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1.
mBio ; 12(4): e0134821, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34372705

RESUMO

Human health is threatened by bacterial infections that are increasingly resistant to multiple drugs. A recently emerged strategy consists of disarming pathogenic bacteria by targeting and blocking their virulence factors. The type VI secretion system (T6SS) is a widespread secretion nanomachine encoded and employed by pathogenic strains to establish their virulence process during host invasion. Given the conservation of T6SS in several human bacterial pathogens, the discovery of an effective broad-spectrum T6SS virulence blocker represents an attractive target for development of antivirulence therapies. Here, we identified and validated a protein-protein interaction interface, TssK-TssG, as a key factor in the assembly of the T6SS baseplate (BP) complex in the pathogen enteroaggregative Escherichia coli (EAEC). In silico and biochemical studies revealed that the determinants of the interface are broadly conserved among pathogenic species, suggesting a role for this interface as a target for T6SS inhibition. Based on the high-resolution structure of the TssKFGE wedge complex, we rationally designed a biomimetic cyclic peptide (BCP) that blocks the assembly of the EAEC BP complex and inhibits the function of T6SS in bacterial cultures. Our BCP is the first compound completely designed from prior structural knowledge with anti-T6SS activity that can be used as a model to target human pathogens. IMPORTANCE New therapeutic options are urgently needed to fight drug-resistant and life-threatening infections. In contrast to antibiotics that inhibit the growth pathways of bacteria, the antivirulence strategy is a promising approach to disarm pathogens by interfering with bacterial virulence factors without exerting evolutionary pressure. The type VI secretion system (T6SS) is used by many pathogens, including members of the antibiotic-resistant ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), to establish their virulence during the invasion of the human host. Although the T6SS is undoubtedly involved in pathogenesis, strategies targeting this virulence factor are crucially lacking. Here, we used a combination of genetics, microbiology, biochemical, biophysics, and bioinformatics approaches to rationally design a biomimetic peptide that interferes with T6SS assembly and functioning. This study represents a novel proof of concept for an antivirulence strategy which aims to interfere with the assembly of the T6SS.


Assuntos
Biomimética/métodos , Escherichia coli/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Sistemas de Secreção Tipo VI/antagonistas & inibidores , Sistemas de Secreção Tipo VI/genética , Escherichia coli/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Humanos , Peptídeos/genética , Peptídeos/farmacologia , Sistemas de Secreção Tipo VI/metabolismo , Fatores de Virulência/antagonistas & inibidores
2.
J Hosp Infect ; 106(1): 10-19, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32652212

RESUMO

BACKGROUND: In the wake of the SARS-CoV-2 pandemic and unprecedented global demand, clinicians are struggling to source adequate access to personal protective equipment. Respirators can be in short supply, though are necessary to protect workers from SARS-CoV-2 exposure. Rapid decontamination and reuse of respirators may provide relief for the strained procurement situation. METHOD: In this study, we investigated the suitability of 70°C dry heat and microwave-generated steam (MGS) for reprocessing of FFP2/N95-type respirators, and Type-II surgical face masks. Staphylococcus aureus was used as a surrogate as it is less susceptible than enveloped viruses to chemical and physical processes. RESULTS: We observed >4 log10 reductions in the viability of dry S. aureus treated by dry heat for 90 min at 70°C and >6 log10 reductions by MGS for 90 s. After 3 reprocessing cycles, neither process was found to negatively impact the bacterial or NaCl filtration efficiency of the respirators that were tested. However, MGS was incompatible with Type-II surgical masks tested, as we confirmed that bacterial filtration capacity was completely lost following reprocessing. MGS was observed to be incompatible with some respirator types due to arcing observed around some types of metal nose clips and by loss of adhesion of clips to the mask. CONCLUSION: Considering the advantages and disadvantages of each approach, we propose a reprocessing personal protective equipment/face mask workflow for use in medical areas.


