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5.
PLoS One ; 15(5): e0233640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453766

RESUMO

Understanding the coagulation process is critical to developing treatments for trauma and coagulopathies. Clinical studies on tranexamic acid (TXA) have resulted in mixed reports on its efficacy in improving outcomes in trauma patients. The largest study, CRASH-2, reported that TXA improved outcomes in patients who received treatment prior to 3 hours after the injury, but worsened outcomes in patients who received treatment after 3 hours. No consensus has been reached about the mechanism behind the duality of these results. In this paper we use a computational model for coagulation and fibrinolysis to propose that deficiencies or depletions of key anti-fibrinolytic proteins, specifically antiplasmin, a1-antitrypsin and a2-macroglobulin, can lead to worsened outcomes through urokinase-mediated hyperfibrinolysis.


Assuntos
Transtornos da Coagulação Sanguínea/tratamento farmacológico , Ácido Tranexâmico/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/genética , Ferimentos e Lesões/tratamento farmacológico , Antifibrinolíticos/uso terapêutico , Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/patologia , Simulação por Computador , Fibrina/genética , Tempo de Lise do Coágulo de Fibrina , Fibrinolisina/genética , Fibrinólise/efeitos dos fármacos , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Hemorragia/genética , Humanos , Proteínas de Membrana/genética , Mortalidade , alfa 2-Macroglobulinas Associadas à Gravidez/genética , Trombina/genética , Trombina/metabolismo , Ferimentos e Lesões/sangue , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia , alfa 1-Antitripsina/genética
6.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276523

RESUMO

It is widely known that glomerulonephritis (GN) often develops after the curing of an infection, a typical example of which is GN in children following streptococcal infections (poststreptococcal acute glomerulonephritis; PSAGN). On the other hand, the term "infection-related glomerulonephritis (IRGN)" has recently been proposed, because infections are usually ongoing at the time of GN onset in adult patients, particularly in older patients with comorbidities. However, there has been no specific diagnostic biomarker for IRGN, and diagnosis is based on the collection of several clinical and pathological findings and the exclusion of differential diagnoses. Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A streptococcus as a candidate nephritogenic protein for PSAGN and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase and plasmin receptor. NAPlr deposition and related plasmin activity were observed with a similar distribution pattern in the glomeruli of patients with PSAGN. However, glomerular NAPlr deposition and plasmin activity could be observed not only in patients with PSAGN but also in patients with other glomerular diseases, in whom a preceding streptococcal infection was suggested. Furthermore, such glomerular staining patterns have been demonstrated in patients with IRGN induced by bacteria other than streptococci. This review discusses the recent advances in our understanding of the pathogenesis of bacterial IRGN, which is characterized by NAPlr and plasmin as key biomarkers.


Assuntos
Fibrinolisina/análise , Glomerulonefrite/diagnóstico , Receptores de Peptídeos/análise , Infecções Estreptocócicas/complicações , Infecções Bacterianas/complicações , Biomarcadores/análise , Glomerulonefrite/etiologia , Humanos , Glomérulos Renais/metabolismo
7.
Physiol Rev ; 100(3): 1065-1075, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: covidwho-17758

RESUMO

Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Suscetibilidade a Doenças/sangue , Fibrinolisina/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Plasminogênio/metabolismo , Pneumonia Viral/sangue , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/sangue , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Fatores de Risco
8.
Physiol Rev ; 100(3): 1065-1075, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32216698

RESUMO

Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Suscetibilidade a Doenças/sangue , Fibrinolisina/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Plasminogênio/metabolismo , Pneumonia Viral/sangue , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/sangue , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Fatores de Risco
9.
FASEB J ; 34(1): 619-630, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914706

RESUMO

Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a specific and efficient inhibitor of plasmin; thus, it represents the first proteinaceous plasmin inhibitor of prokaryotic origin described to date. Miropin inhibits plasmin through the formation of a stable covalent complex triggered by cleavage of the Lys368-Thr369 (P2-P1) reactive site bond with a stoichiometry of inhibition of 3.8 and an association rate constant (kass) of 3.3 × 105 M-1s-1. The inhibition of the fibrinolytic activity of plasmin was nearly as effective as that exerted by α2-antiplasmin. Miropin also acted in vivo by reducing blood loss in a mice tail bleeding assay. Importantly, intact T. forsythia cells or outer membrane vesicles, both of which carry surface-associated miropin, strongly inhibited plasmin. In intact bacterial cells, the antiplasmin activity of miropin protects envelope proteins from plasmin-mediated degradation. In summary, in the environment of periodontal pockets, which are bathed in gingival crevicular fluid consisting of 70% of blood plasma, an abundance of T. forsythia in the bacterial biofilm can cause local inhibition of fibrinolysis, which could have possible deleterious effects on the tooth-supporting structures of the periodontium.


