes and discusses the importance of unbiased experimental design and the selection of proper genetic controls when using genetically altered animal models for prion pathogenesis studies.
[Mh] Termos MeSH primário: Receptor PAR-2/metabolismo
Scrapie/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Feminino
Camundongos
Camundongos Knockout
Receptor PAR-2/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, PAR-2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1099/jgv.0.000803


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[PMID]:28586781
[Au] Autor:Yamada Y; Matsumoto T
[Ad] Endereço:Drug Development Research Laboratories, Kyoto R&D Center, Maruho Co., Ltd., Kyoto, Japan.
[Ti] Título:House Dust Mites Induce Production of Endothelin-1 and Matrix Metalloproteinase-9 in Keratinocytes via Proteinase-Activated Receptor-2 Activation.
[So] Source:Int Arch Allergy Immunol;173(2):84-92, 2017.
[Is] ISSN:1423-0097
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and abnormal immune response. House dust mites (HDM) are a major source of allergens, some of which have cysteine and serine protease activities. Keratinocytes stimulated by HDM-derived proteases have been suggested to contribute to the pathogenesis of AD by producing various cytokines. However, whether keratinocytes contribute to the induction of pruritus in AD, especially by producing pruritus-related mediators upon stimulation with HDM-derived proteases, has not been fully elucidated. METHODS: We examined whether the production of endothelin-1 (ET-1), matrix metalloproteinase (MMP)-2, and MMP-9 in keratinocytes can be induced by stimulation with Dermatophagoides farinae extracts, and if so, whether pretreatment with a protease inhibitor or proteinase-activated receptor-2 (PAR-2) antagonist affects the production of these mediators in keratinocytes. RESULTS: Although MMP-2 levels were undetectable in the culture supernatants, the production of ET-1 and MMP-9 was increased upon stimulation with HDM extracts in a concentration- and time-dependent manner and suppressed by pretreatment of HDM extracts with serine protease inhibitor, but not with cysteine protease inhibitor. Mite-derived serine proteases also induced ET-1 and MMP-9 production in a concentration- and time-dependent manner. Moreover, pretreatment with a PAR-2 antagonist inhibited the production of ET-1 and MMP-9 in keratinocytes. CONCLUSION: These results suggest that the activation of PAR-2 on keratinocytes by HDM-derived serine proteases induces the production of ET-1 and MMP-9, and may contribute to the induction of pruritus in AD.
[Mh] Termos MeSH primário: Alérgenos/farmacologia
Antígenos de Dermatophagoides/farmacologia
Endotelina-1/imunologia
Queratinócitos/efeitos dos fármacos
Metaloproteinase 9 da Matriz/imunologia
Receptor PAR-2/imunologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Seres Humanos
Queratinócitos/imunologia
Metaloproteinase 2 da Matriz/imunologia
Pyroglyphidae/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Allergens); 0 (Antigens, Dermatophagoides); 0 (Endothelin-1); 0 (Receptor, PAR-2); EC 3.4.24.24 (MMP2 protein, human); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9)
[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:170607
[St] Status:MEDLINE
[do] DOI:10.1159/000473700