Assuntos
Infecções por Coronavirus/prevenção & controle , Descontaminação/métodos , Reutilização de Equipamento/normas , Temperatura Alta , Máscaras/virologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Dispositivos de Proteção Respiratória/virologia , Vapor , Betacoronavirus , COVID-19 , Guias como Assunto , Humanos , Micro-Ondas , SARS-CoV-2
4.
Ann Fr Anesth Reanim ; 30(7-8): 589-93, 2011.
Artigo em Francês | MEDLINE | ID: mdl-21602016

RESUMO

Near infrared spectroscopy (NIRS) seems to be an interesting technology to study microcirculatory dysfunction. These alterations have been described after cardiac surgery under cardiopulmonary bypass. We report two case study reports with monitoring of StO(2) and reperfusion slope after an ischemic challenge. These two parameters are early altered notably in case of cardiac dysfunction (decrease of StO(2) and reperfusion slope). We discuss the interest of microcirculatory measurement in this context.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Microcirculação , Complicações Pós-Operatórias/fisiopatologia , Espectroscopia de Luz Próxima ao Infravermelho , Idoso , Humanos , Masculino
5.
Ann Cardiol Angeiol (Paris) ; 59(1): 37-9, 2010 Feb.
Artigo em Francês | MEDLINE | ID: mdl-19875096

RESUMO

Right atrial myxoma is a rare disease and its clinical presentation is not specific. The usual mode of revelation is heart failure. The most frequent complications are pulmonary embolism and atrioventricular valve obstruction by the tumor. A 49-year-old woman was admitted to intensive care unit for heart failure. The echocardiogram showed a voluminous right atrial myxoma, appending to the interatrial septum. Its surgical excision under extracorporeal circulation was successfully performed. Histology confirmed the final diagnosis of myxoma. No complication was observed at 6 months follow-up.


Assuntos
Átrios do Coração , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Neoplasias Cardíacas/diagnóstico , Mixoma/diagnóstico , Diagnóstico Diferencial , Ecocardiografia , Ecocardiografia Transesofagiana , Feminino , Átrios do Coração/cirurgia , Insuficiência Cardíaca/cirurgia , Neoplasias Cardíacas/cirurgia , Humanos , Pessoa de Meia-Idade , Mixoma/cirurgia
6.
Ann Cardiol Angeiol (Paris) ; 59(2): 72-8, 2010 Apr.
Artigo em Francês | MEDLINE | ID: mdl-19962685

RESUMO

Bivalirudin, with provisional GP IIb/IIIa inhibitor use allows the same protection against ischemic complications while reducing the hemorrhagic complications compared with the systematic association of a GP IIb/IIIa inhibitor plus heparin (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 [Replace-2]). In clinical practice, the use of heparin is not systematically associated with a GP IIb/IIIa inhibitor. That's why we studied the clinical and economic interest of bivalirudin only versus heparin (UFH) only. Opened pragmatic monocentric study carried out in 2007. We made a chronological matching: for each patient treated with bivalirudin, we included the next patient with the same clinical presentation treated with unfractionated heparin. Ninety-two patients were included (46 in each group). The need for a GP IIb/IIIa inhibitor during the PCI was not significantly different between the two groups (p=0.11). No major hemorrhagic complications were observed in the two groups. Prevalence of ecchymosis was not significantly different: 22 % in the UFH group versus 13 % in the bivalirudin group (p=0.27). The average troponin level the next day was significantly higher in the bivalirudin group (p=0,049), although the change in troponin levels before and after the procedure was similar in the two groups. The average cost by patient of anticoagulation by bivalirudin and HNF is very different, respectively 473+/-150 and 51+/-146 euro (p=0.0001). Bivalirudin can be an interesting alternative for patients with a high risk of having complications. But considering its cost this therapy must be used only for selected patients.