Assuntos
Antifibrinolíticos/farmacologia , Fibrinólise/efeitos dos fármacos , Doenças Periodontais/tratamento farmacológico , Serpinas/efeitos dos fármacos , Animais , Bactérias/metabolismo , Domínio Catalítico , Feminino , Fibrinolisina/metabolismo , Fibrinolisina/farmacologia , Humanos , Camundongos Endogâmicos C57BL , Inibidores de Proteases/farmacologia , Serpinas/metabolismo
10.
Ophthalmologe ; 117(3): 260-266, 2020 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-31346704

RESUMO

PURPOSE: Ocriplasmin (Jetrea®) is a therapeutic option for patients with focal vitreomacular traction (VMT) with or without small full thickness macular holes (FTMH) < 400 µm. Retinal alterations after injection with ocriplasmin have been described. The purpose of this essay was to determine Ocriplasmin-associated side-effects and changes in the retinal microstructure. METHODS: We included 70 patients with ocriplasmin treatment in our study. On all patients SD-OCT (spectral-domain optical coherence tomography) scans were performed prior to injection with Ocriplasmin. If present, adverse events were registered. The OCT scans were then evaluated taking the following into account: macular hole (MH) size, macular edema, subretinal fluid (SRF), changes in the ellipsoid zone (EZ) and the external limiting membrane (ELM). RESULTS: Twenty of the 70 examined patients showed a preoperative FTMH. One week after ocriplasmin IVI (intravitreal injection) 8 of the 20 FTMHs were already closed. Overall 12 patients showed a FTMH closure and 4 patients developed a FTMH after ocriplasmin IVI. Twelve of the 24 MH (macular hole) patients still required an operative closure of the FTMH. We noticed a resolution of the VMT on 51 patients. Three patients developed a retinal detachment. Furthermore, after ocriplasmin IVI we detected changes in the EZ and ELM on 8 patients. CONCLUSIONS: Ocriplasmin is a substantial minimal invasive option in the therapy of VMT with or without small FTMH. Nevertheless, there seem to be some specific ocriplasmin-associated risks, although usually transient. Severe complications like retinal detachment are rare but exist. Therefore, every indication of ocriplasmin should be considered carefully.


Assuntos
Tomografia de Coerência Óptica , Fibrinolisina , Humanos , Injeções Intravítreas , Fragmentos de Peptídeos , Perfurações Retinianas , Estudos Retrospectivos , Resultado do Tratamento , Acuidade Visual , Descolamento do Vítreo
12.
J Dairy Sci ; 103(1): 179-190, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733849

RESUMO

Fat separation is a limiting factor for the shelf life of UHT milk. It may be promoted by the proteolysis of fat surface-adsorbed proteins (FSAP) by proteases that remain active after UHT treatment. The aim of this research was to explore the relationship between the proteolysis of FSAP and fat destabilization. In this study, we developed a full-fat UHT milk-based model system and added either the major bacterial protease AprX from Pseudomonas fluorescens or the major native milk protease plasmin at high levels to induce fast destabilization of the milk fat globules. We monitored changes in physical properties and FSAP composition, and structural changes in fat globules, over 24 h. Our results showed that AprX-induced sedimentation as a result of the flocculation of fat globules, and plasmin induced cream to float as a result of the coalescence of fat globules. This study confirmed that AprX and plasmin can both lead to fat destabilization in full-fat UHT milk, and it provides insights in the underlying mechanisms.