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[PMID]:28522609
[Au] Autor:Roy A; Ansari SA; Das K; Prasad R; Bhattacharya A; Mallik S; Mukherjee A; Sen P
[Ad] Endereço:From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and.
[Ti] Título:Coagulation factor VIIa-mediated protease-activated receptor 2 activation leads to ß-catenin accumulation via the AKT/GSK3ß pathway and contributes to breast cancer progression.
[So] Source:J Biol Chem;292(33):13688-13701, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell migration and invasion are very characteristic features of cancer cells that promote metastasis, which is one of the most common causes of mortality among cancer patients. Emerging evidence has shown that coagulation factors can directly mediate cancer-associated complications either by enhancing thrombus formation or by initiating various signaling events leading to metastatic cancer progression. It is well established that, apart from its distinct role in blood coagulation, coagulation factor FVIIa enhances aggressive behaviors of breast cancer cells, but the underlying signaling mechanisms still remain elusive. To this end, we investigated FVIIa's role in the migration and invasiveness of the breast cancer cell line MDA-MB-231. Consistent with previous observations, we observed that FVIIa increased the migratory and invasive potential of these cells. We also provide molecular evidence that protease-activated receptor 2 activation followed by PI3K-AKT activation and GSK3ß inactivation is involved in these processes and that ß-catenin, a well known tumor-regulatory protein, contributes to this signaling pathway. The pivotal role of ß-catenin was further indicated by the up-regulation of its downstream targets cyclin D1, c-Myc, COX-2, MMP-7, MMP-14, and Claudin-1. ß-Catenin knockdown almost completely attenuated the FVIIa-induced enhancement of breast cancer migration and invasion. These findings provide a new perspective to counteract the invasive behavior of breast cancer, indicating that blocking PI3K-AKT pathway-dependent ß-catenin accumulation may represent a potential therapeutic approach to control breast cancer.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Fator VIIIa/metabolismo
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/agonistas
Receptor PAR-2/agonistas
Transdução de Sinais
beta Catenina/agonistas
[Mh] Termos MeSH secundário: Mama/citologia
Mama/metabolismo
Mama/patologia
Neoplasias da Mama/enzimologia
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Fator VIIIa/genética
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Genes Reporter/efeitos dos fármacos
Glicogênio Sintase Quinase 3 beta/química
Glicogênio Sintase Quinase 3 beta/metabolismo
Seres Humanos
Invasividade Neoplásica/patologia
Proteínas de Neoplasias/agonistas
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Oligopeptídeos/farmacologia
Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Fosfatidilinositol 3-Quinase/química
Fosfatidilinositol 3-Quinase/metabolismo
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Interferência de RNA
Receptor PAR-2/antagonistas & inibidores
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Transdução de Sinais/efeitos dos fármacos
Tromboplastina/agonistas
Tromboplastina/genética
Tromboplastina/metabolismo
beta Catenina/antagonistas & inibidores
beta Catenina/genética
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTNNB1 protein, human); 0 (Enzyme Inhibitors); 0 (Neoplasm Proteins); 0 (Oligopeptides); 0 (Receptor, PAR-2); 0 (Recombinant Proteins); 0 (beta Catenin); 0 (seryl-leucyl-isoleucyl--glycyl-lysyl-valine); 72175-66-7 (Factor VIIIa); 9035-58-9 (Thromboplastin); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.764670


  7 / 1469 MEDLINE  
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[PMID]:28507169
[Au] Autor:Grechowa I; Horke S; Wallrath A; Vahl CF; Dorweiler B
[Ad] Endereço:Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
[Ti] Título:Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response.
[So] Source:FASEB J;31(9):3868-3881, 2017 Sep.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human neutrophil elastase impacts on atherosclerotic plaque stability by inducing apoptosis in endothelial cells. Our aim was to investigate the proapoptotic mechanism of elastase on endothelial cells and to evaluate the presence of elastase in human plaque material. Human endothelial cells were treated with purified human neutrophil elastase. Apoptosis was assayed by capsase-3/7 activation, TUNEL, and sub-G assay. Activation of unfolded protein response (UPR) effector molecules binding Ig protein, soluble X-binding protein-1, protein kinase RNA-like ER kinase (PERK), and C/EBP-homologous protein (CHOP) was analyzed by RT-PCR, immunocytochemistry, and Western blot. Genetic silencing of CHOP was achieved by small interfering RNA. Elastase induces autophagic-apoptotic forms of endothelial cell death in a time- and dose-dependent manner, in conjunction with a significant increase in phosphorylation/expression of the canonical UPR-activation markers PERK and CHOP. By using CHOP knockdown, we identified CHOP as a key mediator of elastase-induced endothelial cell death. Immunohistochemical analysis of human rupture-prone plaque specimens confirmed the presence of elastase and colocalization with apoptosis. We have demonstrated for the first time that the PERK-CHOP branch of the UPR is causally involved in elastase-induced apoptosis of endothelial cells. analysis of human rupture-prone plaques confirmed the presence of elastase and its colocalization with markers of apoptosis. This novel role of elastase underlines the potential of combined targeting of elastase and endoplasmic reticulum stress in the prevention of plaque progression and cardiovascular events.-Grechowa, I., Horke, S., Wallrath, A., Vahl, C.-F., Dorweiler, B. Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response.
[Mh] Termos MeSH primário: Apoptose/fisiologia
Células Endoteliais/enzimologia
Elastase de Leucócito/metabolismo
Fator de Transcrição CHOP/metabolismo
Resposta a Proteínas não Dobradas/fisiologia
eIF-2 Quinase/metabolismo
[Mh] Termos MeSH secundário: Aterosclerose/patologia
Artérias Carótidas/patologia
Caspase 3/genética
Caspase 3/metabolismo
Caspase 7/genética
Caspase 7/metabolismo
Linhagem Celular
Sobrevivência Celular
Células Endoteliais/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Seres Humanos
Elastase de Leucócito/genética
Receptor PAR-1
Receptor PAR-2
Fator de Transcrição CHOP/genética
eIF-2 Quinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DDIT3 protein, human); 0 (Receptor, PAR-1); 0 (Receptor, PAR-2); 147336-12-7 (Transcription Factor CHOP); EC 2.7.11.1 (PERK kinase); EC 2.7.11.1 (eIF-2 Kinase); EC 3.4.21.37 (Leukocyte Elastase); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700012R


