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1.
Int Immunopharmacol ; 98: 107904, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34214886

RESUMO

Dysregulation of phosphoinositide 3-kinase δ (PI3Kδ) signaling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases. Parsaclisib (INCB050465) represents a potent and selective PI3Kδ inhibitor, which is being clinically investigated for treatment of autoimmune hemolytic anemia and hematological malignancies. We characterized the potential of parsaclisib to ameliorate autoimmune mechanisms implicated in the pathophysiology of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Spontaneous mouse models of SLE and SS were utilized to elucidate the efficacy of orally administered parsaclisib on autoreactive B-cell-mediated antibody-driven disease. Parsaclisib significantly reduced disease symptoms and pathology in three distinct mouse models of SLE. Parsaclisib effectively preserved renal function as measured by glomerular filtration rate, abrogated histopathological evidence of nephritis, modulated discrete immune cell subsets, and decreased anti-dsDNA antibody level. Furthermore, parsaclisib demonstrated efficacy in two spontaneous mouse models of SS. Oral parsaclisib treatment ameliorated the severity of salivary gland inflammation and reduced circulating levels of autoantibodies. Parsaclisib mediated improvement of salivary gland inflammation coincided with reduced B-cell activating cytokine (BAFF) in saliva. Transcriptomic analysis of kidney and salivary gland tissues revealed a downregulation in inflammatory gene expression consistent with PI3Kδ pathway inhibition. Parsaclisib reduced autoreactive B-cells and autoantibody levels, and significantly improved nephritis and salivary gland inflammation. These data provide the scientific rationale for PI3Kδ inhibition as a therapeutic strategy for treatment of B-cell-mediated antibody-driven autoimmune diseases.


Assuntos
Autoanticorpos/sangue , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Síndrome de Sjogren/tratamento farmacológico , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirrolidinas/uso terapêutico , Síndrome de Sjogren/sangue , Síndrome de Sjogren/imunologia
2.
Front Immunol ; 11: 620098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33658996

RESUMO

The goal of this study was to elucidate the anti-pruritic and anti-inflammatory efficacy of ruxolitinib cream in experimentally-induced dermatitis. Atopic dermatitis (AD), the most common chronic relapsing inflammatory skin disease, significantly impairs patients' quality of life, with pruritus being a common complaint. The sensation of itch results from the interplay between epidermal barrier dysfunction, upregulated immune signaling and the activation of the central nervous system. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in pro-inflammatory cytokine signaling in AD. Ruxolitinib cream is a potent and selective JAK1/2 inhibitor currently undergoing clinical evaluation in adults with mild-to-moderate AD (NCT03745638, NCT03920852 and NCT03745651). The efficacy of ruxolitinib cream was tested in murine models of acute and chronic dermatitis and was also characterized in an ex vivo human skin dermatitis model. Ruxolitinib cream was highly effective at ameliorating disease symptoms in multiple murine dermatitis models through downregulation of T helper (Th)2-driven inflammation, resulting in reduced skin thickening and decreased itch. Pathway analysis of mouse ear tissue and human skin explants underscored the role for ruxolitinib in ameliorating inflammation and reducing itch via modulation of the JAK-STAT pathway. Together, the data offer a strong rationale for the use of ruxolitinib cream as a potent therapeutic agent for the clinical management of atopic dermatitis.


Assuntos
Dermatite/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Prurido/tratamento farmacológico , Pirazóis/uso terapêutico , Administração Cutânea , Animais , Betametasona/administração & dosagem , Betametasona/uso terapêutico , Clobetasol/administração & dosagem , Clobetasol/uso terapêutico , Citocinas/biossíntese , Citocinas/genética , Citocinas/toxicidade , Modelos Animais de Doenças , Toxidermias/tratamento farmacológico , Toxidermias/imunologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Fluoresceína-5-Isotiocianato/toxicidade , Asseio Animal/efeitos dos fármacos , Humanos , Técnicas In Vitro , Interleucina-33/genética , Inibidores de Janus Quinases/administração & dosagem , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Nitrilas , Pomadas , Técnicas de Cultura de Órgãos , Pirazóis/administração & dosagem , Pirimidinas , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma , Linfopoietina do Estroma do Timo
3.
Curr Protoc Pharmacol ; 86(1): e65, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539922

RESUMO

The non-obese diabetic (NOD) mouse model is the most widely described and validated method for investigating human primary Sjögren's syndrome (SS) and represents a useful model for translational studies. However, the systemic disease manifestation in NOD mice is sensitive to the housing environment, as stress modulates the immune system, so it is essential to confirm that readouts are robust, reproducible, and sensitive to known clinical treatments. This protocol describes the establishment of the spontaneous NOD model of SS and underscores the necessity of model validation to ensure that the housing environment is compatible. © 2019 by John Wiley & Sons, Inc.


Assuntos
Modelos Animais de Doenças , Síndrome de Sjogren , Animais , Feminino , Camundongos Endogâmicos NOD , Salivação
4.
Artigo em Inglês | MEDLINE | ID: mdl-27995094

RESUMO

This review summarizes the current status and recent advances in our understanding of the role that the cytolethal distending toxin (Cdt) plays as a virulence factor in promoting disease by toxin-producing pathogens. A major focus of this review is on the relationship between structure and function of the individual subunits that comprise the AB2 Cdt holotoxin. In particular, we concentrate on the molecular mechanisms that characterize this toxin and which account for the ability of Cdt to intoxicate multiple cell types by utilizing a ubiquitous binding partner on the cell membrane. Furthermore, we propose a paradigm shift for the molecular mode of action by which the active Cdt subunit, CdtB, is able to block a key signaling cascade and thereby lead to outcomes based upon programming and the role of the phosphatidylinositol 3-kinase (PI-3K) in a variety of cells. Based upon the collective Cdt literature, we now propose that Cdt is a unique and potent virulence factor capable of acting as a tri-perditious toxin that impairs host defenses by: (1) disrupting epithelial barriers; (2) suppressing acquired immunity; (3) promoting pro-inflammatory responses. Thus, Cdt plays a key role in facilitating the early stages of infection and the later stages of disease progression by contributing to persistence and impairing host elimination.


Assuntos
Infecções Bacterianas/patologia , Toxinas Bacterianas/metabolismo , Fatores de Virulência/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Ligação Proteica , Subunidades Proteicas/metabolismo , Transdução de Sinais
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