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1.
Rev Mal Respir ; 39(2): 79-83, 2022 Feb.
Artigo em Francês | MEDLINE | ID: mdl-35151521

RESUMO

Pulmonary hypertension is a pulmonary circulation pathology characterized by remodelling and hyperreactivity of the pulmonary arteries. Vasodilatation/vasoconstriction balance is modified in favour of constriction via, among other things, the proliferation of smooth muscle cells and the development of endothelial dysfunction. In addition, the pulmonary arteries undergo modification of mechanical forces, inducing modified activation of stretch-activated channels (SAC) such as Piezo1 and TRPV4. These ionic channels are sensitive to stretch and their activation can induce various cellular physiological responses, which strongly contribute to development and continuation of the pathology.


Assuntos
Hipertensão Pulmonar , Humanos , Hipóxia/patologia , Canais Iônicos , Miócitos de Músculo Liso , Artéria Pulmonar/patologia , Circulação Pulmonar/fisiologia , Canais de Cátion TRPV
2.
Cardiovasc Toxicol ; 22(1): 14-28, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524626

RESUMO

Several epidemiological studies have revealed the involvement of nanoparticles (NPs) in respiratory and cardiovascular mortality. In this work, the focus will be on the effect of manufactured carbon black NPs for risk assessment of consumers and workers, as human exposure is likely to increase. Since the pulmonary circulation could be one of the primary targets of inhaled NPs, patients suffering from pulmonary hypertension (PH) could be a population at risk. To compare the toxic effect of carbon black NPs in the pulmonary circulation under physiologic and pathological conditions, we developed a new in vitro model mimicking the endothelial dysfunction and vascular dynamics observed in vascular pathology such as PH. Human pulmonary artery endothelial cells were cultured under physiological conditions (static and normoxia 21% O2) or under pathological conditions (20% cycle stretch and hypoxia 1% O2). Then, cells were treated for 4 or 6 h with carbon black FW2 NPs from 5 to 10 µg/cm2. Different endpoints were studied: (i) NPs internalization by transmission electronic microscopy; (ii) oxidative stress by CM-H2DCFDA probe and electron paramagnetic resonance; (iii) NO (nitrites and nitrates) production by Griess reaction; (iv) inflammation by ELISA assay; and (v) calcium signaling by confocal microscopy. The present study characterizes the in vitro model mimicking endothelial dysfunction in PH and indicates that, under such pathological conditions, oxidative stress and inflammation are increased along with calcium signaling alterations, as compared to the physiological conditions. Human exposure to carbon black NPs could produce greater deleterious effects in vulnerable patients suffering from cardiovascular diseases.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Hipertensão Pulmonar/metabolismo , Nanopartículas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Fuligem/toxicidade , Hipóxia Celular , Células Cultivadas , Espectroscopia de Ressonância de Spin Eletrônica , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , Humanos , Hipertensão Pulmonar/patologia , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Nanopartículas/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/ultraestrutura , Fuligem/metabolismo
3.
Cell Death Differ ; 23(10): 1702-16, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27367565

RESUMO

Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca(2+) signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca(2+) transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca(2+) uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs.


Assuntos
Apoptose , Cálcio/metabolismo , Movimento Celular , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Proteína bcl-X/metabolismo , Receptor fas/metabolismo , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Regulação para Baixo/genética , Feminino , Humanos , Camundongos Knockout , Membranas Mitocondriais/metabolismo , Modelos Biológicos , Ligação Proteica , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo
4.
Eur Respir J ; 34(6): 1338-47, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19541711

RESUMO

Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs). Intact and beta-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca(2+)-sensitisation. Microspectrofluorimetry was used for intracellular Ca(2+) recordings in cultured HPA smooth muscle cells. Voltage-operated Ca(2+) channel blockers (nitrendipine and nifedipine) partially reduced the contraction to 5-HT. Thapsigargin or cyclopiazonic acid (CPA), known to deplete sarcoplasmic reticulum Ca(2+) stores, also partially inhibited the contraction, whereas removal of extracellular Ca(2+) under these conditions further inhibited the contraction. Changing from Ca(2+)-free to Ca(2+) containing solution, in the presence of nitrendipine and CPA, a protocol known to stimulate store-operated Ca(2+) channels, induced HPA contractions that were blocked by nickel. Nickel or gadolinium also reduced the contraction to 5-HT. Finally, 5-HT increased intracellular Ca(2+) responses in cultured HPA smooth muscle cells and myofilament Ca(2+)-sensitisation in HPA rings. Collectively, these results indicate that voltage-operated and voltage-independent Ca(2+) channels, as well as Ca(2+) release and myofilament Ca(2+)-sensitisation, participate in 5-HT-induced contraction in HPAs.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Serotonina/metabolismo , Serotonina/farmacologia , Idoso , Cálcio/metabolismo , Escina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Contração Miocárdica , Nifedipino/farmacologia , Nitrendipino/farmacologia , Retículo Sarcoplasmático/metabolismo , Transdução de Sinais , Espectrometria de Fluorescência/métodos
5.
FASEB J ; 20(1): 136-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16254044

