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[PMID]:29287725
[Au] Autor:Cates C; Rousselle T; Wang J; Quan N; Wang L; Chen X; Yang L; Rezaie AR; Li J
[Ad] Endereço:Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA.
[Ti] Título:Activated protein C protects against pressure overload-induced hypertrophy through AMPK signaling.
[So] Source:Biochem Biophys Res Commun;495(4):2584-2594, 2018 01 22.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We found that the anticoagulant plasma protease, activated protein C (APC), stimulates the energy sensor kinase, AMPK, in the stressed heart by activating protease-activated receptor 1 (PAR1) on cardiomyocytes. Wild-type (WT) and AMPK-kinase dead (KD) transgenic mice were subjected to transverse aortic constriction (TAC) surgery. The results demonstrated that while no phenotypic differences can be observed between WT and AMPK-KD mice under normal physiological conditions, AMPK-KD mice exhibit significantly larger hearts after 4 weeks of TAC surgery. Analysis by echocardiography suggested that the impairment in the cardiac function of AMPK-KD hearts is significantly greater than that of WT hearts. Immunohistochemical staining revealed increased macrophage infiltration and ROS generation in AMPK-KD hearts after 4 weeks of TAC surgery. Immunoblotting results demonstrated that the redox markers, pShc , 4-hydroxynonenal and ERK, were all up-regulated at a higher extent in AMPK-KD hearts after 4 weeks of TAC surgery. Administration of APC-WT and the signaling selective APC-2Cys mutant, but not the anticoagulant selective APC-E170A mutant, significantly attenuated pressure overload-induced hypertrophy and fibrosis. Macrophage infiltration and pShc activation caused by pressure overload were also inhibited by APC and APC-2Cys but not by APC-E170A. Therefore, the cardiac AMPK protects against pressure overload-induced hypertrophy and the signaling selective APC-2Cys may have therapeutic potential for treating hypertension-related hypertrophy without increasing the risk of bleeding.
[Mh] Termos MeSH primário: Pressão Sanguínea
Cardiomegalia/fisiopatologia
Hipertensão/fisiopatologia
Proteína C/metabolismo
Proteínas Quinases/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Resistência à Proteína C Ativada
Animais
Cardiomegalia/patologia
Hipertensão/patologia
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein C); EC 2.7.- (Protein Kinases); EC 2.7.1.- (AMP-activated protein kinase kinase)
[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:171231
[St] Status:MEDLINE


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[PMID]:29242206
[Au] Autor:Lentz SR
[Ad] Endereço:UNIVERSITY OF IOWA.
[Ti] Título:On PAR with aPC to target inflammasomes.
[So] Source:Blood;130(24):2579-2581, 2017 12 14.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Inflamassomos
Receptor PAR-1
[Mh] Termos MeSH secundário: Proteína C
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Inflammasomes); 0 (Protein C); 0 (Receptor, PAR-1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-09-806307


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[PMID]:28468828
[Au] Autor:Essalmani R; Susan-Resiga D; Guillemot J; Kim W; Sachan V; Awan Z; Chamberland A; Asselin MC; Ly K; Desjardins R; Day R; Prat A; Seidah NG
[Ad] Endereço:From the Laboratories of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec H2W 1R7, Canada and.
[Ti] Título:Thrombin activation of protein C requires prior processing by a liver proprotein convertase.
[So] Source:J Biol Chem;292(25):10564-10573, 2017 06 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein C, a secretory vitamin K-dependent anticoagulant serine protease, inactivates factors Va/VIIIa. It is exclusively synthesized in liver hepatocytes as an inactive zymogen (proprotein C). In humans, thrombin cleavage of the propeptide at PR ↓ results in activated protein C (APC; residues 222-461). However, the propeptide is also cleaved by a furin-like proprotein convertase(s) (PCs) at K SHL ↓ (underlined basic residues critical for the recognition by PCs), but the order of cleavage is unknown. Herein, we present evidence that at the surface of COS-1 cells, mouse proprotein C is first cleaved by the convertases furin, PC5/6A, and PACE4. In mice, this cleavage occurs at the equivalent site, K KIL ↓, and requires the presence of Arg at P1 and a combination of two other basic residues at either P2 (Lys ), P6 (Arg ), or P8 (Lys ) positions. Notably, the thrombin-resistant R221A mutant is still cleaved by these PCs, revealing that convertase cleavage can precede thrombin activation. This conclusion was supported by the fact that the APC-specific activity in the medium of COS-1 cells is exclusively dependent on prior cleavage by the convertases, because both R198A and R221A lack protein C activity. Primary cultures of hepatocytes derived from wild-type or hepatocyte-specific furin, PC5/6, or complete PACE4 knock-out mice suggested that the cleavage of overexpressed proprotein C is predominantly performed by furin intracellularly and by all three proprotein convertases at the cell surface. Indeed, plasma analyses of single-proprotein convertase-knock-out mice showed that loss of the convertase furin or PC5/6 in hepatocytes results in a ∼30% decrease in APC levels, with no significant contribution from PACE4. We conclude that prior convertase cleavage of protein C in hepatocytes is critical for its thrombin activation.
[Mh] Termos MeSH primário: Hepatócitos/enzimologia
Fígado/enzimologia
Pró-Proteína Convertase 5/metabolismo
Proteína C/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células COS
Cercopithecus aethiops
Ativação Enzimática/fisiologia
Células Hep G2
Seres Humanos
Camundongos
Camundongos Knockout
Mutação de Sentido Incorreto
Pró-Proteína Convertase 5/genética
Pró-Proteína Convertases/genética
Pró-Proteína Convertases/metabolismo
Proteína C/genética
Serina Endopeptidases/genética
Serina Endopeptidases/metabolismo
Trombina/genética
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein C); EC 3.4.21.- (PCSK6 protein, human); EC 3.4.21.- (Pcsk6 protein, mouse); EC 3.4.21.- (Proprotein Convertase 5); EC 3.4.21.- (Proprotein Convertases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.770040