Assuntos
Proteínas de Bactérias/metabolismo , Fibrinolisina/análise , Glicolipídeos/química , Glicoproteínas/química , Leite/enzimologia , Peptídeo Hidrolases/metabolismo , Pseudomonas fluorescens/enzimologia , Serina Endopeptidases/metabolismo , Animais , Proteínas de Bactérias/genética , Leite/química , Proteólise , Pseudomonas fluorescens/fisiologia , Serina Endopeptidases/genética
13.
Pediatr Blood Cancer ; 67(1): e28016, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556233

RESUMO

BACKGROUND: L-asparaginase (L-Asp)-associated thromboembolisms are serious complications in pediatrics patients with acute lymphoblastic leukemia (ALL), especially at ≥10.0 years old, but the pathogenesis remains to be clarified. PROCEDURE: We conducted a multicenter, prospective study of 72 patients with ALL aged 1.0 to 15.2 years treated with either a Berlin-Frankfurt-Münster (BFM) 95-ALL oriented regimen or Japan Association of Childhood Leukemia Study ALL-02 protocol. We divided patients into each treatment protocol and investigated the dynamic changes in coagulation and fibrinolysis using simultaneous thrombin and plasmin generation assay. Patients' plasma samples were collected at the prephase (T0), intermittent phase (T1), and postphase of L-Asp therapy (T2), and postinduction phase (T3). Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) were compared to normal plasma. RESULTS: None of the cases developed thromboembolisms. Median ratios of T-EP and P-Peak for the controls in the JACLS group were 1.06 and 0.87 (T0), 1.04 and 0.71 (T1), 1.02 and 0.69 (T2), and 1.20 and 0.92 (T3), respectively, while those in the BFM group were 1.06 and 1.00 (T0), 1.04 and 0.64 (T1), 1.16 and 0.58 (T2), and 1.16 and 0.85 (T3), respectively. In particular, P-Peak ratios were depressed at T1 and T2 compared to T0 in the BFM group (P < .01). Moreover, P-Peak ratios in patients ≥10.0 years old were lower at T1 in the BFM group (P = .02). CONCLUSIONS: The results demonstrated that hemostatic dynamics appeared to shift to a hypercoagulable state with marked hypofibrinolysis associated with L-Asp therapy, especially in patients ≥10.0 years old following the BFM regimen.


Assuntos
Asparaginase/efeitos adversos , Transtornos da Coagulação Sanguínea/patologia , Fibrinolisina/metabolismo , Fibrinólise/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombina/metabolismo , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Asparaginase/administração & dosagem , Transtornos da Coagulação Sanguínea/induzido quimicamente , Transtornos da Coagulação Sanguínea/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Quimioterapia de Indução , Lactente , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos
14.
Rev Col Bras Cir ; 46(5): e20192245, 2019.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31778393

RESUMO

OBJECTIVE: to compare the healing by second intention under the effects of topical application of honey, copaíba oil-resin and a commercial product (fibrinolysin, deoxyribonuclease and chloramphenicol) with a control group in rats. METHODS: we carried out a skin resection, 1cm in diameter, on the back of 40 rats allocated to four groups of ten animals. All wounds were cleaned daily with 2ml of 0.9% NaCl solution. The first group (control - GC) was restricted to such procedure. In the wounds of the second (GM), third (GO) and fourth groups (GF), after cleaning, we respectively applied 1ml of honey, 1ml of copaíba oil-resin and 1ml of cream containing fibrinolysin, deoxyribonuclease and chloramphenicol. The wounds were occluded with sterile gauze. Immediately after the incision and on days three, seven and 14 of the experiment, the wounds were copied and contraction was analyzed using planimetry. After euthanasia, we histologically evaluated the inflammatory reaction and collagen in the scars. RESULTS: the reduction of the wound area of GM (p=0.003), GO (p=0.011) and GF (p=0.002) were higher than the GC. The amount of type-I collagen present in GM and GO was higher than in GC and GF groups (p<0.05). There was a predominance of chronic inflammatory stage in GM (p=0.004), GO (p<0.001) and GF (p=0.003) when compared with GC. CONCLUSION: the topical use of honey and copaíba oil-resin increases wound contraction, the presence of type-I collagen and accelerates healing.


Assuntos
Anti-Infecciosos/administração & dosagem , Fabaceae/química , Mel , Extratos Vegetais/administração & dosagem , Óleos Vegetais/administração & dosagem , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Cloranfenicol/administração & dosagem , Desoxirribonuclease I/administração & dosagem , Modelos Animais de Doenças , Fibrinolisina/administração & dosagem , Masculino , Ratos , Ratos Wistar
15.
J Sci Food Agric ; 99(15): 6922-6930, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31393601