  8 / 1469 MEDLINE  
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[PMID]:28445455
[Au] Autor:Cheng RKY; Fiez-Vandal C; Schlenker O; Edman K; Aggeler B; Brown DG; Brown GA; Cooke RM; Dumelin CE; Doré AS; Geschwindner S; Grebner C; Hermansson NO; Jazayeri A; Johansson P; Leong L; Prihandoko R; Rappas M; Soutter H; Snijder A; Sundström L; Tehan B; Thornton P; Troast D; Wiggin G; Zhukov A; Marshall FH; Dekker N
[Ad] Endereço:Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK.
[Ti] Título:Structural insight into allosteric modulation of protease-activated receptor 2.
[So] Source:Nature;545(7652):112-115, 2017 05 04.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.
[Mh] Termos MeSH primário: Receptor PAR-2/química
Receptor PAR-2/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Sítio Alostérico/efeitos dos fármacos
Anticorpos Bloqueadores/química
Anticorpos Bloqueadores/farmacologia
Benzimidazóis/química
Benzimidazóis/farmacologia
Benzodioxóis/química
Benzodioxóis/farmacologia
Álcoois Benzílicos/química
Álcoois Benzílicos/farmacologia
Cristalografia por Raios X
Seres Humanos
Imidazóis/química
Imidazóis/farmacologia
Fragmentos Fab das Imunoglobulinas/química
Fragmentos Fab das Imunoglobulinas/farmacologia
Cinética
Ligantes
Modelos Moleculares
Receptor PAR-2/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AZ3451); 0 (AZ8838); 0 (Antibodies, Blocking); 0 (Benzimidazoles); 0 (Benzodioxoles); 0 (Benzyl Alcohols); 0 (Imidazoles); 0 (Immunoglobulin Fab Fragments); 0 (Ligands); 0 (Receptor, PAR-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1038/nature22309


  9 / 1469 MEDLINE  
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[PMID]:28245472
[Au] Autor:Wang Y; He Y; Wang M; Lv P; Liu J; Wang J
[Ti] Título:Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis.
[So] Source:Cell Physiol Biochem;41(3):1147-1155, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Background /Aims: The underlying mechanisms leading to focal segmental glomerulosclerosis (FSGS) are lacking. In this report, we examined the role of protease-activated receptors (PARs) subtype PAR2 and its downstream signals in regulating the pathophysiological process of FSGS. METHODS: Nephropathy was induced by intravenous injections of adriamycin (ADR) in rats to study FSGS. Western Blot analysis and ELISA were employed to determine the protein expression levels of PAR2 and its downstream signal pathways as well as the levels of PICs. RESULTS: In ADR rats, expression of PAR2, PKCε and PKA was amplified and this was accompanied with increases of pro-inflammatory cytokines (PICs) including IL-1ß, IL-6 and TNF-α. Inhibition of PAR2 signal by systemic administration of FSLLRY-NH2 (FSL) attenuated amplification of PICs. Notably, FSL further influenced key molecular mediators during development of FSGS. i.e., it specifically restored the impaired nephrin and attenuated the exaggerated transforming growth factor beta 1 (TGF-ß1), caspase-9 and desmin thereby improving worsened renal functions and glomerular injury. Consistent with this, in cultured podocytes FSL also largely restored downregulation of nephrin and attenuated amplifications of caspase-9 and desmin induced by TGF-ß1. CONCLUSIONS: Results of this study suggest that PAR2 plays an important role in mediating renal injury induced by glomerulosclerosis. Inhibition of PAR2 signal pathway has a protective effect on FSGS mainly via PIC and TGF-ß1 mechanisms. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of FSGS observed in patients.
[Mh] Termos MeSH primário: Glomerulosclerose Segmentar e Focal/genética
Oligopeptídeos/farmacologia
Podócitos/metabolismo
Receptor PAR-2/genética
Fator de Crescimento Transformador beta1/genética
[Mh] Termos MeSH secundário: Animais
Caspase 9/genética
Caspase 9/metabolismo
Linhagem Celular Transformada
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Desmina/genética
Desmina/metabolismo
Doxorrubicina
Regulação da Expressão Gênica
Glomerulosclerose Segmentar e Focal/induzido quimicamente
Glomerulosclerose Segmentar e Focal/tratamento farmacológico
Glomerulosclerose Segmentar e Focal/patologia
Interleucina-1beta/genética
Interleucina-1beta/metabolismo
Interleucina-6/genética
Interleucina-6/metabolismo
Masculino
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Podócitos/efeitos dos fármacos
Podócitos/patologia
Proteína Quinase C-épsilon/genética
Proteína Quinase C-épsilon/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor PAR-2/antagonistas & inibidores
Receptor PAR-2/metabolismo
Transdução de Sinais
Fator de Crescimento Transformador beta1/metabolismo
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Desmin); 0 (H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2); 0 (IL1B protein, rat); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (Membrane Proteins); 0 (Oligopeptides); 0 (Receptor, PAR-2); 0 (Transforming Growth Factor beta1); 0 (Tumor Necrosis Factor-alpha); 0 (nephrin); 80168379AG (Doxorubicin); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.13 (Protein Kinase C-epsilon); EC 3.4.22.- (Casp9 protein, rat); EC 3.4.22.- (Caspase 9)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE
[do] DOI:10.1159/000464121