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[PMID]:29040284
[Au] Autor:Lee SY; Kim EK; Kim MS; Shin SH; Chang H; Jang SY; Kim HJ; Kim DK
[Ad] Endereço:Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
[Ti] Título:The prevalence and clinical manifestation of hereditary thrombophilia in Korean patients with unprovoked venous thromboembolisms.
[So] Source:PLoS One;12(10):e0185785, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE). METHODS: Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months. RESULTS: Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32-50] vs. 52 [43-65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age <45 years and a family history of VTE were independent predictors for unprovoked VTE with HT (odds ratio, 9.435 [2.45-36.35]; P = 0.001 and 92.667 [14.95-574.29]; P < 0.001). CONCLUSIONS: About 15% of patients with unprovoked VTE had HT. A positive family history of VTE and age <45 years were independent predictors for unprovoked VTE caused by HT.
[Mh] Termos MeSH primário: Deficiência de Antitrombina III/fisiopatologia
Conjuntivite/fisiopatologia
Plasminogênio/deficiência
Deficiência de Proteína C/fisiopatologia
Deficiência de Proteína S/fisiopatologia
Dermatopatias Genéticas/fisiopatologia
Trombofilia/fisiopatologia
Tromboembolia Venosa/fisiopatologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Antitrombina III/genética
Deficiência de Antitrombina III/complicações
Deficiência de Antitrombina III/diagnóstico
Deficiência de Antitrombina III/genética
Conjuntivite/complicações
Conjuntivite/diagnóstico
Conjuntivite/genética
Feminino
Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Plasminogênio/genética
Proteína C/genética
Deficiência de Proteína C/complicações
Deficiência de Proteína C/diagnóstico
Deficiência de Proteína C/genética
Proteína S/genética
Deficiência de Proteína S/complicações
Deficiência de Proteína S/diagnóstico
Deficiência de Proteína S/genética
República da Coreia
Estudos Retrospectivos
Análise de Sequência de DNA
Dermatopatias Genéticas/complicações
Dermatopatias Genéticas/diagnóstico
Dermatopatias Genéticas/genética
Trombofilia/diagnóstico
Trombofilia/etiologia
Trombofilia/genética
Tromboembolia Venosa/diagnóstico
Tromboembolia Venosa/etiologia
Tromboembolia Venosa/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein C); 0 (Protein S); 9000-94-6 (Antithrombin III); 9001-91-6 (Plasminogen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171018
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185785


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[PMID]:29019866
[Au] Autor:Kalambokis GN; Christou L; Christodoulou D; Baltayiannis G
[Ad] Endereço:aDepartment of Internal Medicine bDepartment of Gastroenterology, Medical School, University of Ioannina, Ioannina, Greece.
[Ti] Título:Haemostatic balance in patients with end-stage cirrhosis: low protein C is the predominant coagulant protein deficiency.
[So] Source:Blood Coagul Fibrinolysis;28(7):585-586, 2017 10.
[Is] ISSN:1473-5733
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Hemostasia
Proteína C
[Mh] Termos MeSH secundário: Hemostáticos
Seres Humanos
Cirrose Hepática
Deficiência de Proteína
[Pt] Tipo de publicação:LETTER; COMMENT
[Nm] Nome de substância:
0 (Hemostatics); 0 (Protein C)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE
[do] DOI:10.1097/MBC.0000000000000651


