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1.
Int J Cardiol ; 299: 81-86, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31279662

RESUMO

BACKGROUND: Optical coherence tomography (OCT) was used to assess serial changes in severe acute stent malapposition (ASM) after drug-eluting stent (DES) implantation. METHODS: The maximal depth and axial lengths of ASM after DES implantation were serially quantified at percutaneous coronary intervention (PCI), and at 3 and 12-month follow-up, for 100 lesions in 96 patients. Severe ASM was defined as a maximal malapposed depth ≥400 µm or maximal malapposed axial length ≥1 mm. RESULTS: Of the 100 lesions, 23 lesions (23%) had a severe ASM depth at PCI. At 3 months, the maximal depth decreased to <400 µm in 12 of 23 lesions (52%). At 12 months, the maximal depth further decreased to <400 µm in 8 of the remaining 11 lesions (73%). Similarly, of 53 lesions (53%) with a severe ASM length at PCI, the maximal length decreased to 0 mm in 26 (49%) but remained severe in 17 lesions (32%) at 3 months. At 12 months, 9 of the 17 remaining lesions (53%) further decreased to 0 mm. The cut-off values for the maximal malapposed depth and length to predict the absence of stent malapposition at 12 months were 565 µm at PCI and 165 µm at 3 months, and were 2.7 mm at PCI and 0.1 mm at 3 months, respectively. CONCLUSION: Half of the severe ASM cases resolved within 3 months, and another half resolved during 3-12 months of follow-up. Our findings provide a better understanding of the time-dependent natural course of severe ASM using OCT.


Assuntos
Doença da Artéria Coronariana/cirurgia , Vasos Coronários/diagnóstico por imagem , Stents Farmacológicos/efeitos adversos , Everolimo/uso terapêutico , Intervenção Coronária Percutânea/instrumentação , Ajuste de Prótese/efeitos adversos , Sirolimo/uso terapêutico , Tomografia de Coerência Óptica/métodos , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Análise de Falha de Equipamento/métodos , Análise de Falha de Equipamento/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Fatores de Tempo
2.
Mol Cell ; 66(1): 129-140.e7, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28388438

RESUMO

ATAXIN-2 (ATX2) has been implicated in human neurodegenerative diseases, yet it remains elusive how ATX2 assembles specific protein complexes to execute its physiological roles. Here we employ the posttranscriptional co-activator function of Drosophila ATX2 to demonstrate that LSM12 and ME31B/DDX6 are two ATX2-associating factors crucial for sustaining circadian rhythms. LSM12 acts as a molecular adaptor for the recruitment of TWENTY-FOUR (TYF) to ATX2. The ATX2-LSM12-TYF complex thereby stimulates TYF-dependent translation of the rate-limiting clock gene period (per) to maintain 24 hr periodicity in circadian behaviors. In contrast, ATX2 contributes to NOT1-mediated gene silencing and associates with NOT1 in a ME31B/DDX6-dependent manner. The ME31B/DDX6-NOT1 complex does not affect PER translation but supports high-amplitude behavioral rhythms along with ATX2, indicating a PER-independent clock function of ATX2. Taken together, these data suggest that the ATX2 complex may switch distinct modes of posttranscriptional regulation through its associating factors to control circadian clocks and ATX2-related physiology.


Assuntos
Ataxina-2/metabolismo , Comportamento Animal , Relógios Circadianos , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Ritmo Circadiano , RNA Helicases DEAD-box/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Locomoção , Neurônios/enzimologia , Interferência de RNA , Animais , Animais Geneticamente Modificados , Ataxina-2/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , RNA Helicases DEAD-box/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Genótipo , Complexos Multiproteicos , Mutação , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fenótipo , Proteínas de Ligação a RNA , Transdução de Sinais , Fatores de Tempo , Transfecção
3.
J Immunol ; 196(10): 4378-89, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27067007