Assuntos
Angioplastia Coronária com Balão/métodos , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Síndrome Coronariana Aguda/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/terapia , Angioplastia Coronária com Balão/efeitos adversos , Anticoagulantes/economia , Antitrombinas/economia , Estudos de Casos e Controles , Custos de Medicamentos , Equimose/etiologia , Feminino , Hemorragia/prevenção & controle , Heparina/uso terapêutico , Hirudinas/economia , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/economia , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Estudos Prospectivos , Punções/efeitos adversos , Proteínas Recombinantes/economia , Proteínas Recombinantes/uso terapêutico , Fatores de Risco , Resultado do Tratamento , Troponina/análise
7.
Rev Med Interne ; 28(8): 552-5, 2007 Aug.
Artigo em Francês | MEDLINE | ID: mdl-17559983

RESUMO

INTRODUCTION: Peripheral T cell lymphomas are a heterogeneous group of post-thymic, mature lymphoid malignancies, accounting for approximately 10-15% of all non-Hodgkin's lymphomas. A rare entity within this group is represented by hepatosplenic T cell lymphoma, characterized by primary extranodal disease with infiltration of the liver and the spleen and by expression of the T cell receptor gamma delta chain. EXEGESIS: A 64-year old man with dermatomyositis developed rapid-onset paraparesia and deafness. Cerebrospinal fluid analysis revealed large granular lymphomatous cells with CD3+ CD4- CD8- CD7+ CD16- CD56- surface antigens, expressing the gamma delta T-cell receptor. There was no evidence of skin or bone marrow infiltration by lymphoma or any other involvement. This is the first report of dermatomyositis associated with a gamma delta T-cell lymphoma (GDTL). Moreover, primitive and isolated meningeal involvement of such lymphomas has never been described before. CONCLUSION: GDTL should be added to the differential list of neoplasia associated with dermatomyositis. Physiopathological mechanisms implicated in the neurological involvement of such lymphomas need to be elucidated.


Assuntos
Dermatomiosite/etiologia , Neoplasias Hepáticas/diagnóstico , Linfoma de Células T/diagnóstico , Síndromes Paraneoplásicas/diagnóstico , Neoplasias Esplênicas/diagnóstico , Humanos , Neoplasias Hepáticas/metabolismo , Linfoma de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Neoplasias Esplênicas/metabolismo
8.
J Vasc Res ; 44(2): 119-28, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17215583

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO) has previously been evaluated in hyperlipidemic rabbits. The aim of this study was therefore to compare USPIO in ruptured and non-ruptured arteries in an atherosclerotic rabbit model. METHODS: Atherosclerotic-like lesions were induced by the combination of endothelial abrasion and high-cholesterol diet in iliac rabbit arteries (n = 16). Rupture of atherosclerotic lesions was realized by oversized balloon angioplasty in one iliac artery, whereas the contralateral artery was used as control. USPIO (ferumoxtran-10: 1 mmol Fe/kg) was administered immediately (n = 10) or 28 days (n = 6) after injury. MRI and histological analysis were performed 7 and 35 days after injury and in control arteries. RESULTS: In vivo MRI analysis showed extended susceptibility artifact with transluminal signal loss in all ruptured arteries 7 days after injury. In contrast, hyposignal was reduced 35 days following injury (i.e. after healing), and absent in non-ruptured arteries. Similarly, histological analysis of iron uptake was significantly increased 7 days after injury compared to healed-ruptured and control arteries. CONCLUSIONS: Accumulation ofUSPIO is significantly increased in ruptured as compared to non-ruptured arteries in the atherosclerotic rabbit model.


Assuntos
Aterosclerose/patologia , Óxido Ferroso-Férrico/farmacologia , Hiperlipidemias/patologia , Imageamento por Ressonância Magnética/métodos , Animais , Artefatos , Artéria Femoral/patologia , Artéria Ilíaca/patologia , Processamento de Imagem Assistida por Computador , Masculino , Coelhos , Ruptura Espontânea
10.
Rev Med Interne ; 26(6): 508-10, 2005 Jun.
Artigo em Francês | MEDLINE | ID: mdl-15936479

RESUMO

INTRODUCTION: Adult dermatomyositis is a rare inflammatory myopathy associated with typical cutaneous lesions and an increased incidence of internal malignancies, notably cancers of the female genital tract. Nevertheless, fallopian tube carcinoma is exceptionally associated with dermatomyositis. EXEGESIS: We report an unusual case of dermatomyositis because of cutaneous necrosis revealing a cancer of the fallopian tube. CONCLUSION: Predictive factors of cancer can improve prognosis of dermatomyositis due to earlier diagnosis of associated cancer. In our observation as in literature review, cutaneous necrosis lesions are highly predictive of an associated neoplasia even as rare as a fallopian tube carcinoma.