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[PMID]:28918742
[Au] Autor:Gorbacheva LR; Kiseleva EV; Savinkova IG; Strukova SM
[Ad] Endereço:Lomonosov Moscow State University, Faculty of Biology, Moscow, 119991, Russia. sstrukova@yahoo.com.
[Ti] Título:A New Concept of Action of Hemostatic Proteases on Inflammation, Neurotoxicity, and Tissue Regeneration.
[So] Source:Biochemistry (Mosc);82(7):778-790, 2017 Jul.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Key hemostatic serine proteases such as thrombin and activated protein C (APC) are signaling molecules controlling blood coagulation and inflammation, tissue regeneration, neurodegeneration, and some other processes. By interacting with protease-activated receptors (PARs), these enzymes cleave a receptor exodomain and liberate new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signaling pathways and cell responses. Among four PAR family members, APC and thrombin mainly act via PAR1, and they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective activity, whereas thrombin is a protease with procoagulant and proinflammatory effects. Hallmark features of APC-induced effects result from acting via different pathways: limited proteolysis of PAR1 localized in membrane caveolae with coreceptor (endothelial protein C receptor) as well as its targeted proteolytic action at a receptor exodomain site differing from the canonical thrombin cleavage site. Hence, a new noncanonical tethered PAR1 agonist peptide (PAR1-AP) is formed, whose effects are poorly investigated in inflammation, tissue regeneration, and neurotoxicity. In this review, a concept about a role of biased agonism in effects exerted by APC and PAR1-AP via PAR1 on cells involved in inflammation and related processes is developed. New evidence showing a role for a biased agonism in activating PAR1 both by APC and PAR1-AP as well as induction of antiinflammatory and cytoprotective cellular responses in experimental inflammation, wound healing, and excitotoxicity is presented. It seems that synthetic PAR1 peptide-agonists may compete with APC in controlling some inflammatory and neurodegenerative diseases.
[Mh] Termos MeSH primário: Inflamação
Proteína C/metabolismo
Regeneração/fisiologia
Trombina/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Fatores de Coagulação Sanguínea/agonistas
Fatores de Coagulação Sanguínea/metabolismo
Ácido Glutâmico/toxicidade
Seres Humanos
Mastócitos/citologia
Mastócitos/efeitos dos fármacos
Mastócitos/metabolismo
Fármacos Neuroprotetores/farmacologia
Receptor PAR-1/agonistas
Receptor PAR-1/metabolismo
Receptores de Superfície Celular/agonistas
Receptores de Superfície Celular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Blood Coagulation Factors); 0 (Neuroprotective Agents); 0 (Protein C); 0 (Receptor, PAR-1); 0 (Receptors, Cell Surface); 0 (activated protein C receptor); 3KX376GY7L (Glutamic Acid); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917070033


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[PMID]:28877991
[Au] Autor:Sarangi PP; Lee HW; Lerman YV; Trzeciak A; Harrower EJ; Rezaie AR; Kim M
[Ad] Endereço:Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642.
[Ti] Título:Activated Protein C Attenuates Severe Inflammation by Targeting VLA-3 Neutrophil Subpopulation in Mice.
[So] Source:J Immunol;199(8):2930-2936, 2017 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The host injury involved in multiorgan system failure during severe inflammation is mediated, in part, by massive infiltration and sequestration of hyperactive neutrophils in the visceral organ. A recombinant form of human activated protein C (rhAPC) has shown cytoprotective and anti-inflammatory functions in some clinical and animal studies, but the direct mechanism is not fully understood. Recently, we reported that, during endotoxemia and severe polymicrobial peritonitis, integrin VLA-3 (CD49c/CD29) is specifically upregulated on hyperinflammatory neutrophils and that targeting the VLA-3 neutrophil subpopulation improved survival in mice. In this article, we report that rhAPC binds to human neutrophils via integrin VLA-3 (CD49c/CD29) with a higher affinity compared with other Arg-Gly-Asp binding integrins. Similarly, there is preferential binding of activated protein C (PC) to Gr1 CD11b VLA-3 cells isolated from the bone marrow of septic mice. Furthermore, specific binding of rhAPC to human neutrophils via VLA-3 was inhibited by an antagonistic peptide (LXY2). In addition, genetically modified mutant activated PC, with a high affinity for VLA-3, shows significantly improved binding to neutrophils compared with wild-type activated PC and significantly reduced neutrophil infiltration into the lungs of septic mice. These data indicate that variants of activated PC have a stronger affinity for integrin VLA-3, which reveals novel therapeutic possibilities.
[Mh] Termos MeSH primário: Inflamação/imunologia
Integrina alfa3beta1/metabolismo
Pulmão/imunologia
Insuficiência de Múltiplos Órgãos/imunologia
Neutrófilos/imunologia
Peritonite/imunologia
Proteína C/metabolismo
[Mh] Termos MeSH secundário: Animais
Terapia Biológica
Células Cultivadas
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Mutação/genética
Ativação de Neutrófilo
Ligação Proteica
Proteína C/genética
Proteínas Recombinantes/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin alpha3beta1); 0 (Protein C); 0 (Recombinant Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700541