RESUMO

BACKGROUND: The potential use of polyphenols to improve the functional characteristics of dairy products has gained much attention. However, the effects of the polyphenols on naturally occurring enzymes in milk have not been studied extensively. Excess plasmin activity in dairy products might result in several quality defects. The objective of this study was to assess the ability of polyphenols to inhibit plasmin in milk using a molecular and kinetic approach. RESULTS: Epicatechin gallate (ECG), epigallocatechin gallate (EGCG), quercetin (QUER), and myricetin (MYR) caused a significant decrease in plasmin activity by 60, 86, 65, and 90%, respectively. The inhibition rates were alleviated in the presence of milk proteins. EGCG, QUER, and MYR, exhibited noncompetitive inhibition against plasmin, whereas ECG caused a mixed-type inhibition. A decrease in the random structure of plasmin upon the complex formation with ECG, EGCG, QUER, and MYR was found. The other phenolics that were evaluated did not cause any significant changes in plasmin conformation. The observed inhibitory phenolic-plasmin interactions were dominated by H-bonds and electrostatic attractions. Green tea extract (GTE) rich in catechins also inhibited plasmin activity in the milk. CONCLUSION: Significant changes in the secondary structure of plasmin upon binding of ECG, EGCG, QUER, and MYR led to diminished plasmin activity both in the absence and presence of milk proteins. These flavonoids with promising plasmin inhibitory potential could be used in new dairy formulations leading to controlled undesired consequences of plasmin activity. © 2019 Society of Chemical Industry.


Assuntos
Antifibrinolíticos/química , Camellia sinensis/química , Leite/enzimologia , Extratos Vegetais/química , Polifenóis/química , Animais , Catequina/análogos & derivados , Catequina/química , Bovinos , Fibrinolisina/química , Cinética , Leite/química
16.
Haemophilia ; 25(6): 1073-1082, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31469483

RESUMO

INTRODUCTION: Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI-1 do not provide an accurate correlation with clinical phenotype. METHODS: The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI-1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. RESULTS: Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI-1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. CONCLUSION: Patients with either PLGD or PAI-1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.


Assuntos
Transtornos de Proteínas de Coagulação/metabolismo , Fibrinolisina/biossíntese , Transtornos Hemorrágicos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/deficiência , Trombina/biossíntese , Adulto , Criança , Transtornos de Proteínas de Coagulação/genética , Feminino , Genótipo , Transtornos Hemorrágicos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo
17.
Am J Pathol ; 189(10): 1986-2001, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31381887

RESUMO

Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce promitogenic cytokines and growth factors, and they phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury. In these studies, inhibition of plasmin in mice with tranexamic acid delayed up-regulation of proinflammatory cytokines after APAP overdose. In culture, plasmin directly, and in synergy with high-mobility group B1, stimulated Kupffer cells and bone marrow-derived macrophages to produce cytokines by a mechanism that required NF-κB. Inhibition of plasmin in vivo also prevented trafficking of monocyte-derived macrophages into necrotic lesions after APAP overdose. This prevented phagocytic removal of dead cells, prevented maturation of monocyte-derived macrophages into F4/80-expressing macrophages, and prevented termination of proinflammatory cytokine production. Our studies reveal further that phagocytosis is an important stimulus for cessation of proinflammatory cytokine production as treatment of proinflammatory, monocyte-derived macrophages, isolated from APAP-treated mice, with necrotic hepatocytes decreased expression of proinflammatory cytokines. Collectively, these studies demonstrate that plasmin is an important regulator of macrophage function after APAP overdose.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrinolisina/metabolismo , Macrófagos do Fígado/patologia , Macrófagos/patologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Overdose de Drogas , Mediadores da Inflamação/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose
18.
Tuberculosis (Edinb) ; 117: 36-44, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31378266

RESUMO

Plasminogen and plasmin are fundamental components of the fibrinolytic system that interact with microorganisms generating different immunopathological effects. The molecules of Mycobacterium tuberculosis interplaying with plasminogen have already been identified and characterized. In this work, we studied the effects of plasmin(ogen) bound toMycobacterium bovisCalmette-Guérin (BCG) on phagocytosis in THP1 macrophages as well as in granuloma formation and development on in vitrohuman granuloma model. For this purpose, BCG was coated with plasminogen and plasmin, obtained after activation of zymogen by tissue plasminogen activator. The results showed a significant reduction in the number of bacteria phagocytosed by macrophages in presence of plasminogen or plasmin on BCG surface. On the other hand, at 3 days BCG/plasminogen/plasmin induced an increase granuloma numbers with respect to those induced by uncoated bacteria. BCG/plasminogen/environments also showed a significant increase of IL-6 secretion. At 7 days, a reduced number of granulomas and an increased number of bacteria was observed with respect to uncoated BCG environment. Altogether, these results showed that plasmin(ogen) on the mycobacterial surface affects phagocytosis, granuloma development and the cytokine context, thus resulting in an increased number of bacteria in granulomas.