RESUMO

IL-21, a pleiotropic cytokine strongly linked with autoimmunity and inflammation, regulates diverse immune responses. IL-21 can be potently induced in CD4(+) T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il21 gene at the chromatin level. In this study, we demonstrated that a conserved noncoding sequence located 49 kb upstream of the Il21 gene contains an enhancer element that can upregulate Il21 gene expression in a STAT3- and NFAT-dependent manner. Additionally, we identified enhancer-blocking insulator elements in the Il21 locus, which constitutively bind CTCF and cohesin. In naive CD4(+) T cells, these upstream and downstream CTCF binding sites interact with each other to make a DNA loop; however, the Il21 promoter does not interact with any cis-elements in the Il21 locus. In contrast, stimulation of CD4(+) T cells with IL-6 leads to recruitment of STAT3 to the promoter and novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity. The long-range interaction between the promoter and distal enhancer region was dependent on IL-6/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of the Il21 gene.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Cromatina/genética , Proteínas de Ligação a DNA/genética , Interleucinas/genética , Animais , Sequência de Bases , Fator de Ligação a CCCTC , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Sequência Conservada , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Humanos , Interleucina-6/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Coesinas
4.
J Biosci Bioeng ; 121(3): 317-24, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26454770

RESUMO

A human hybrid cell line, F2N78, was developed by somatic fusion of HEK293 and Namalwa cells for the production recombinant biopharmaceutical proteins. In this study, we performed perfusion culture to verify its potential in culture process used for human cell expression platform. Cell viability could be maintained over 90% and high viable cell density was obtained at higher than 1.0 × 10(7) cells/mL by bleeding process in perfusion culture. The cells were adapted well in both culture modes, but there were apparent differences in protein quality. Compared to fed-batch culture, degalactosylated forms such as G0F and G0 as well as Man5 showed no significant increases in perfusion culture. In terms of charge variants, acidic peaks increased, whereas main peaks constantly decreased according to the length of culture period in both methods.


Assuntos
Anticorpos/metabolismo , Técnicas de Cultura Celular por Lotes , Técnicas de Cultura de Células/métodos , Células Híbridas/citologia , Células Híbridas/metabolismo , Proteínas Recombinantes/biossíntese , Contagem de Células , Fusão Celular , Linhagem Celular , Sobrevivência Celular , Células HEK293 , Humanos , Perfusão
5.
Mol Cells ; 36(4): 368-75, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23996530

RESUMO

ABCG2 is a member of the ATP binding cassette (ABC) transmembrane proteins that plays an important role in stem cell biology and drug resistance of cancer cells. In this study, we investigated how expression of human ABCG2 gene is regulated in lung cancer A549 cells. Binding of Sp1 and Sp3 transcription factors to the ABCG2 promoter in vitro and in vivo was elucidated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. The ABCG2 promoter activity was impaired when Sp1 sites were mutated but was enhanced by overexpression of Sp1 or Sp3 proteins. Knockdown of Sp1 or Sp3 expression by short interfering RNA significantly decreased the expression of ABCG2 mRNA and protein, resulting in attenuated formation of the side population in A549 cells. In addition, Sp1 inhibition in vivo by mithramycin A suppressed the percentage of the side population fraction and sphere forming activities of A549 cells. Moreover, inhibiting Sp1- or Sp3-dependent ABCG2 expression caused chemosensitization to the anticancer drug cisplatin. Collectively, our results demonstrate that Sp1 and Sp3 transcription factors are the primary determinants for activating basal transcription of the ABCG2 gene and play an important role in maintaining the side population phenotype of lung cancer cells.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp3/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Sítios de Ligação , Linhagem Celular , Cisplatino/farmacologia , Ensaio de Desvio de Mobilidade Eletroforética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Plicamicina/análogos & derivados , Plicamicina/farmacologia , Regiões Promotoras Genéticas , Células da Side Population/fisiologia , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp3/genética
6.
Korean J Parasitol ; 50(2): 173-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22711932

RESUMO

Opisthorchis viverrini infection was found to be highly prevalent in 3 riverside villages (Ang Svay Chek A, B, and C) of the Prey Kabas District, Takeo Province. This area is located in the southern part of Cambodia, where the recovery of adult O. viverrini worms was recently reported. From May 2006 until May 2010, fecal examinations were performed on a total of 1,799 villagers using the Kato-Katz thick smear technique. In the 3 villages, the overall positive rate for helminth eggs ranged from 51.7 to 59.0% (av. 57.4%), and the percentage positive for O. viverrini was 46.4-50.6% (47.5%). Other helminths detected included hookworms (13.2%), echinostomes (2.9%), Trichuris trichiura (1.3%), Ascaris lumbricoides (0.6%), and Taenia spp. (0.06%). The prevalence of O. viverrini eggs appeared to reflect a lower infection in younger individuals (<20 years) than in the adult population (>20 years). Men (50.4%) revealed a significantly higher (P=0.02) prevalence than women (44.3%). The Ang Svay Chek villages of the Prey Kabas District, Takeo Province, Cambodia have been confirmed to be a highly endemic area for human O. viverrini infection.