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[PMID]:28801460
[Au] Autor:Muehl EM; Gajsiewicz JM; Medfisch SM; Wiersma ZSB; Morrissey JH; Bailey RC
[Ad] Endereço:From the Departments of Chemistry and.
[Ti] Título:Multiplexed silicon photonic sensor arrays enable facile characterization of coagulation protein binding to nanodiscs with variable lipid content.
[So] Source:J Biol Chem;292(39):16249-16256, 2017 Sep 29.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Interactions of soluble proteins with the cell membrane are critical within the blood coagulation cascade. Of particular interest are the interactions of γ-carboxyglutamic acid-rich domain-containing clotting proteins with lipids. Variability among conventional analytical methods presents challenges for comparing clotting protein-lipid interactions. Most previous studies have investigated only a single clotting protein and lipid composition and have yielded widely different binding constants. Herein, we demonstrate that a combination of lipid bilayer nanodiscs and a multiplexed silicon photonic analysis technology enables high-throughput probing of many protein-lipid interactions among blood-clotting proteins. This approach allowed direct comparison of the binding constants of prothrombin, factor X, activated factor VII, and activated protein C to seven different binary lipid compositions. In a single experiment, the binding constants of one protein interacting with all lipid compositions were simultaneously determined. A simple surface regeneration then facilitated similar binding measurements for three other coagulation proteins. As expected, our results indicated that all proteins exhibit tighter binding (lower ) as the proportion of anionic lipid increases. Interestingly, at high proportions of phosphatidylserine, the values of all four proteins began to converge. We also found that although values for all four proteins followed trends similar to those observed for the values, the variation among the proteins was much lower, indicating that much of the variation came from the kinetic binding ( ) of the proteins. These findings indicate that the combination of silicon photonic microring resonator arrays and nanodiscs enables rapid interrogation of biomolecular binding interactions at model cell membrane interfaces.
[Mh] Termos MeSH primário: Fator VIIa/metabolismo
Fator X/metabolismo
Ácidos Fosfatídicos/metabolismo
Fosfatidilcolinas/metabolismo
Fosfatidilserinas/metabolismo
Proteína C/metabolismo
Protrombina/metabolismo
[Mh] Termos MeSH secundário: Fator VIIa/química
Fator VIIa/genética
Fator X/química
Ensaios de Triagem em Larga Escala
Seres Humanos
Cinética
Bicamadas Lipídicas/química
Bicamadas Lipídicas/metabolismo
Nanoestruturas/química
Fenômenos Ópticos
Ácidos Fosfatídicos/química
Fosfatidilcolinas/química
Fosfatidilserinas/química
Análise Serial de Proteínas
Proteína C/química
Protrombina/química
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Silício/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-palmitoyl-2-oleoyl-glycero-3-phosphatidic acid); 0 (Lipid Bilayers); 0 (Phosphatidic Acids); 0 (Phosphatidylcholines); 0 (Phosphatidylserines); 0 (Protein C); 0 (Recombinant Proteins); 40290-44-6 (1-palmitoyl-2-oleoylglycero-3-phosphoserine); 9001-26-7 (Prothrombin); 9001-29-0 (Factor X); EC 3.4.21.21 (Factor VIIa); TE895536Y5 (1-palmitoyl-2-oleoylphosphatidylcholine); Z4152N8IUI (Silicon)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170813
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.800938