Assuntos
Carcinoma/diagnóstico , Dermatomiosite/etiologia , Neoplasias das Tubas Uterinas/diagnóstico , Carcinoma/patologia , Dermatomiosite/patologia , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Necrose , Pele/patologia
11.
Ann Cardiol Angeiol (Paris) ; 54(2): 49-54, 2005 Mar.
Artigo em Francês | MEDLINE | ID: mdl-15828457

RESUMO

More and more elderly people are hospitalised with myocardial infarction. Little is known on their pre-hospital management. In 2001 and 2002, 105 patients aged 80 years or more with suspected ST elevation infarction were managed by the mobile intensive care unit system of the SAMU de Paris-Necker. Diagnosis of infarction was confirmed in 92 (88%). Over 60% of the patients were women. Median time delay from symptom onset to call to the emergency service was 127 minutes, longer in nonagenarians (175 vs 101 minutes). Prehospital use of aspirin was 81% and 39% received an intravenous bolus of heparin. A reperfusion strategy was decided in only 30% (primary PCI: 23/26). One-month mortality was 21% and was related to older age, time when the call to the Samu was made, and absence of current smoking. Overall, the prehospital management of very elderly patients with suspected ST elevation infarction appears far from optimal.


Assuntos
Ambulâncias , Eletrocardiografia , Serviços Médicos de Emergência , Infarto do Miocárdio/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Distribuição de Qui-Quadrado , Interpretação Estatística de Dados , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/uso terapêutico , Heparina/administração & dosagem , Heparina/uso terapêutico , Mortalidade Hospitalar , Humanos , Injeções Intravenosas , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Paris , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Fatores de Tempo
12.
Circulation ; 109(21): 2503-6, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15148270

RESUMO

BACKGROUND: The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. METHODS AND RESULTS: Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43+/-0.30 versus 0.93+/-0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries. CONCLUSIONS: In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.


Assuntos
Apoptose , Cateterismo/efeitos adversos , Endotélio Vascular/patologia , Trombose/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Arteriosclerose/complicações , Arteriosclerose/patologia , Arteriosclerose/terapia , Inibidores de Cisteína Proteinase/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/lesões , Artéria Femoral , Fibrina/administração & dosagem , Marcação In Situ das Extremidades Cortadas , Contagem de Plaquetas , Coelhos , Estaurosporina/toxicidade , Tromboplastina/administração & dosagem , Trombose/induzido quimicamente , Trombose/etiologia , Trombose/prevenção & controle , Túnica Íntima/patologia
13.
Oncogene ; 20(17): 2190-6, 2001 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-11360204

RESUMO

A combination of antitumor approaches acting on different death pathways seems ideal for increasing therapeutic responses, especially when defined resistance mechanisms interfere with individual cellular processes. Apoptosis pathways triggered by ionizing radiation (XRT) and the death ligand TRAIL were analysed in Jurkat lymphoma cells. Both induced the activation of caspase-8, caspase-3, BID and mitochondrial potential loss. TRAIL induced apoptosis required caspase-8, whereas it was not essential for radiation induced apoptosis. The inhibition of mitochondrial damage by Bcl-2 abrogated XRT induced apoptosis and caspase activation, but only marginally attenuated TRAIL induced cell death. The combined treatment with TRAIL and XRT exerted additive apoptotic effects in control cells, whereas highly synergistic effects occurred in cells overexpressing Bcl-2. In addition, a strong effect of TRAIL on radiation induced clonogenic cell death was found. In conclusion, TRAIL seems to be of high potential value for a combination with ionizing radiation in tumor therapy.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linfoma de Células T/patologia , Glicoproteínas de Membrana/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose , Caspase 8 , Caspase 9 , Inibidores de Caspase , Caspases/metabolismo , Terapia Combinada , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Ativação Enzimática , Humanos , Células Jurkat/efeitos dos fármacos , Células Jurkat/patologia , Células Jurkat/efeitos da radiação , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/radioterapia , Radiossensibilizantes/farmacologia , Proteínas Recombinantes/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF
14.
Biochem Pharmacol ; 61(4): 387-98, 2001 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11226372

