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1.
Eur J Med Genet ; 63(3): 103764, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31518693

RESUMO

We describe a female infant with incontinentia pigmenti complicated by severe pulmonary arterial hypertension that was markedly improved by tadalafil administration. The infant was referred to our institution because of neonatal seizures and generalized skin rash at the age of 1 day. She was diagnosed with incontinentia pigmenti on skin biopsy findings. In addition to incontinentia pigmenti, she had pulmonary arterial hypertension without structural heart disease. The pulmonary hypertension rapidly worsened at the age of 2 months and was confirmed by cardiac catheterization. The pulmonary artery pressure was equal to systemic pressure but it decreased in response to nitric oxide inhalation. We, therefore, initiated treatment with tadalafil of 1 mg/kg/day. The follow-up cardiac catheterization performed at 9 months revealed dramatic improvement in the pulmonary artery pressure. An IKBKG mutation with deletion of exons 4-10 was detected in the blood of both the patient and her mother. Our experience indicates that tadalafil may be beneficial in treating pulmonary arterial hypertension associated with incontinentia pigmenti.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Incontinência Pigmentar/complicações , Tadalafila/uso terapêutico , Éxons , Feminino , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Quinase I-kappa B/sangue , Quinase I-kappa B/genética , Incontinência Pigmentar/diagnóstico , Recém-Nascido , NF-kappa B/genética , NF-kappa B/metabolismo , Convulsões/genética , Deleção de Sequência , Pele/patologia , Tadalafila/administração & dosagem
2.
Clin Chem ; 65(8): 1023-1030, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072836

RESUMO

BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD). METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses. RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls. CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts.


Assuntos
Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Vasos Coronários/patologia , Inflamação/sangue , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Idoso , Proteína Relacionada com Agouti/sangue , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Quinase I-kappa B/sangue , Inflamação/epidemiologia , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Renina/sangue
3.
Front Biosci (Landmark Ed) ; 22(5): 757-771, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27814644

RESUMO

It has been shown that functional recovery of patients with acute congestive heart failure (ACHF) after treatment with conventional drugs (CD) is mediated by suppression of inflammation in peripheral blood mononuclear cells. Here, we analyzed gene expression profiles of monocytes from symptomatic ACHF patients (NYHA Class III-IV) before and after pharmacological treatment with CD. The treatment was associated with selective down-regulation of "TNFR signaling" and pro-inflammatory mediators CCL5, MIP-1α receptor, CD14, ITGAM, and significant up-regulation of "TNFR signaling" as evidenced by increase in anti-inflammatory factors including NF-kBIA, TNFAIP3 and SHP-1. In monocyte TNF-alpha-stimulated there is a down-regulation of the phosphatase SHP-1 which induces a significant activation of TAK-1/IKK/NF-kB signaling. These findings suggest that the therapeutic impact of CD treatment in symptomatic ACHF includes negative regulation of the NF-kB signaling in monocytes and the improvement of the SHP-1 activity.


Assuntos
Insuficiência Cardíaca/sangue , Monócitos/metabolismo , NF-kappa B/sangue , Proteína Tirosina Fosfatase não Receptora Tipo 6/sangue , Idoso , Estudos de Casos e Controles , Feminino , Insuficiência Cardíaca/genética , Humanos , Quinase I-kappa B/sangue , Linfócitos/metabolismo , MAP Quinase Quinase Quinases/sangue , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Transcriptoma , Fator de Necrose Tumoral alfa/sangue
4.
Arthritis Res Ther ; 17: 22, 2015 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-25648164

RESUMO

INTRODUCTION: The link between cardiovascular disease (CVD) and patients with chronic inflammation is not clearly understood. We examined a knock-in mouse expressing a poly-ubiquitin-binding-defective mutant of the protein ABIN1 (ABIN1(D485N)), which develops a systemic lupus erythematosus-like autoimmune disease because of the hyperactivation of IκB kinases (IκKs) and mitogen-activated protein kinases (MAPKs). These mice were used to determine the potential role of these signaling pathways in inflammation-mediated CVD development. METHODS: Laser Doppler imaging in combination with the iontophoresis of vasoactive chemicals were used to assess endothelium-dependent vasodilatation in vivo in ABIN1 (D485N)) mutant defective (n=29) and wild-type (WT) control (n=26) mice. Measurements were made at baseline, and animals were subdivided to receive either chow or a proatherogenic diet for 4 weeks, after which, follow-up assessments were made. Paired and unpaired t tests, and ANOVA with post hoc Bonferroni correction were used for statistical significance at P<0.05. RESULTS: Endothelium-dependent vasodilatation to acetylcholine was attenuated at 4 weeks in ABIN1(D485N)-chow-fed mice compared with age-matched WT-chow-fed mice (P<0.05). The magnitude of attenuation was similar to that observed in WT-cholesterol-fed animals (versus WT-chow, P<0.01). ABIN1(D485N)-cholesterol-fed mice had the poorest endothelium-dependent responses compared with other groups (P<0.001). ABIN1(D485N)-chow-fed mice had increased plasma interleukin-6 (IL-6) levels (versus WT-chow, P<0.001), and this was further elevated in ABIN1(D485N)-cholesterol-fed mice (versus ABIN1(D485N)-chow; P<0.05). IL-1α was significantly greater in all groups compared with WT-chow (P<0.01). ABIN1(D485N) mice showed significant cardiac hypertrophy (P<0.05). CONCLUSIONS: The ABIN(D485N) mice display endothelial dysfunction and cardiac hypertrophy, which is possibly mediated through IL-6 and, to a lesser degree, IL-1α. These results suggest that the ABIN1-mediated hyperactivation of IKKs and MAPKs might mediate chronic inflammation and CVD development.