RESUMO

Defective expression of dystrophin in muscle cells is the primary feature of Duchenne muscular dystrophy (DMD), which is accompanied by fiber necrosis and intracellular calcium mishandling. These features led to the hypothesis that dystrophin could control calcium movements. Calcium mishandling in human DMD myotubes is dependent on contraction and/or calcium release activity, suggesting the involvement of channels being activated during these processes. Forced expression of minidystrophin at the plasma membrane of dystrophin-deficient Sol8 myotubes reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and results in normal calcium homeostasis. In active dystrophic myotubes, store-operated calcium channels could be responsible for a sustained calcium influx in muscle cells. We show here that depletion of calcium stores (sarcoplasmic reticulum) by repetitive activation of calcium release and blockade of SERCA leads to a calcium influx. In myotubes expressing recombinant minidystrophin, these store-dependent influxes were reduced to a level similar to that observed in myotubes expressing native dystrophin. High store-dependent calcium influxes in dystrophin-deficient myotubes were associated with sustained cytosolic calcium transients and high intramitochondrial entries, while lower store-dependent calcium influx in myotubes expressing minidystrophin resulted in shorter calcium transients and reduced calcium uptake into mitochondria. We propose that minidystrophin negatively regulates sarcolemmal store-dependent calcium channels, which reduces store-dependent calcium influx, as well as its mitochondrial uptake. Forced expression of minidystrophin in dystrophic cells might restore the regulation of sarcolemmal store-dependent channels, which could protect against calcium mishandling.


Assuntos
Cálcio/metabolismo , Distrofina/química , Distrofina/metabolismo , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Compostos de Boro , Cafeína , Linhagem Celular , Distrofina/deficiência , Distrofina/genética , Regulação da Expressão Gênica , Músculo Esquelético/metabolismo , Retículo Sarcoplasmático/metabolismo , Tapsigargina
6.
Proc Natl Acad Sci U S A ; 91(6): 2041-5, 1994 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-8134347

RESUMO

Many theories of memory postulate that processing of information outlasts the learning situation and involves several different physiological substrates. If such physiologically distinct mechanisms or stages of memory do in fact exist, they should be differentially affected by particular experimental manipulations. Accordingly, a selective improvement of the processes underlying short-term memory should be detectable only while the information is encoded in the short-term mode, and a selective influence on long-term memory should be detectable only from the moment when memory is based on the long-term trace. Our comparative study of the time course of the effects of the cholinergic agonist arecoline, the gamma-aminobutyric acid type B receptor antagonist CGP 36742, the angiotensin-converting enzyme inhibitor captopril, and the nootropic oxiracetam, four substances with completely different primary sites of action, show that the memory-enhancing effects consistently come into evidence no sooner than 16-24 h after the learning trial. On the one hand, this finding suggests that all these substances act by way of the same type of mechanism; on the other hand, it demonstrates that the substrate modulated by the compounds forms the basis of memory only after 16-24 h. From the observation that animals also show clear signs of retention during the first 16 h--i.e., before the effects of the substances are measurable--it can be inferred that retention during this time is mediated by other mechanisms that are not influenced by any of the substances.


Assuntos
Arecolina/farmacologia , Captopril/farmacologia , Memória/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Pirrolidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Antagonistas de Receptores de GABA-A , Masculino , Camundongos , Psicotrópicos/farmacologia , Fatores de Tempo
7.
Behav Neural Biol ; 57(2): 149-56, 1992 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-1586354

RESUMO

CGS 5649 B improves the learning performance of aged rats in a one-way active-avoidance situation. If, under reversed conditions, treated aged rats are also tested for passive avoidance, they show "place learning," which our findings have demonstrated to be typical of young rats. The effects of the substance are not confined to these experimental models nor are they species specific: it also facilitates passive avoidance in mice and social learning in rats. The compound is effective if administered before or immediately after the learning trial.