RESUMO

Inhibition of acyl-coenzyme A: cholesterol O-acyltransferase (EC 2.3.1.26; ACAT) reduces intracellular cholesteryl esters that are substrates for steroidogenesis in adrenal cells. The adrenal side effects of ACAT inhibitors remain a key point for their development as antiatherosclerotic agents. The aim of this study was to characterize the effects of a novel and powerful ACAT inhibitor, F 12511 (S)-2',3',5'-trimethyl-4'-hydroxy-alpha-dodecylthio-phenylacetanilide, on the NCI-H295R cell line, which has functional properties comparable to those of normal human adrenal cells. F 12511 incubated with cultured cells for 4-72 hr strongly inhibited cholesteryl oleate formation. The concentrations required to produce 50% inhibition (IC50) values) ranged from 20 to 50 nM; in the presence of low-density lipoproteins (LDL), this effect was paralleled by a decrease in cholesteryl ester mass and an increase in intracellular free cholesterol. At concentrations 100-fold larger than the IC(50) value for up to 48 hr, F 12511 reduced neither the basal release of cortisol and aldosterone nor the production of cortisol stimulated by forskolin. F 12511 did not modify the mRNA levels of the steroidogenic enzyme genes cytochrome P450 cholesterol side-chain cleavage (P450scc), cytochrome P450 17alpha-hydroxylase (P450c17), or cytochrome P450 21-hydroxylase (P450c21) or those of the LDL receptor and high-density lipoprotein scavenger receptor class B, type I (SR-BI) genes, either in the presence or absence of adenosine 3',5'-cyclic monophosphate stimulation for 24 hr. Exposure to F 12511 at up to 3 microM for 24 or 48 hr did not result in significant change in morphological and ultrastructural characteristics; the cytoplasm contained large numbers of mitochondria with intact crystae, and the same typical features of secretory activity were observed in NCI-H295R control cells. Exposure to 3 microM of F 12511 for 96 hr also did not affect cell viability. These data demonstrate that reduction of the substrate for steroidogenesis by the ACAT inhibitor F 12511 impairs neither steroid production nor transcription of genes involved in steroidogenesis and lipoprotein uptake in the pluripotent human adrenal cell line NCI-H295R.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Anilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Neoplasias do Córtex Suprarrenal , Glândulas Suprarrenais/enzimologia , Sítios de Ligação , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Colesterol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Receptores de Lipoproteínas/metabolismo , Esteroides/metabolismo , Esterol O-Aciltransferase/metabolismo , Células Tumorais Cultivadas
15.
Toxicol Lett ; 114(1-3): 203-14, 2000 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-10713486

RESUMO

4-Hydroxy-2-nonenal (HNE) is a major aldehydic product of lipid peroxidation known to exert several biological and cytotoxic effects. The in vitro metabolism of [4-(3)H]-HNE by rat precision-cut liver slices was investigated. Liver slices rapidly metabolize HNE - about 85% of 0.1 microM [4-(3)H]-HNE was degraded within 5 min of incubation. The main metabolites of HNE identified were 4-hydroxynonenoic acid (HNA), glutathione-HNE-conjugate (HNE-GSH), glutathione-1,4-dihydroxynonene-conjugate (DHN-GSH) and cysteine-HNE-conjugate (HNE-CYS). Whereas glutathione conjugation demonstrated saturation kinetics (K(m)=412.2+/-152.7 microM and V(max)=12.3+/-2.5 nmol h(-1) per milligram protein), HNA formation was linear up to 500 microM HNE in liver slices. In contrast to previous reports, no trace of the corresponding alcohol of the HNE, 1,4-dihydroxynon-2-ene was detected in the present study. Furthermore, the beta-oxidation of HNA including the formation of tritiated water was demonstrated. The identification of 4-hydroxy-9-carboxy-2-nonenoic acid and 4,9-dihydroxynonanoic acid demonstrated that omega-oxidation significantly contributes to the biotransformation of HNE in liver slices.


