Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Life Sci ; 246: 117404, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035128

RESUMO

AIMS: The study aims to investigate the effect of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of fibrinolytic process, on blood glucose in type 2 diabetes mellitus (T2DM) and its mechanism. MATERIALS AND METHODS: We developed a highly potent and highly specific PAI-1 inhibitor, named PAItrap3, based on the inactivated urokinase. Meanwhile, a single point mutation of PAItrap3 (i.e., PAItrapNC) was parallelly prepared as negative control. PAItrap3 was intravenously injected into type 2 diabetic (T2D) mice and its effect on metabolic system was evaluated by measuring the levels of blood glucose, PAI-1, and tumor necrosis factor alpha (TNF-α) in T2D mice. KEY FINDINGS: PAItrap3 significantly reduced the high blood glucose level and PAI-1 level in streptozotocin-induced T2D mice. PAItrapNC did not have any hypoglycemic effect at all on T2D mice. Mechanistically, both PAI-1 and TNF-α levels were attenuated by the administration of PAItrap3. In addition, we observed that PAItrap3 reduced the amount of fat droplets in adipocytes. SIGNIFICANCE: These findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition.


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Adipócitos/efeitos dos fármacos , Animais , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangue
2.
Food Chem Toxicol ; 125: 190-197, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30610936

RESUMO

The imbalance between clot formation and fibrinolysis is mainly attributed to increased levels of plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolysis closely involved in inflammatory responses such as septic shock. This increase is mediated by many factors, including reactive oxygen species (ROS). The present study was designed to evaluate the prophylactic effect of crocin, a potent natural antioxidant, on PAI-1 in the rat model of endotoxic shock. Lipopolysaccharide-infused rats (500 µg/kg) showed significant changes in thrombosis-related haematological parameters such as decrease of platelet blood counts and increase (7 fold) of PAI-1 concentration in blood plasma. No effect on t-PA activity was observed. Crocin administration in two different doses (10 mg/kg and 100 mg/kg) 30 min prior to the injection of LPS, inhibited the reduction of platelet counts and ameliorated the concentration of PAI-1 in the liver and the brain. Moreover, crocin inhibited the deposition of fibrin in the renal glomeruli. No significant changes were recorded in the healthy groups of crocin (10 mg/kg and 100 mg/kg) compared to the control group. These data demonstrate the potential of crocin to prevent LPS-induced organ injury and suggest it is worthwhile to investigate the use of antioxidants for the treatment of septicemia.


Assuntos
Carotenoides/farmacologia , Lipopolissacarídeos/farmacologia , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Trombose/induzido quimicamente , Animais , Feminino , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Sepse/patologia
3.
J Diet Suppl ; 16(3): 331-344, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29708806

RESUMO

Angelica keiskei koidzumi (ashitaba) is consumed as a traditional folk medicine and health food in Japan. Ashitaba extract contains abundant flavonoids containing chalcones. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue plasminogen activator. Excessive amounts of PAI-1 in plasma disrupt the fibrinolytic balance and promote a prothrombotic state with which thrombosis and cardiovascular diseases are associated. In the present study, we investigated the effects of ashitaba yellow exudate (AE) on enhanced PAI-1 levels in Tsumura Suzuki obese diabetic (TSOD) mice. AE significantly decreased food efficiency and plasma PAI-1 in TSOD mice but did not affect lean control Tsumura Suzuki nonobese (TSNO) mice. AE also decreased some parameters in the plasma, such as glucose, insulin, tumor necrosis factor alpha (TNF-α) and gains in body weight, subcutaneous, mesenteric fat weight in TSOD mice but had little effect on these parameters in TSNO mice. Levels of adipose PAI-1 were significantly higher in TSOD than in TSNO mice. Major sources of plasma PAI-1 are thought to be adipose tissue and liver. AE significantly suppressed PAI-1 protein levels in the livers of both TSOD and TSNO mice. These results suggest that AE decreased plasma PAI-1 levels by suppressing both the adipose tissue retention of PAI-1 protein and liver PAI-1 production in TSOD mice. Supplementing the diet with AE might help to prevent thrombotic diseases or alleviate the risk of thrombotic diseases as well as to suppress metabolic state in obese individuals.