Assuntos
Cardiomegalia/metabolismo , Cisteína Endopeptidases/fisiologia , Endotélio Vascular/metabolismo , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Acetilcolina/administração & dosagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Doenças Autoimunes/fisiopatologia , Cardiomegalia/fisiopatologia , Colesterol/administração & dosagem , Endotélio Vascular/fisiopatologia , Técnicas de Introdução de Genes , Quinase I-kappa B/sangue , Interleucina-1alfa/sangue , Interleucina-6/sangue , Iontoforese , Fluxometria por Laser-Doppler , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transdução de Sinais/fisiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
5.
Arterioscler Thromb Vasc Biol ; 33(2): 241-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23241410

RESUMO

OBJECTIVE: On the luminal surface of injured arteries, platelet activation and leukocyte-platelet interactions are critical for the initiation and progression of arterial restenosis. The transcription factor nuclear factor-κB is a critical molecule in platelet activation. Here, we investigated the role of the platelet nuclear factor-κB pathway in forming arterial neointima after arterial injury. METHODS AND RESULTS: We performed carotid artery wire injuries in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice with a platelet-specific deletion of IκB kinase-ß (IKKß) (IKKß(fl/fl)/PF4(cre)/LDLR(-/-)) and in control mice (IKKß(fl/fl)/LDLR(-/-)). The size of the arterial neointima was 61% larger in the IKKß(fl/fl)/PF4(cre)/LDLR(-/-) mice compared with the littermate control IKKß(fl/fl)/LDLR(-/-) mice. Compared with the control mice, the IKKß(fl/fl)/PF4(cre)/LDLR(-/-) mice exhibited more leukocyte adhesion at the injured area. The extent of glycoprotein Ibα shedding after platelet activation was compromised in the IKKß-deficient platelets. This effect was associated with a low level of the active form of A Disintegrin And Metalloproteinase 17, the key enzyme involved in mediating glycoprotein Ibα shedding in activated IKKß-deficient platelets. CONCLUSIONS: Platelet IKKß deficiency increases the formation of injury-induced arterial neointima formation. Thus, nuclear factor-κB-related inhibitors should be carefully evaluated for use in patients after an arterial intervention.


Assuntos
Plaquetas/enzimologia , Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/enzimologia , Quinase I-kappa B/deficiência , Neointima , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Lesões do Sistema Vascular/enzimologia , Proteínas ADAM/sangue , Proteína ADAM17 , Animais , Sítios de Ligação , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Adesão Celular , Modelos Animais de Doenças , Quinase I-kappa B/sangue , Quinase I-kappa B/genética , Leucócitos/metabolismo , Antígeno de Macrófago 1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Adesividade Plaquetária , Agregação Plaquetária , Ligação Proteica , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo , Lesões do Sistema Vascular/sangue , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
6.
Mol Nutr Food Res ; 56(3): 510-4, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22162245

RESUMO

SCOPE: Heating during the process of cooking alters the chemical properties of foods and may affect subsequent postprandial inflammation. We tested the effects of four meals rich in different oils subjected to heating on the postprandial inflammatory metabolism of peripheral blood mononuclear cells (PBMCs). METHODS AND RESULTS: Twenty obese participants received four breakfasts following a randomized crossover design, consisting of milk and muffins made with different oils (virgin olive oil (VOO), sunflower oil (SFO), and a mixture of seeds oil (SFO/canola oil) with added either dimethylpolysiloxane (SOD), or natural antioxidants from olive mill wastewater alperujo (phenols; SOP)), previously subjected to 20 heating cycles. Postprandial inflammatory status in PBMCs was assessed by the activation of nuclear NF-κB, the concentration in cytoplasm of the NF-κB inhibitor (IκB-α), the mRNA levels of NF-κB subunits and activators (p65, IKKß, and IKKα) and other inflammatory molecules (TNF-α, IL-1ß, IL-6, MIF, and JNK), and lipopolysaccharide (LPS) levels. VOO and SOP breakfasts reduced NF-κB activation, increased IκB-α, and decreased LPS plasma concentration. SFO increased IKKα, IKKß, p65, IL-1b, IL-6, MIF, and JNK mRNA levels, and plasma LPS. CONCLUSION: Oils rich in phenols, whether natural (VOO) or artificially added (SOP), reduce postprandial inflammation, compared with seed oil (sunflower).


Assuntos
Antioxidantes/administração & dosagem , Ácidos Graxos Monoinsaturados/administração & dosagem , Obesidade/metabolismo , Fenol/administração & dosagem , Óleos de Plantas/administração & dosagem , Estudos Cross-Over , Dimetilpolisiloxanos/metabolismo , Ácidos Graxos Monoinsaturados/química , Manipulação de Alimentos/métodos , Temperatura Alta , Humanos , Quinase I-kappa B/sangue , Proteínas I-kappa B/sangue , Inflamação/tratamento farmacológico , Interleucina-1beta/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/sangue , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa , NF-kappa B/sangue , Obesidade/fisiopatologia , Azeite de Oliva , Óleos de Plantas/química , Período Pós-Prandial , Óleo de Brassica napus , Óleo de Girassol , Fator de Necrose Tumoral alfa/metabolismo
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