Assuntos
Envelhecimento/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Fumaratos/farmacologia , Rememoração Mental/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Mesilatos Ergoloides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Piracetam/farmacologia , Pré-Medicação , Ratos , Ratos Endogâmicos , Reversão de Aprendizagem/efeitos dos fármacos , Comportamento Social
8.
Psychopharmacology (Berl) ; 108(1-2): 11-5, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1410129

RESUMO

Oral pretreatment of mice with aldosterone or corticosterone blocked the memory-enhancing effects of piracetam, pramiracetam, aniracetam and oxiracetam in a dose-related manner, without, however, impairing the animals' learning performance. The improvement of memory induced by physostigmine, arecoline, and tacrine (THA) was similarly inhibited. The fact that elevated steroid levels suppress the memory-enhancing effects of entirely different substances could indicate that these substances have a common site of action. In the light of new observations showing increased cortisol concentrations in Alzheimer patients, this steroid dependency of the effects of memory enhancers might explain why only a limited number of these patients respond to therapy with nootropics or cholinomimetics.


Assuntos
Corticosteroides/sangue , Memória/efeitos dos fármacos , Parassimpatomiméticos/farmacologia , Psicotrópicos/farmacologia , Corticosteroides/fisiologia , Aldosterona/sangue , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Corticosterona/sangue , Masculino , Camundongos , Radioimunoensaio
9.
Psychopharmacology (Berl) ; 109(4): 383-9, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1365851

RESUMO

Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.


Assuntos
Aldosterona/farmacologia , Corticosterona/farmacologia , Memória/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/antagonistas & inibidores , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Captopril/antagonistas & inibidores , Captopril/farmacologia , Escuridão , Masculino , Camundongos , Nimodipina/antagonistas & inibidores , Nimodipina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estricnina/antagonistas & inibidores , Estricnina/farmacologia
10.
Brain Res ; 555(1): 107-11, 1991 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-1933323

RESUMO

The 'nootropics' are a new class of psychoactive substances that improve learning and memory. Their almost exclusive effect on memory may indicate that they act on processes specifically involved in information storage. When administered after the learning trial, these substances improve subsequent retention performance in mice, even if an interval of 8 h has elapsed between learning and treatment. CGS 5649B, a highly active new substance, is effective even after an interval of 24 h. Although consonant with the 'consolidation' hypothesis, the results may challenge prevailing notions about the formation of memory traces.


Assuntos
Memória/efeitos dos fármacos , Psicotrópicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Fatores de Tempo
11.
Behav Brain Res ; 34(1-2): 155-8, 1989 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-2765169

RESUMO

The present experiments demonstrate that the absence of any memory-improving action of nootropics in adrenalectomized animals cannot be ascribed to an effect of dosage. Doses of 1, 10, 100, 1000 and 3000 mg/kg p.o. of piracetam, oxiracetam, aniracetam or pramiracetam are ineffective in adrenalectomized mice.


Assuntos
Adrenalectomia , Nível de Alerta/efeitos dos fármacos , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Piracetam/farmacologia , Pirrolidinonas/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos , Pirrolidinas/farmacologia , Retenção Psicológica/efeitos dos fármacos
12.
Behav Brain Res ; 33(1): 79-82, 1989 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-2736062

RESUMO

The effects of the nootropic agent piracetam and its congeners oxiracetam, pramiracetam and aniracetam on the retention performance of mice in a passive-avoidance situation are dependent on the intensity of the foot-shock applied. This phenomenon is observed upon both pre-trial and post-trial drug administration.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Piracetam/farmacologia , Pirrolidinonas/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos , Pirrolidinas/farmacologia
13.
Clin Neuropharmacol ; 9 Suppl 3: S27-38, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3594453

RESUMO

The effects of oxiracetam and piracetam were compared in learning and memory tests in rats and mice. In the dose range examined, the two nootropics were equally active in reducing the amnesia induced by cerebral electroshock in the mouse. Step-down retention performance, however, was distinctly improved by oxiracetam but unaffected by piracetam, no matter whether it was given before or immediately after the learning trial. Oxiracetam also improved acquisition performance in aged (24- to 27-month-old) rats in an active-avoidance situation at doses of 30 and 100 mg/kg i.p. whereas piracetam showed no effect at 100 mg/kg i.p.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Memória/efeitos dos fármacos , Piracetam/farmacologia , Pirrolidinas/farmacologia , Pirrolidinonas/farmacologia , Envelhecimento/fisiologia , Animais , Esquema de Medicação , Eletrochoque , Camundongos , Ratos
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