Assuntos
Angelica , Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Exsudatos e Transudatos , Masculino , Camundongos , Camundongos Obesos , Obesidade/sangue , Obesidade/complicações , Inibidor 1 de Ativador de Plasminogênio/sangue
4.
Taiwan J Obstet Gynecol ; 57(3): 411-416, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29880175

RESUMO

OBJECTIVE: This study was designed to evaluate the effects of 3 mg drospirenone/30 µg ethinyl estradiol (OC) alone or combined with 1700 mg metformin on metabolic risk factors. MATERIALS AND METHODS: In this randomized, prospective, controlled study, 87 non-obese (18-30 BMI) women of reproductive age (18-39) with polycystic ovary syndrome (PCOS) were assigned to control (n = 17), OC (n = 21), combination (n = 20) and metformin (n = 29) therapy groups. RESULTS: Adiponectin levels changed -28.27%, -20.37% and 35.78% after OC, combination and metformin therapies, respectively. High sensitive C-reactive protein levels (hsCRP) changed with OC, combination and metformin therapies by 102.32%, 3.2% and -7.14%, respectively. Plasminogen activator inhibitor-1 levels decreased 41.34% in the metformin group. Apolipoprotein-B levels changed in a manner similar to changes in hsCRP levels. The homeostatic model insulin resistance index changed significantly between the groups following treatment (p = 0.001). CONCLUSION: Six cycles of treatments with OC alone may cause metabolic variables to deteriorate in non-obese women with PCOS. The addition of metformin to OC may ameliorate some aspects of this effect.


Assuntos
Apolipoproteínas B/efeitos dos fármacos , Glicemia/metabolismo , Proteína C-Reativa/efeitos dos fármacos , Resistência à Insulina , Fragmentos de Peptídeos/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Androstenos/administração & dosagem , Apolipoproteínas B/metabolismo , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Quimioterapia Combinada , Etinilestradiol/administração & dosagem , Feminino , Homocisteína/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Síndrome Metabólica/prevenção & controle , Metformina/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Síndrome do Ovário Policístico/complicações , Substâncias para o Controle da Reprodução/administração & dosagem , Fatores de Risco , Adulto Jovem
5.
Maturitas ; 99: 1-9, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28364860

RESUMO

BACKGROUND: Estetrol (E4) is a natural estrogen produced solely during human pregnancy. E4 is suitable for clinical use since it acts as a selective estrogen receptor modulator. In clinical trials E4 has been seen to have little or no effect on coagulation. Hence, it is interesting to investigate whether E4 alters endothelial-dependent fibrinolysis. OBJECTIVES: We studied the effects of E4 on the fibrinolytic system and whether this could influence the ability of endothelial cells to migrate. In addition, we compared the effects of E4 with those of 17ß-estradiol (E2). STUDY DESIGN: Human umbilical vein endothelial cells (HUVEC) were obtained from healthy women. Expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) proteins was evaluated by Western blot analysis. Endothelial cell migration was studied by razor-scrape horizontal and multiwell insert systems assays. RESULTS: E4 increased the expression of t-PA, u-PA and PAI-1 in HUVEC, but less so than did equimolar amounts of E2. The effects of E4 on t-PA, u-PA and PAI-1 were mediated by the induction of the early-immediate genes c-Jun and c-Fos. E4 in combination with E2 antagonized the effects induced by pregnancy-like E2 concentrations but did not impair the effects of postmenopausal-like E2 levels. We also found that the increased synthesis of PAI-1, u-PA and t-PA induced by E2 and E4 is important for horizontal and three-dimensional migration of HUVEC. CONCLUSIONS: These results support the hypothesis that E4 acts as an endogenous selective estrogen receptor modulator (SERM), controlling the fibrinolytic system and endothelial cell migration.