  10 / 1469 MEDLINE  
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[PMID]:28245465
[Au] Autor:Wang Z; Li Q; Xiang M; Zhang F; Wei D; Wen Z; Zhou Y
[Ti] Título:Astragaloside Alleviates Hepatic Fibrosis Function via PAR2 Signaling Pathway in Diabetic Rats.
[So] Source:Cell Physiol Biochem;41(3):1156-1166, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Astragaloside (AGS) extracted from radix astragalin (Huangqi) has been considered to be beneficial to liver diseases. In this study, we examined the role played by AGS in alleviating hepatic fibrosis function via protease-activated receptor-2 (PAR2) mechanisms. We hypothesized that AGS affects PAR2 signaling pathway thereby improving hepatic function in rats with hepatic fibrosis induced by carbon tetrachloride (CCl4). We further hypothesized that AGS attenuates impaired hepatic function evoked by CCl4 to a greater degree in diabetic animals. METHODS: ELISA and Western Blot analysis were used to examine PAR2 signaling pathway in diabetic CCl4-rats and non-diabetic CCl4-rats. RESULTS: AGS inhibited the protein expression of PAR2 and its downstream pathway PKA and PKCÉ› in CCl4-rats. Notably, the effects of AGS were greater in CCl4-rats with diabetes. AGS also significantly attenuated the CCl4-induced upregulations of pro-inflammatory cytokines, namely interleukin-1ß, interleukin-6 and tumor necrosis factor-α accompanied with decreases of collagenic parameters such as hexadecenoic acid, laminin and hydroxyproline. Additionally, AGS improved the CCl4-induced exaggerations of liver index and functions including alanine aminotransferase, aspartate aminotransferase. Moreover, TGF-ß1, a marker of hepatic fibrosis, was increased in CCl4-rats and AGS inhibited increases in TGF-ß1 induced by CCl4. CONCLUSIONS: AGS alleviates hepatic fibrosis by inhibiting PAR2 signaling expression and its effects are largely enhanced in diabetic animals. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of hepatic fibrosis; and results of our study are likely to shed light on strategies for application of AGS because it has potentially greater therapeutic effectiveness for hepatic fibrosis in diabetes.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Cirrose Hepática/tratamento farmacológico
Receptor PAR-2/genética
Saponinas/farmacologia
Fator de Crescimento Transformador beta1/genética
Triterpenos/farmacologia
[Mh] Termos MeSH secundário: Alanina Transaminase/metabolismo
Animais
Aspartato Aminotransferases/metabolismo
Tetracloreto de Carbono
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Diabetes Mellitus Experimental/induzido quimicamente
Diabetes Mellitus Experimental/genética
Diabetes Mellitus Experimental/patologia
Regulação da Expressão Gênica
Interleucina-1beta/genética
Interleucina-1beta/metabolismo
Interleucina-6/genética
Interleucina-6/metabolismo
Cirrose Hepática/induzido quimicamente
Cirrose Hepática/genética
Cirrose Hepática/patologia
Masculino
Proteína Quinase C-épsilon/genética
Proteína Quinase C-épsilon/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor PAR-2/antagonistas & inibidores
Receptor PAR-2/metabolismo
Transdução de Sinais
Estreptozocina
Fator de Crescimento Transformador beta1/metabolismo
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL1B protein, rat); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (Receptor, PAR-2); 0 (Saponins); 0 (Transforming Growth Factor beta1); 0 (Triterpenes); 0 (Tumor Necrosis Factor-alpha); 3A592W8XKE (astragaloside A); 5W494URQ81 (Streptozocin); CL2T97X0V0 (Carbon Tetrachloride); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.13 (Protein Kinase C-epsilon)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE
[do] DOI:10.1159/000464122



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