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1.
J Neurochem ; 154(3): 330-348, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31957020

RESUMO

Angiopoietin-1, an angiogenic factor, stabilizes brain microvessels through Tie-2 receptor tyrosine kinase. In traumatic brain injury, blood-brain barrier (BBB) disruption is an aggravating factor that induces brain edema and neuroinflammation. We previously showed that BQ788, an endothelin ETB receptor antagonist, promoted recovery of BBB function after lateral fluid percussion injury (FPI) in mice. To clarify the mechanisms underlying BBB recovery mediated by BQ788, we examined the involvements of the angiopoietin-1/Tie-2 signal. When angiopoietin-1 production and Tie-2 phosphorylation were assayed by quantitative reverse transcription polymerase chain reaction and western blotting, increased angiopoietin-1 production and Tie-2 phosphorylation were observed in 7-10 days after FPI in the mouse cerebrum, whereas no significant effects were obtained at 5 days. When BQ788 (15 nmol/day, i.c.v.) were administered in 2-5 days after FPI, increased angiopoietin-1 production and Tie-2 phosphorylation were observed. Immunohistochemical observations showed that brain microvessels and astrocytes contained angiopoietin-1 after FPI, and brain microvessels also contained phosphorylated Tie-2. Treatment with endothelin-1 (100 nM) decreased angiopoietin-1 production in cultured astrocytes and the effect was inhibited by BQ788 (1 µM). Five days after FPI, increased extravasation of Evans blue dye accompanied by reduction in claudin-5, occludin, and zonula occludens-1 proteins were observed in mouse cerebrum while these effects of FPI were reduced by BQ788 and exogenous angiopoietin-1 (1 µg/day, i.c.v.). The effects of BQ788 were inhibited by co-administration of a Tie-2 kinase inhibitor (40 nmol/day, i.c.v.). These results suggest that BQ788 administration after traumatic brain injury promotes recovery of BBB function through activation of the angiopoietin-1/Tie-2 signal.


Assuntos
Angiopoietina-1/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/metabolismo , Antagonistas do Receptor de Endotelina B/farmacologia , Oligopeptídeos/farmacologia , Piperidinas/farmacologia , Receptor TIE-2/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Cérebro/efeitos dos fármacos , Cérebro/lesões , Cérebro/metabolismo , Masculino , Camundongos
2.
Mol Cell Biol ; 38(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29866655

RESUMO

Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear. N6-Methyladenosine (m6A) posttranscriptional RNA modification, whose methylation and demethylation are performed by respective enzyme molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N6-adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like 3 (METTL3), and METTL14 positively controls adipogenesis by promoting cell cycle transition in MCE during adipogenesis. WTAP, coupled with METTL3 and METTL14, is increased and distributed in nucleus by the induction of adipogenesis dependently on RNA in vitro Knockdown of each of these three proteins leads to cell cycle arrest and impaired adipogenesis associated with suppression of cyclin A2 upregulation during MCE, whose knockdown also impairs adipogenesis. Consistent with this, Wtap heterozygous knockout mice are protected from diet-induced obesity with smaller size and number of adipocytes, leading to improved insulin sensitivity. These data provide a mechanism for adipogenesis through the WTAP-METTL3-METTL14 complex and a potential strategy for treatment of obesity and associated disorders.


Assuntos
Adipogenia/fisiologia , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/metabolismo , Metiltransferases/metabolismo , Proteínas Nucleares/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Animais , Proteínas de Transporte/genética , Contagem de Células , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Núcleo Celular/metabolismo , Tamanho Celular , Células Clonais/citologia , Células Clonais/metabolismo , Ciclina A2/genética , Ciclina A2/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Metiltransferases/deficiência , Metiltransferases/genética , Camundongos , Camundongos Knockout , Mitose/genética , Mitose/fisiologia , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Processamento Pós-Transcricional do RNA , Fatores de Processamento de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Bioorg Med Chem ; 20(3): 1188-200, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22261023

RESUMO

The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3ß inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3ß inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2µM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Animais , Diabetes Mellitus Tipo 2/enzimologia , Desenho de Fármacos , Teste de Tolerância a Glucose , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células Hep G2 , Humanos , Masculino , Camundongos , Modelos Moleculares , Quinolonas/síntese química , Quinolonas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia
4.
Cell Metab ; 13(4): 401-412, 2011 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-21459325

RESUMO

Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.


Assuntos
Adiponectina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Interleucina-6/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Adiponectina/deficiência , Adiponectina/genética , Animais , Modelos Animais de Doenças , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina , Interleucina-6/deficiência , Interleucina-6/genética , Camundongos , Camundongos Obesos , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Receptores de Adiponectina/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
5.
Proc Natl Acad Sci U S A ; 108(14): 5753-8, 2011 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-21436039

RESUMO

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.


Assuntos
Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/complicações , Inibidores de Fosfoinositídeo-3 Quinase , Tecido Adiposo/citologia , Animais , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Técnicas Histológicas , Inflamação/etiologia , Fígado/citologia , Macrófagos/fisiologia , Camundongos , Camundongos Knockout , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologia
6.
Biol Reprod ; 69(1): 195-201, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12620936

RESUMO

To determine the prostaglandin (PG) H2 synthase (generally referred to as cyclooxygenase [COX]) isozyme responsible for producing uterotonic PGs during parturition, we used PGF2alpha receptor-deficient mice, which exhibit parturition failure due to impaired withdrawal of serum progesterone at term. On ovariectomy-induced parturition in these mice, uterine COX-2 mRNA expression was drastically induced in the myometrium, whereas COX-1 mRNA expression in the endometrial epithelium decreased. The concomitant administration of progesterone with ovariectomy resulted in a delay in parturition and the disappearance of both the increase in COX-2 mRNA and the decrease in COX-1 mRNA. Thus, the expression of myometrial COX-2 and the occurrence of parturition are closely associated in this model. Furthermore, administration of the COX-nonselective inhibitor, indomethacin, or the COX-2-selective inhibitor, Dup-697 or JTE-522, effectively delayed ovariectomy-induced parturition in these mice. These findings suggest that COX-2-derived PGs contribute to the onset of parturition after the decrease in serum progesterone level.


Assuntos
Isoenzimas/metabolismo , Parto/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Prostaglandina/deficiência , Animais , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Endométrio/enzimologia , Estradiol/farmacologia , Feminino , Isoenzimas/genética , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miométrio/enzimologia , Ovariectomia , Parto/efeitos dos fármacos , Parto/genética , Gravidez , Progesterona/sangue , Progesterona/farmacologia , Prostaglandina-Endoperóxido Sintases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Prostaglandina/genética
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