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1.
J Immunol ; 198(7): 2735-2746, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28242647

RESUMO

Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases.


Assuntos
Diferenciação Celular/imunologia , Colite/imunologia , Ativação Linfocitária/imunologia , Fosforilação Oxidativa , Células Th17/imunologia , Animais , Separação Celular , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
2.
J Med Chem ; 64(18): 13410-13428, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34499493

RESUMO

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.


Assuntos
Antineoplásicos/uso terapêutico , Benzoxazinas/uso terapêutico , Neoplasias/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Propionatos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzoxazinas/síntese química , Benzoxazinas/farmacocinética , Feminino , Macaca fascicularis , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Propionatos/síntese química , Propionatos/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade
3.
J Invest Dermatol ; 138(2): 282-290, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28942363

RESUMO

It is generally recognized that only relatively small molecular weight (typically < ∼ 500 Da) drugs can effectively permeate through intact stratum corneum. Here, we challenge this orthodoxy using a 62-nucleotide (molecular weight = 20,395 Da) RNA-based aptamer, highly specific to the human IL-23 cytokine, with picomolar activity. Results demonstrate penetration of the aptamer into freshly excised human skin using two different fluorescent labels. A dual hybridization assay quantified aptamer from the epidermis and dermis, giving levels far exceeding the cellular half maximal inhibitory concentration values (>100,000-fold), and aptamer integrity was confirmed using an oligonucleotide precipitation assay. A T helper 17 response was stimulated in freshly excised human skin resulting in significantly upregulated IL-17f, and IL-22; topical application of the IL-23 aptamer decreased both IL-17f and IL-22 by approximately 45% but did not result in significant changes to IL-23 mRNA levels, confirming that the aptamer did not globally suppress mRNA levels. This study demonstrates that very-large-molecular-weight RNA aptamers can permeate across the intact human skin barrier to therapeutically relevant levels into both the epidermis and dermis and that the skin-penetrating aptamer retains its biologically active conformational structure capable of binding to endogenous IL-23.


Assuntos
Aptâmeros de Nucleotídeos/administração & dosagem , Derme/metabolismo , Epiderme/metabolismo , RNA/administração & dosagem , Absorção Cutânea , Administração Cutânea , Aptâmeros de Nucleotídeos/genética , Células Epidérmicas/metabolismo , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucinas/genética , Interleucinas/metabolismo , RNA/genética , Regulação para Cima , Interleucina 22
4.
Mol Cancer Ther ; 9(10): 2737-51, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20924124

RESUMO

We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients.


Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Animais , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Transplante Heterólogo
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