Assuntos
Aldeídos/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Peroxidação de Lipídeos/fisiologia , Fígado/metabolismo , Alcenos/análise , Animais , Biotransformação/fisiologia , Radioisótopos de Carbono/análise , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Técnicas de Cultura , Ácidos Graxos Monoinsaturados/análise , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos Insaturados/análise , Ácidos Graxos Insaturados/síntese química , Glutationa/análise , Glutationa/metabolismo , Hidroxiácidos/análise , Hidroxiácidos/síntese química , Cinética , Masculino , Espectrometria de Massas , Ratos , Ratos Wistar , Trítio/análise
16.
J Clin Invest ; 104(9): R41-8, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10545531

RESUMO

Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged individuals, caused by an imbalance between insulin production and action. Genetic studies point to major genetic components, but, with the exception of maturity-onset diabetes of the young (MODY), specific diabetes susceptibility genes remain to be identified. Recent studies showed that a dominant negative mutation in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell specific transcription factor, causes pancreatic agenesis and MODY. Thus, we investigated 192 French, non-MODY type 2 diabetic families for mutations in IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation assays of these IPF-1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF-1 expression plasmids demonstrate a significant inhibition of basal insulin promoter activity (stronger with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion becomes progressively impaired. The lower penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes in humans.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteínas de Homeodomínio , Transativadores/genética , Glicemia/análise , Western Blotting , Cloranfenicol O-Acetiltransferase/metabolismo , Análise Mutacional de DNA , Feminino , França , Predisposição Genética para Doença , Genótipo , Humanos , Insulina/sangue , Masculino , Mutação , Linhagem , Fenótipo , Fatores de Tempo
17.
Xenobiotica ; 29(5): 499-509, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10379987

RESUMO

1. The biotransformation of pentachlorophenol (PCP), aniline and biphenyl in rainbow trout (Oncorhynchus mykiss) isolated liver cells was investigated to examine if fish hepatocytes represent a suitable alternative to the in vivo approach for studying the biotransformation of chemicals. Each compound was incubated at two concentrations (10 and 60 microM) for 2 h. For comparison, the metabolic profile of these xenobiotics was also studied in urine and bile of trout orally exposed to 1.8-4.0 mg/kg wet wt of each compound. 2. In vitro as in vivo, PCP glucuronide and to a lesser extent PCP sulphate were the metabolites formed by trout from PCP. 3. Aniline was mainly metabolized to acetanilide and to a lesser extent to 2-aminophenol by isolated hepatocytes, but neither hydroxylated acetanilide nor conjugates were found in vitro whereas they were present in bile and urine of trout treated with this chemical. 4. Trout hepatocytes metabolized biphenyl to hydroxylated and dihydroxylated products and the corresponding glucuronides. These results correlated well with the metabolic profile obtained from the bile of trout exposed to this pesticide. 5. It is concluded that although hepatocytes are well suited for several types of biotransformation studies, the fact that this system may in some cases produce a different metabolic pattern than in vivo should be considered when attempting to extrapolate in vitro to in vivo data.