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[PMID]:28732053
[Au] Autor:Maknitikul S; Luplertlop N; Grau GER; Ampawong S
[Ad] Endereço:Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand.
[Ti] Título:Dysregulation of pulmonary endothelial protein C receptor and thrombomodulin in severe falciparum malaria-associated ARDS relevant to hemozoin.
[So] Source:PLoS One;12(7):e0181674, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To investigate the role of the protein C system, endothelial protein C receptor (EPCR) and thrombomodulin (TM) in the pathogenesis of malaria-associated acute respiratory distress syndrome (ARDS) in relation to hemozoin and proinflammatory cytokines-induced type II pneumocyte injury and -aggravated pulmonary resolution. A total of 29 left-over lung specimens that were obtained from patients who died from severe falciparum malaria were examined. Histopathological, immunohistochemical and electron microscopic analyses revealed that ARDS coexisted with pulmonary edema and systemic bleeding; the severity was dependent on the level of hemozoin deposition in the lung and internal alveolar hemorrhaging. The loss of EPCR and TM was primarily identified in ARDS patients and was related to the level of hemozoin, parasitized red blood cell (PRBC) and white blood cell accumulation in the lung. Moreover, an in vitro analysis demonstrated that interleukin-13 and -31 and hemozoin induced pneumocytic cell injury and apoptosis, as assessed by EB/AO staining, electron microscopy and the up-regulation of CARD-9 mRNA (caspase recruitment domain-9 messenger-ribonucleic acid). The dysregulation of EPCR and TM in the lung, especially in those with increased levels of hemozoin, may play an important role in the pathogenesis of malaria-associated ARDS through an apoptotic pathway.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Hemeproteínas/uso terapêutico
Pulmão/metabolismo
Malária Falciparum/tratamento farmacológico
Receptores de Superfície Celular/metabolismo
Síndrome do Desconforto Respiratório do Adulto/metabolismo
Síndrome do Desconforto Respiratório do Adulto/parasitologia
Trombomodulina/metabolismo
[Mh] Termos MeSH secundário: Células A549
Adolescente
Adulto
Criança
Pré-Escolar
Citocinas/metabolismo
Receptor de Proteína C Endotelial
Feminino
Seres Humanos
Interleucina-13/metabolismo
Pulmão/parasitologia
Masculino
Meia-Idade
Proteína C/metabolismo
Edema Pulmonar/metabolismo
Edema Pulmonar/parasitologia
Regulação para Cima/efeitos dos fármacos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Cytokines); 0 (Endothelial Protein C Receptor); 0 (Hemeproteins); 0 (Interleukin-13); 0 (PROCR protein, human); 0 (Protein C); 0 (Receptors, Cell Surface); 0 (Thrombomodulin); 39404-00-7 (hemozoin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181674


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[PMID]:28687614
[Au] Autor:Madhusudhan T; Wang H; Ghosh S; Dong W; Kumar V; Al-Dabet MM; Manoharan J; Nazir S; Elwakiel A; Bock F; Kohli S; Marquardt A; Sögüt I; Shahzad K; Müller AJ; Esmon CT; Nawroth PP; Reiser J; Chavakis T; Ruf W; Isermann B
[Ad] Endereço:Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University Magdeburg, Magdeburg, Germany.
[Ti] Título:Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function.
[So] Source:Blood;130(12):1445-1455, 2017 Sep 21.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum (ER) homeostasis. Analogous to insulin, physiological levels of aPC maintain ER proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER response, whereas genetic or pharmacological restoration of aPC maintains ER proteostasis in DKD models. Importantly, in mice with podocyte-specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85α and p85ß. Genome-wide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant unfolded protein response target genes are involved in maintenance of ER proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to reconfigure ER signaling and restore proteostasis. These results identify ER reprogramming as a novel hormonelike function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.
[Mh] Termos MeSH primário: Coagulação Sanguínea
Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo
Insulina/metabolismo
Peptídeo Hidrolases/metabolismo
Proteína C/metabolismo
Transdução de Sinais
Proteína 1 de Ligação a X-Box/metabolismo
[Mh] Termos MeSH secundário: Animais
Nefropatias Diabéticas/metabolismo
Retículo Endoplasmático/metabolismo
Regulação da Expressão Gênica
Homeostase
Seres Humanos
Camundongos Endogâmicos C57BL
Modelos Biológicos
Trombomodulina/metabolismo
Resposta a Proteínas não Dobradas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Protein C); 0 (THBD protein, mouse); 0 (Thrombomodulin); 0 (X-Box Binding Protein 1); 0 (Xbp1 protein, mouse); EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase); EC 3.4.- (Peptide Hydrolases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-02-767921



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