Assuntos
Opistorquíase/epidemiologia , Opisthorchis/isolamento & purificação , Adolescente , Adulto , Idoso de 80 Anos ou mais , Animais , Camboja/epidemiologia , Criança , Pré-Escolar , Coinfecção/epidemiologia , Fezes/parasitologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , População Rural , Adulto Jovem
7.
Nanoscale Res Lett ; 7: 74, 2012 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-22230259

RESUMO

We have used hafnium metallocene compounds as cathode interfacial layers for organic solar cells [OSCs]. A metallocene compound consists of a transition metal and two cyclopentadienyl ligands coordinated in a sandwich structure. For the fabrication of the OSCs, poly[3,4-ethylenedioxythiophene]:poly(styrene sulfonate), poly(3-hexylthiophene-2,5-diyl) + 66-phenyl C61 butyric acid methyl ester, bis-(ethylcyclopentadienyl)hafnium(IV) dichloride, and aluminum were deposited as a hole transport layer, an active layer, a cathode interfacial layer, and a cathode, respectively. The hafnium metallocene compound cathode interfacial layer improved the performance of OSCs compared to that of OSCs without the interfacial layer. The current density-voltage characteristics of OSCs with an interfacial layer thickness of 0.7 nm and of those without an interfacial layer showed power conversion efficiency [PCE] values of 2.96% and 2.34%, respectively, under an illumination condition of 100 mW/cm2 (AM 1.5). It is thought that a cathode interfacial layer of an appropriate thickness enhances the electron transfer between the active layer and the cathode, and thus increases the PCE of the OSCs.

8.
J Leukoc Biol ; 91(2): 245-57, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22045870

RESUMO

IL-31, a newly identified member of the IL-6 cytokine family, is involved in many pathological conditions, including atopic dermatitis and pruritis. In this study, we investigated how expression of IL-31 is regulated in T cells and mast cells. We observed that expression of IL-31 required a calcium signal and was dependent on the calcineurin-NFAT signaling pathway. Moreover, we found that IL-31 promoter contains a positive regulatory region that mediates calcium- and IL-4-dependent induction of the IL-31 gene and demonstrated that a change into an open chromatin conformation occurs in this region after stimulation with calcium and IL-4. Whereas IL-4 responsiveness required STAT6 binding sites, calcium responsiveness of IL-31 promoter required NFAT binding sites that bind NFATc1 and NFATc2 in vitro and in vivo. The induction of IL-31 promoter activity was impaired when these sites were mutated but was enhanced by CA-NFATc1 or STAT6 proteins and further increased synergistically by combinations of both proteins. Furthermore, the importance of STAT6 proteins was indicated by impaired, IL-4-mediated induction of IL-31 in STAT6-diminished Jurkat cells. Thus, our data demonstrate that calcium and IL-4 signals are required to mediate induction of IL-31 in Th2 cells and mast cells and that this induction appears to result from specific binding of NFAT and STAT6 proteins.


Assuntos
Interleucinas/genética , Fatores de Transcrição NFATC/fisiologia , Fator de Transcrição STAT6/fisiologia , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Cálcio/fisiologia , Dinitrofenóis/farmacologia , Células HEK293/efeitos dos fármacos , Células HEK293/metabolismo , Humanos , Interleucina-4/farmacologia , Interleucinas/biossíntese , Ionomicina/farmacologia , Células Jurkat/efeitos dos fármacos , Células Jurkat/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Ratos , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Sequências Reguladoras de Ácido Nucleico , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Albumina Sérica/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Transcrição Gênica
9.
Biochem Biophys Res Commun ; 409(2): 222-8, 2011 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-21554857