Assuntos
Compostos de Anilina/farmacocinética , Compostos de Bifenilo/farmacocinética , Fígado/metabolismo , Oncorhynchus mykiss/metabolismo , Pentaclorofenol/farmacocinética , Compostos de Anilina/urina , Animais , Biotransformação , Compostos de Bifenilo/urina , Carcinógenos/farmacocinética , Feminino , Fungicidas Industriais/farmacocinética , Fungicidas Industriais/urina , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Pentaclorofenol/urina , Poluentes Químicos da Água/farmacocinética
18.
J Pharmacol Exp Ther ; 290(1): 83-95, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10381763

RESUMO

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Nitrilas/farmacologia , Piperazinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Colforsina/farmacologia , AMP Cíclico/farmacologia , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Cobaias , Coração/efeitos dos fármacos , Coração/fisiologia , Hemodinâmica/efeitos dos fármacos , Humanos , Hipotermia/induzido quimicamente , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Neurônios/efeitos dos fármacos , Coelhos , Ensaio Radioligante , Ratos , Receptor 5-HT1B de Serotonina , Receptor 5-HT1D de Serotonina , Veia Safena/efeitos dos fármacos , Suínos , Gânglio Trigeminal/citologia , Gânglio Trigeminal/efeitos dos fármacos , Triptaminas
19.
J Pharmacol Exp Ther ; 287(1): 266-83, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9765347

RESUMO

F 11440 (4-methyl-2-[4-(4-(pyrimidin-2-yl)-piperazino)-butyl]-2H, 4H-1,2,4-triazin-3,5-dione) was the outcome of a research effort guided by the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines the magnitude of their antidepressant and anxiolytic-like effects. The affinity of F 11440 for 5-HT1A binding sites (pKi, 8.33) was higher than that of buspirone (pKi, 7.50), and somewhat lower than that of flesinoxan (pKi, 8.91). In vivo, F 11440 was 4- to 20-fold more potent than flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal extracellular serotonin (5-HT) levels and to increase plasma corticosterone levels, respectively). F 11440 did not have detectable antidopaminergic activity (unlike buspirone, which inhibited all of the directly observable behavioral effects of methylphenidate in rats), showed no evidence of antihistaminergic activity (unlike flesinoxan, which protected against the effects of a histamine aerosol in guinea pigs), and had a 70-fold separation between its 5-HT1A agonist and alpha-1 adrenergic antagonist properties (measured as the ability to inhibit the methoxamineinduced increase in blood pressure in rats), unlike flesinoxan, which showed a <3-fold separation. In HeLa cells expressing human 5-HT1A receptors, F 11440 decreased the forskolin-induced increase in AMP, and, based on its maximal effect, was found to have an intrinsic activity of 1.0 relative to that of 5-HT, which was significantly higher than that of buspirone (0.49), ipsapirone (0.46) and flesinoxan (0.93). Consistent with the aforementioned hypothesis, F 11440 produced anxiolytic- and antidepressant-like effects in animal models (i.e., increased punished responding in a pigeon conflict procedure and decreased immobility in a rat forced swimming test, respectively) that were more substantial than those of buspirone, ipsapirone and flesinoxan. Thus, F 11440, shown here to be a potent, selective, high efficacy 5-HT1A receptor agonist, appears to have the potential to exert marked anxiolytic and antidepressant activity in humans.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Pirimidinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Triazinas/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1 , Animais , Colforsina/farmacologia , Columbidae , Conflito Psicológico , Corticosterona/metabolismo , AMP Cíclico/biossíntese , Antagonistas de Dopamina/farmacologia , Células HeLa , Humanos , Masculino , Microdiálise , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina
20.
Eur Radiol ; 8(1): 97-9, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9442138

RESUMO

Cardiac leiomyosarcoma is a rare tumour which can grow either intramurally or extramurally. Its prognosis is dismal. Surgery lengthens survival, but recurrences usually occur in the short term. Gated MRI is useful for the assessment of cardiac masses since it provides fine spatial and contrast resolution. We present the case of a left atrial leiomyosarcoma whose recurrence was diagnosed by gated MRI. Our patient underwent a second resection but died soon after.


Assuntos
Átrios do Coração/patologia , Neoplasias Cardíacas/diagnóstico , Leiomiossarcoma/diagnóstico , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico , Ecocardiografia Transesofagiana , Evolução Fatal , Feminino , Seguimentos , Átrios do Coração/diagnóstico por imagem , Neoplasias Cardíacas/cirurgia , Transplante de Coração , Humanos , Leiomiossarcoma/cirurgia , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
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