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Brain Res ; 1718: 126-136, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085157


Inward rectification in response to membrane hyperpolarization is a prominent feature of mesencephalic trigeminal (Mes V) neurons and the hyperpolarization-activated inward current (Ih), as the basis of this property, regulates the spike discharge characteristics and input frequency preference (resonance) in these neurons, suggesting that Ih modulation is an important regulator of oral motor activity. To examine a possible contribution of serotonin (5-HT) to the modulation of Ih activation characteristics, in the present study, we investigated the modulatory effects of 5-HT receptor activation on Ih in postnatal day (P) 2-12 rat Mes V neurons by whole-cell patch-clamp recording. Bath application of 5-HT suppressed the Ih-dependent voltage sag and Ih conductance, but induced only a modest shift in the voltage dependence of Ih activation. This 5-HT-induced suppression of Ih was greater in P10-12 than P2-4 neurons, and involved the cAMP/protein kinase A (PKA) signaling pathway but not the PKC pathway. Pharmacological activation of the 5-HT1A receptor mimicked the effect of 5-HT, while modulation of other receptor subtypes, including 5-HT1B,1D, 5-HT2, and 5-HT3, had little or no effect on Ih. Low-frequency (<10 Hz) resonance at membrane potentials below the resting potential were reduced by 5-HT, suggesting that serotonergic Ih modulation can substantially alter the frequency preference to synaptic inputs. These results suggest that changes in resonance properties through serotonergic modulation of Ih may tune the firing of Mes V neurons to different afferent input frequencies and alter motor outputs to the jaw, thereby regulating oral motor activity.

J Dermatol ; 46(5): 444-448, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30897229


Cyclin-dependent kinase 4 and 6 (CDK4/6) plays an important role in cell cycle progression, and the CDK4/6-cyclin D1 complex controls the cell cycle transition from G1 phase to S phase. CDK4 is enhanced in several types of cancers and CDK4/6 inhibitors attenuate the proliferation of several types of cancer in vitro/in vivo. The purpose of our study was to investigate the expression pattern of CDK4 and evaluate its clinical importance in extramammary Paget's disease (EMPD). Almost all EMPD tissues were positive for CDK4, and metastatic lesions had a similar immunostaining intensity to primary lesions. In addition, CDK4 protein levels were positively correlated with those of cyclin D1 protein. Taken together, CDK4 may assume a crucial role in EMPD progression.

Quinase 4 Dependente de Ciclina/metabolismo , Doença de Paget Extramamária/patologia , Neoplasias Cutâneas/patologia , Idoso , Idoso de 80 Anos ou mais , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/análise , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia
J Nat Med ; 72(1): 260-266, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29151157


Erypoegin K is an isoflavone isolated from the stem bark of Erythrina poeppigiana. It contains a furan group at the A-ring of the core isoflavone structure and can inhibit the activity of glyoxalase I, an enzyme that catalyzes the detoxification of methylglyoxal (MG), a by-product of glycolysis. In the present study, we found that erypoegin K has a potent cytotoxic effect on human leukemia HL-60 cells. Its cytotoxic effect was much stronger than that of a known glyoxalase I inhibitor S-p-bromobenzylglutathione cyclopentyl diester. Conversely, erypoegin K demonstrated weak cytotoxicity toward normal human peripheral lymphocytes. The treatment of HL-60 cells with erypoegin K significantly induced caspase-3 activity, whereas the pretreatment of the cells with caspase-3 inhibitor suppressed erypoegin K-induced cell death. Furthermore, nuclear condensation and apoptotic genome DNA fragmentation were observed in erypoegin K-treated HL-60 cells. These results indicated that the observed cell death was mediated by apoptosis. In addition, the toxic compound MG was highly accumulated in the culture medium of erypoegin K-treated HL-60 cells, suggesting that cell apoptosis was triggered by extracellular MG. The present study showed that erypoegin K has a potent apoptosis-inducing effect on cancerous cell lines, such as HL-60.