RESUMO

Transforming growth factor beta 1-induced (TGFBI) protein is an extracellular matrix (ECM) protein that is associated with other ECM proteins and functions as a ligand for various types of integrins. In this study, we investigated how human TGFBI expression is regulated in lung and breast cancer cells. We observed that the TGFBI promoter in A549 and MBA-MD-231 cells, which constitutively express TGFBI, existed in an open chromatin conformation associated with transcriptionally permissive histone modifications. Moreover, we found that TGFBI expression required Sp1 transcription elements that can bind transcription factors Sp1 and Sp3 in vitro. Occupancy of the TGFBI promoter by Sp1 and Sp3 in vivo was only observed in TGFBI-expressing cells, indicating that open chromatin conformation might facilitate the binding of Sp1 and Sp3 to the TGFBI promoter region. TGFBI promoter activity was impaired when Sp1 elements were mutated, but was increased when Sp1 or Sp3 factors was overexpressed. Furthermore, Sp1 inhibition in vivo by mithramycin A, as well as knockdown of Sp1 and/or Sp3 expression by short interfering RNA, significantly reduced TGFBI mRNA and protein levels. Thus, our data demonstrated that the expression of TGFBI is well correlated with chromatin conformation at the TGFBI promoter, and that factors Sp1 and Sp3 are the primary determinants for the control of constitutive expression of TGFBI gene.


Assuntos
Cromatina/metabolismo , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp3/metabolismo , Fator de Crescimento Transformador beta/genética , Linhagem Celular , Linhagem Celular Tumoral , Cromatina/química , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Humanos , Regiões Promotoras Genéticas , Interferência de RNA , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp3/genética
10.
Mol Endocrinol ; 23(7): 966-74, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19342446

RESUMO

Activating signal cointegrator-2 (ASC-2) functions as a transcriptional coactivator of many nuclear receptors and also plays important roles in the physiology of the liver and pancreas by interacting with liver X receptors (LXRs), which antagonize the development of atherosclerosis. This study was undertaken to establish the specific function of ASC-2 in macrophages and atherogenesis. Intriguingly, ASC-2 was more highly expressed in macrophages than in the liver and pancreas. To inhibit LXR-specific activity of ASC-2, we used DN2, which contains the C-terminal LXXLL motif of ASC-2 and thereby acts as an LXR-specific, dominant-negative mutant of ASC-2. In DN2-overexpressing transgenic macrophages, cellular cholesterol content was higher and cholesterol efflux lower than in control macrophages. DN2 reduced LXR ligand-dependent increases in the levels of ABCA1, ABCG1, and apolipoprotein E (apoE) transcripts as well as the activity of luciferase reporters driven by the LXR response elements (LXREs) of ABCA1, ABCG1, and apoE genes. These inhibitory effects of DN2 were reversed by overexpression of ASC-2. Chromatin immunoprecipitation analysis demonstrated that ASC-2 was recruited to the LXREs of the ABCA1, ABCG1, and apoE genes in a ligand-dependent manner and that DN2 interfered with the recruitment of ASC-2 to these LXREs. Furthermore, low-density lipoprotein receptor (LDLR)-null mice receiving bone marrow transplantation from DN2-transgenic mice showed accelerated atherogenesis when administered a high-fat diet. Taken together, these results indicate that suppression of the LXR-specific activity of ASC-2 results in both defective cholesterol metabolism in macrophages and accelerated atherogenesis, suggesting that ASC-2 is an antiatherogenic coactivator of LXRs in macrophages.


Assuntos
Aterosclerose/genética , Proteínas de Ligação a DNA/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Macrófagos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transativadores/fisiologia , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apolipoproteínas E/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipoproteínas/genética , Receptores X do Fígado , Masculino , Camundongos , Camundongos Knockout , Proteínas Mutantes/metabolismo , Proteínas Mutantes/fisiologia , Coativadores de Receptor Nuclear , Receptores Nucleares Órfãos , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/fisiologia , Transativadores/genética , Transativadores/metabolismo , Ativação Transcricional/genética , Ativação Transcricional/fisiologia
11.
J Immunol ; 181(10): 7380-9, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18981161