Assuntos
Fibrinolisina/metabolismo , Granuloma/microbiologia , Mycobacterium bovis/metabolismo , Fagocitose/fisiologia , Plasminogênio/metabolismo , Tuberculose/microbiologia , Células Cultivadas , Citocinas/biossíntese , Granuloma/imunologia , Humanos , Macrófagos/microbiologia , Mycobacterium bovis/isolamento & purificação , Tuberculina , Tuberculose/imunologia , Tuberculose/metabolismo
19.
Invest Ophthalmol Vis Sci ; 60(8): 2895-2903, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266061

RESUMO

Purpose: The proinflammatory cytokine interleukin (IL)-1 is implicated in corneal ulceration and promotes collagen degradation by corneal fibroblasts cultured in a three-dimensional (3D) collagen gel. Epigallocatechin-3-gallate (EGCG), the principal polyphenol in extracts of green tea, has various beneficial health effects, some of which appear to be mediated through direct or indirect inhibition of protease activity. We therefore examined the effect of EGCG on IL-1ß-induced collagen degradation by corneal fibroblasts embedded in a collagen gel. Methods: Human corneal fibroblasts were cultured in a type I collagen gel. Collagen degradation was assessed by measurement of hydroxyproline in acid hydrolysates of culture supernatants. The expression of urokinase-type plasminogen activator (uPA) was examined by real-time and RT-PCR analysis and by fibrin zymography, and that of the collagenase matrix metalloproteinase 1 (MMP1) was detected by immunoblot analysis. Results: EGCG inhibited IL-1ß-induced, plasminogen-dependent collagen degradation by corneal fibroblasts in a concentration-dependent manner. It also attenuated the IL-1ß-induced expression of uPA at both mRNA and protein levels. EGCG inhibited the IL-1ß-induced conversion of exogenous plasminogen to plasmin as well as the plasminogen-dependent activation of pro-MMP1 in the 3D cultures without a substantial effect on pro-MMP1 abundance. Conclusions: EGCG inhibits IL-1ß-induced collagen degradation by corneal fibroblasts, with this effect likely being mediated by suppression of the upregulation of uPA, the uPA-mediated conversion of plasminogen to plasmin, and the plasmin-mediated activation of pro-MMP1. EGCG thus warrants further investigation as a potential treatment for corneal ulcer.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Colágeno/metabolismo , Ceratócitos da Córnea/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/genética , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ceratócitos da Córnea/metabolismo , Relação Dose-Resposta a Droga , Fibrina/metabolismo , Fibrinolisina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Hidroxiprolina/metabolismo , Interleucina-1beta/farmacologia , Metaloproteinase 1 da Matriz/metabolismo , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
20.
Arch Dermatol Res ; 311(7): 545-553, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147768

RESUMO

An effective method to protect the skin from natural aging is unknown. Therefore, in this study, we examined the ameliorative effects of tranexamic acid on natural skin aging. In addition, we examined the sex difference in the effect exhibited by tranexamic acid. We bred hairless mice without ultraviolet ray irradiation and physical stress for 2 years. During the study period, mice were orally administered tranexamic acid (12 mg/kg/day) three times per week. Development of signs of skin aging was found to be ameliorated by tranexamic acid. Furthermore, synthetic inhibition of plasmin was observed following tranexamic acid treatment. The synthetic reinforcement of hyaluronic acid by an increase in the number of epidermal cells and the degradative inhibition of extracellular matrix (ECM) by matrix metalloproteinase (MMP) suppression were observed. These results indicate that natural skin aging was ameliorated by tranexamic acid via the regulation of the plasmin/TGF-ß/epidermal cells/hyaluronic acid and plasmin/MMPs/ECM signal transmission pathways. Taken together, sex difference was observed for the ameliorative effect of tranexamic acid on skin aging, with a stronger effect observed in females than in males. More importantly, we found that the synthesis of hyaluronic acid was stronger in female mice than in male mice.


Assuntos
Antifibrinolíticos/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Ácido Tranexâmico/administração & dosagem , Administração Oral , Animais , Feminino , Fibrinolisina/metabolismo , Ácido Hialurônico/biossíntese , Masculino , Camundongos , Camundongos Pelados , Modelos Animais , Globulina de Ligação a Hormônio Sexual , Transdução de Sinais/efeitos dos fármacos , Pele/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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