Benzofuranos/química , Erythrina/química , Células HL-60/química , Isoflavonas/química , Leucemia/tratamento farmacológico , Apoptose , Humanos , Leucemia/patologia
Drug Discov Ther ; 10(3): 172-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27169370


We focused on the interaction of cytokines in squamous cell carcinoma (SCC), and determined the expression profile of multiple cytokines in the serum of each patient with SCC in the present study. Serum samples were obtained from 12 SCC patients and 7 normal subjects. Four cytokines (IFN-γ, IL-6, GM-CSF, and TGF-ß) were selected because they are reported to be involved in keratinocyte proliferation and SCC progression. Serum levels were measured using ELISA. We found a statistically significant increase of serum IFN-γ levels in SCC patients compared to those in normal subjects, and areas under the curve (AUC) of 0.82 for the serum levels of IFN-γ were higher than those for other cytokine levels according to ROC curve analysis. Patients with increased IFN-γ levels had a significantly more severe cancer stage. Furthermore, the combination of IFN-γ levels and TGF-ß levels could improve the AUC to 0.84. We also found there was a significant correlation between IFN-γ levels and GM-CSF levels or between GM-CSF levels and TGF-ß levels only in SCC patients. Our results suggest that the combination of IFN-γ levels and TGF-ß levels is more effective to diagnose SCC, while serum levels of IFN-γ alone are useful to evaluate tumor progression. Furthermore, expression of these cytokines was not independent, but may be regulated by common upstream factors (e.g. cytokines or methylation) in SCC patients, and such factors may play some roles in the pathogenesis of SCC.

Carcinoma de Células Escamosas/sangue , Citocinas/sangue , Neoplasias Cutâneas/sangue , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Proliferação de Células/efeitos dos fármacos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Interferon gama/análise , Interleucina-6 , Queratinócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Curva ROC
J Dermatol ; 43(5): 522-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26507968


Infliximab is an anti-tumor necrosis factor (TNF)-α antibody drug that suppresses TNF-α and its associated inflammatory responses. Although infliximab therapy generally results in a 75% or greater improvement in the Psoriasis Area and Severity Index from baseline in psoriasis patients, there is the heterogeneity of therapeutic efficacy in psoriasis patients among patients of a similar PASI baseline score. However, there are few published reports about the predictors of the clinical response among psoriasis patients who undergo biologic therapies. We thus evaluated the possible existence of biologic markers that would indicate poor prognosis of infliximab using skin biopsy specimens. This was because we assumed that the inhibitors for upregulated chemokine/chemokine receptors in non-responders may have the ability to reduce the occurrence of psoriatic eruptions. PCR array analyses identified that the levels of various chemokines and chemokine receptors were increased in non-responders in comparison to responders. Immunohistochemical analyses revealed that upregulation of the CCR9 protein levels was not associated with the pretherapeutic PASI score, but with poor response to infliximab. Our results indicated that the expression levels of CCR9 in lesional skin may be a useful biologic marker of the clinical efficacy of infliximab therapy in psoriasis patients.

Biomarcadores Farmacológicos/metabolismo , Fármacos Dermatológicos/uso terapêutico , Infliximab/uso terapêutico , Psoríase/tratamento farmacológico , Receptores CCR/metabolismo , Pele/metabolismo , Adulto , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Psoríase/metabolismo , Psoríase/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
Nat Prod Commun ; 10(9): 1581-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26594764


It has been reported that many malignant human tissues, including breast, colon, and lung cancers, may show an elevated expression of glyoxalase I (GLO I). GLO I catalyzes the reaction to transform hemimercaptal, a compound formed from methylglyoxal (MG) and reduced glutathione, into S-D-lactoylglutathione, which is then converted to D-lactic acid by glyoxalase II. GLO I inhibitors are expected to be useful for inhibiting tumorigenesis through the accumulation of apoptosis-inducible MG in tumor cells. Here, we investigated the anti-proliferative activity of eight kinds of isoflavone isolated from Erythrina poeppigiana against the growth of HL-60 human leukemia cells from the viewpoint of GLO I inhibition. Of the compounds tested, the diprenyl isoflavone, isolupalbigenin, was shown to exhibit the highest anti-proliferative activity against HL-60 cells. Upon the treatment of HL-60 cells with isolupalbigenin, MG was significantly accumulated in the culture medium, and the caspase 3 activity of the cell lysate was elevated in a time-dependent manner. Thus, it is suggested that isolupalbigenin inhibits the enzyme GLO I, resulting in MG accumulation in the medium, and leading to cell apoptosis. Isolupalbigenin, with two prenyl groups in its A- and B-rings, might be expected to become a potent leading compound for the development of anticancer agents.

Antineoplásicos Fitogênicos/farmacologia , Erythrina/química , Isoflavonas/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Antineoplásicos Fitogênicos/química , Sobrevivência Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Células HL-60 , Humanos , Isoflavonas/química , Lactoilglutationa Liase/genética , Estrutura Molecular