RESUMO

In the DBA/2 --> unirradiated (C57BL/6 x DBA/2)F(1) model of chronic graft-vs-host disease (cGVHD), donor CD4(+) T cells play a critical role in breaking host B cell tolerance, while donor CD8(+) T cells are rapidly removed and the remaining cells fall into anergy. Previously we have demonstrated that in vivo ligation of GITR (glucocorticoid-induced TNF receptor-related gene) can activate donor CD8(+) T cells, subsequently converting the disease pattern from cGVHD to an acute form. In this study, we investigated the effect of an agonistic mAb against CD40 on cGVHD. Treatment of anti-CD40 mAb inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis. The inhibition of cGVHD occurred because anti-CD40 mAb prevented donor CD8(+) T cell anergy such that subsequently activated donor CD8(+) T cells deleted host CD4(+) T cells and host B cells involved in autoantibody production. Additionally, functionally activated donor CD8(+) T cells induced full engraftment of donor hematopoietic cells and exhibited an increased graft-vs-leukemia effect. However, induction of acute GVHD by donor CD8(+) T cells seemed to be not so apparent. Further CTL analysis indicated that there were lower levels of donor CTL activity against host cells in mice that received anti-CD40 mAb, compared with mice that received anti-GITR mAb. Taken together, our results suggest that a different intensity of donor CTL activity is required for removal of host hematopoietic cells, including leukemia vs induction of acute GVHD.


Assuntos
Antígenos CD40/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Anergia Clonal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/imunologia , Autoantígenos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Citotoxicidade Imunológica , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Efeito Enxerto vs Leucemia/imunologia , Imuno-Histoquímica , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
J Nanosci Nanotechnol ; 8(10): 5279-83, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19198438

RESUMO

The efficiency of polymer solar cells was improved by patterning indium tin oxide (ITO) electrode layer in this work. Light absorbance was enhanced with ITO layer patterning resulting in the improvement of power conversion efficiency of polymer solar cells. The line-and-space grooved patterns of polystyrene layer are formed on the top of 100 nm thick indium tin oxide layer by capillary force lithography process. The surface patterning of the ITO layer were completed with O2 and Ar plasma etching with various step heights of 22 nm to 64 nm. The active layer was fabricated with one-to-one ratio of P3HT (poly-3-hexylthiophene) and PCBM ([6,6]-phenyl C61-butyric acid methyl ester) conjugated polymers on the top of the patterned ITO layer. Efficiency of the polymer solar cell was improved from 0.96% to 1.35% with this approach. We attribute the efficiency improvement to periodic grooved patterns of electrode. The periodic grooved patterns are believed to enhance light trapping resulting in the increase of diffraction and also to increase contact area of the electron-collecting electrode leading to increase of short circuit current.

13.
Blood ; 110(2): 776-82, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17363737

RESUMO

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2-->Balb/c (H-2(d)) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4(+) T-cell cytokines and increased apoptosis of donor CD4(+) T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4(+) T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.


Assuntos
Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/terapia , Imunoterapia , Transplante de Células-Tronco/efeitos adversos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Transplante Homólogo
14.
Mol Cell Biol ; 23(10): 3583-92, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12724417

RESUMO

Activating signal cointegrator 2 (ASC-2), a cancer-amplified transcriptional coactivator of nuclear receptors and many other transcription factors, contains two LXXLL-type nuclear receptor interaction domains. Interestingly, the second LXXLL motif is highly specific to the liver X receptors (LXRs). In cotransfection, DN2, an ASC-2 fragment encompassing this motif, exerts a potent dominant-negative effect on transactivation by LXRs, which is rescued by ectopic coexpression of the full-length ASC-2 but not by other LXXLL-type coactivators, such as SRC-1 and TRAP220. In contrast, DN2/m, in which the LXXLL motif is mutated to LXXAA to abolish the interactions with LXRs, is without any effect. Accordingly, expression of DN2, but not DN2/m, in transgenic mice results in phenotypes that are highly homologous to those previously observed with LXRalpha(-/-) mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXRalpha in the liver upon being fed a high-cholesterol diet. These results identify ASC-2 as a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Metabolismo dos Lipídeos , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Colesterol/metabolismo , Cromatina/metabolismo , DNA Complementar/metabolismo , Proteínas de Ligação a DNA , Genes Dominantes , Glutationa Transferase/metabolismo , Humanos , Imuno-Histoquímica , Receptores X do Fígado , Luciferases/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Coativadores de Receptor Nuclear , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Nucleares Órfãos , Fenótipo , Testes de Precipitina , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Transfecção , Técnicas do Sistema de Duplo-Híbrido
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