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3.
Leuk Lymphoma ; 61(10): 2409-2418, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32306816

RESUMO

Ibrutinib is a BTK/ITK inhibitor with efficacy for the treatment of various lymphoid cancers, including CLL. Considering that innate and adaptative immune defects are a dominant feature of CLL patients, we evaluated whether in vitro ibrutinib affects the survival and function of neutrophils and γδ T cells, key players of the early immune response against microbes. Neutrophils and γδ T cells were obtained from peripheral blood of healthy donors and CLL patients. We found that ibrutinib reduces the production of reactive oxygen species (ROS) and bacteria killing capacity, and slightly impairs neutrophil extracellular traps (NETs) production without affecting bacteria-uptake and CD62L-downregulation induced by fMLP or aggregated IgG. In addition, ibrutinib reduces γδ T cell activation and CD107a degranulation induced by phosphoantigens or anti-CD3. These findings are in agreement with previous data suggesting that ibrutinib interferes with the protective immune response to pathogens, particularly Mycobacteria and Aspergillus.


Assuntos
Neutrófilos , Linfócitos T , Adenina/análogos & derivados , Humanos , Ativação Linfocitária , Piperidinas , Espécies Reativas de Oxigênio
4.
Arch Biochem Biophys ; 685: 108347, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32194045

RESUMO

The reason that determines the pathological deposition of human apolipoprotein A-I variants inducing organ failure has been under research since the early description of natural mutations in patients. To shed light into the events associated with protein aggregation, we studied the structural perturbations that may occur in the natural variant that shows a substitution of a Leucine by an Arginine in position 60 (L60R). Circular dichroism, intrinsic fluorescence measurements, and proteolysis analysis indicated that L60R was more unstable, more sensitive to cleavage and the N-terminus was more disorganized than the protein with the native sequence (Wt). A higher tendency to aggregate was also detected when L60R was incubated at physiological pH. In addition, the small structural rearrangement observed for the freshly folded variant led to the release of tumor necrosis factor-α and interleukin-1ß from a model of macrophages. However, the mutant preserved both its dimeric conformation and its lipid-binding capacity. Our results strongly suggest that the chronic disease may be a consequence of the native conformation loss which elicits the release of protein conformations that could be either cytotoxic or precursors of amyloid conformations.


Assuntos
Proteínas Amiloidogênicas/metabolismo , Apolipoproteína A-I/metabolismo , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/genética , Amiloidose/etiologia , Amiloidose/genética , Apolipoproteína A-I/química , Apolipoproteína A-I/genética , Humanos , Mutação Puntual , Multimerização Proteica , Estabilidade Proteica , Estrutura Secundária de Proteína
6.
Sci Rep ; 7(1): 15714, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29146966

RESUMO

The proliferation and survival of malignant B cells in chronic lymphocytic leukemia (CLL) depend on signals from the microenvironment in lymphoid tissues. Among a plethora of soluble factors, IL-8 has been considered one of the most relevant to support CLL B cell progression in an autocrine fashion, even though the expression of IL-8 receptors, CXCR1 and CXCR2, on leukemic B cells has not been reported. Here we show that circulating CLL B cells neither express CXCR1 or CXCR2 nor they respond to exogenous IL-8 when cultured in vitro alone or in the presence of monocytes/nurse-like cells. By intracellular staining and ELISA we show that highly purified CLL B cells do not produce IL-8 spontaneously or upon activation through the B cell receptor. By contrast, we found that a minor proportion (<0.5%) of contaminating monocytes in enriched suspensions of leukemic cells might be the actual source of IL-8 due to their strong capacity to release this cytokine. Altogether our results indicate that CLL B cells are not able to secrete or respond to IL-8 and highlight the importance of methodological details in in vitro experiments.


Assuntos
Interleucina-8/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Idoso , Idoso de 80 Anos ou mais , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Receptores de Interleucina-8/metabolismo
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