Assuntos
Movimento Celular/efeitos dos fármacos , Estetrol/farmacologia , Fibrinólise/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos , Western Blotting , Células Cultivadas , Células Endoteliais , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
6.
Eur Heart J ; 38(12): 916-919, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28065908

RESUMO

Aims: Oral anticoagulation is considered standard therapy for stroke prevention in atrial fibrillation (AF). Endocardial activation triggers expression of pro-thrombotic mediators including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), and contributes to thrombus formation in the left atrial appendage (LAA) of AF patients. Recently, pleiotropic effects of specific P2Y12 receptor antagonists were demonstrated; however, whether these drugs possess antithrombotic effects on LAA endocardial cells currently remains unknown. Methods and results: LAA were obtained from 14 patients with known AF undergoing elective cardiac surgery including LAA removal at the University Hospital Zurich. LAA endocardial cells were isolated and pre-incubated with ticagrelor (10-7, 10-6, 10-5M) or clopidogrel active metabolite (CAM) (1.5 × 10-8, 1.5 × 10-7, 1.5 × 10-6 M) before stimulation with tumour necrosis factor-alpha (TNF-α) (10 ng/mL). Finally, TF and PAI-1 expression and activity were analysed. Ticagrelor, unlike CAM, concentration dependently decreased TNF-α-induced TF expression and TF activity in LAA endocardial cells. Further, ticagrelor, but not CAM reduced PAI-1 expression and enzyme activity in TNF-α-stimulated LAA endocardial cells. In contrast, TF pathway inhibitor (TFPI) remained unaffected by both dugs. Conclusion: Ticagrelor, but not CAM, reduces expression and activity of TF and PAI-1 in LAA endocardial cells isolated from patients with AF, indicating possible local antithrombotic effects. Such pleiotropic properties of ticagrelor may contribute to a reduction in thromboembolic complications in patients with AF.


Assuntos
Adenosina/análogos & derivados , Antitrombinas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ticlopidina/análogos & derivados , Adenosina/farmacologia , Apêndice Atrial , Fibrilação Atrial , Clopidogrel , Endocárdio/metabolismo , Átrios do Coração , Humanos , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Tromboplastina/antagonistas & inibidores , Ticagrelor , Ticlopidina/metabolismo , Ticlopidina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
7.
Ren Fail ; 38(9): 1359-1363, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27756191

RESUMO

Disturbances in hemostasis are common complications of kidney diseases and correlate well with cardiovascular mortality. Little is known about the effects of fasudil on tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression in peripheral blood mononuclear cells (PBMCs) in CAPD patients. PBMCs were isolated from 13 individuals with CAPD and 13 healthy subjects. After 4 h of incubation with or without LPS (10 ng/mL), TF and PAI-1 mRNA of PBMCs were detected by RT-PCR. The levels of TF and PAI-1 in culture supernatants of PBMCs were determined by ELISA. Compared with healthy controls, CAPD patients had increased TF, PAI-1 protein and mRNA expression by PBMCs at baseline and after stimulated by LPS (10 ng/mL) [p < 0.001]. The fasudil treatment resulted in a significant effect in decreasing TF and PAI-1 [p < 0.05] synthesis in PBMCs. TF and PAI-1 mRNA expression and activities in PBMCs were increased in CAPD patients. Fasudil reduced LPS-mediated TF and PAI-1 expression and activity in PBMCs. These effects may partially be relevant to the clinical benefits of fasudil in the treatment of CAPD patients.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Regulação da Expressão Gênica , Falência Renal Crônica/terapia , Leucócitos Mononucleares/metabolismo , Diálise Peritoneal Ambulatorial Contínua , Inibidor 1 de Ativador de Plasminogênio/genética , Tromboplastina/genética , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Adulto , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tromboplastina/antagonistas & inibidores , Tromboplastina/biossíntese
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA