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1.
Int J Mol Sci ; 23(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35955556

RESUMO

In the last years, radiofrequency (RF) has demonstrated that it can reduce DNA damage induced by a subsequent treatment with chemical or physical agents in different cell types, resembling the adaptive response, a phenomenon well documented in radiobiology. Such an effect has also been reported by other authors both in vitro and in vivo, and plausible hypotheses have been formulated, spanning from the perturbation of the cell redox status, to DNA repair mechanisms, and stress response machinery, as possible cellular mechanisms activated by RF pre-exposure. These mechanisms may underpin the observed phenomenon, and require deeper investigations. The present study aimed to determine whether autophagy contributes to RF-induced adaptive response. To this purpose, SH-SY5Y human neuroblastoma cells were exposed for 20 h to 1950 MHz, UMTS signal, and then treated with menadione. The results obtained indicated a reduction in menadione-induced DNA damage, assessed by applying the comet assay. Such a reduction was negated when autophagy was inhibited by bafilomycin A1 and E64d. Moreover, CRISPR SH-SY5Y cell lines defective for ATG7 or ATG5 genes did not show an adaptive response. These findings suggest the involvement of autophagy in the RF-induced adaptive response in human neuroblastoma cells; although, further investigation is required to extend such observation at the molecular level.


Assuntos
Neuroblastoma , Vitamina K 3 , Autofagia , Linhagem Celular Tumoral , Ensaio Cometa , Humanos , Neuroblastoma/metabolismo , Ondas de Rádio
2.
Int J Mol Sci ; 23(2)2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35054844

RESUMO

It remains controversial whether exposure to environmental radiofrequency signals (RF) impacts cell status or response to cellular stress such as apoptosis or autophagy. We used two label-free techniques, cellular impedancemetry and Digital Holographic Microscopy (DHM), to assess the overall cellular response during RF exposure alone, or during co-exposure to RF and chemical treatments known to induce either apoptosis or autophagy. Two human cell lines (SH-SY5Y and HCT116) and two cultures of primary rat cortex cells (astrocytes and co-culture of neurons and glial cells) were exposed to RF using an 1800 MHz carrier wave modulated with various environmental signals (GSM: Global System for Mobile Communications, 2G signal), UMTS (Universal Mobile Telecommunications System, 3G signal), LTE (Long-Term Evolution, 4G signal, and Wi-Fi) or unmodulated RF (continuous wave, CW). The specific absorption rates (S.A.R.) used were 1.5 and 6 W/kg during DHM experiments and ranged from 5 to 24 W/kg during the recording of cellular impedance. Cells were continuously exposed for three to five consecutive days while the temporal phenotypic signature of cells behavior was recorded at constant temperature. Statistical analysis of the results does not indicate that RF-EMF exposure impacted the global behavior of healthy, apoptotic, or autophagic cells, even at S.A.R. levels higher than the guidelines, provided that the temperature was kept constant.


Assuntos
Apoptose , Autofagia , Ondas de Rádio , Coloração e Rotulagem , Trióxido de Arsênio/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Meios de Cultura Livres de Soro , Impedância Elétrica , Holografia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fatores de Tempo
3.
Methods ; 200: 3-14, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34843979

RESUMO

Our current knowledge on protein deamidation results from a journey that started almost 100 years ago, when a handful of researchers first described the non-enzymatic "desamidation" of glutamine, and the effect of different anions on the catalytic rate of the reaction. Since then, the field has tremendously expended and now finds outreach in very diverse areas. In light of all the recent articles published in these areas, it seemed timely to propose an integrated review on the subject, including a short historical overview of the landmark discoveries in the field, highlighting the current global positioning of protein deamidation in biology and non-biology fields, and concluding with a workflow for those asking if a protein can deamidate, and identify the residues involved. This review is essentially intended to provide newcomers in the field with an overview of how deamidation has penetrated our society and what tools are currently at hand to identify and quantify protein deamidation.


Assuntos
Glutamina , Proteínas , Amidas/química , Glutamina/química , Glutamina/metabolismo , Fluxo de Trabalho
4.
Int J Mol Sci ; 20(22)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717257

RESUMO

Bcl-xL is an oncogene of which the survival functions are finely tuned by post-translational modifications (PTM). Within the Bcl-2 family of proteins, Bcl-xL shows unique eligibility to deamidation, a time-related spontaneous reaction. Deamidation is still a largely overlooked PTM due to a lack of easy techniques to monitor Asn→Asp/IsoAsp conversions or Glu→Gln conversions. Being able to detect PTMs is essential to achieve a comprehensive description of all the regulatory mechanisms and functions a protein can carry out. Here, we report a gel composition improving the electrophoretic separation of deamidated forms of Bcl-xL generated either by mutagenesis or by alkaline treatment. Importantly, this new gel formulation proved efficient to provide the long-sought evidence that even doubly-deamidated Bcl-xL remains eligible for regulation by phosphorylation.


Assuntos
Eletroforese/métodos , Processamento de Proteína Pós-Traducional , Proteína bcl-X/metabolismo , Células HCT116 , Humanos , Proteínas Mutantes/isolamento & purificação , Mutação/genética , Fosforilação
5.
Cancer Med ; 8(11): 4976-4985, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31287239

RESUMO

BACKGROUND: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. METHODS: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. RESULTS: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates. CONCLUSION: These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse.


Assuntos
Variação Genética , Genótipo , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Receptores KIR/genética , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores , Feminino , Haplótipos , Humanos , Mesilato de Imatinib/uso terapêutico , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Receptores KIR/metabolismo , Receptores KIR2DL5/genética , Indução de Remissão , Resultado do Tratamento , Suspensão de Tratamento
6.
Haematologica ; 104(10): 2017-2027, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30923103

RESUMO

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.


Assuntos
Benzotiazóis/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Fator de Transcrição STAT5/metabolismo , Microambiente Tumoral , Tirosina Quinase 3 Semelhante a fms/metabolismo , Hipóxia Celular , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Fator de Transcrição STAT5/genética , Regulação para Cima/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/genética , Receptor Tirosina Quinase Axl
7.
Exp Dermatol ; 26(10): 963-966, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28267869

RESUMO

Development of new immunotherapeutic strategies relies on the ability to activate the right cells at the right place and at the right moment and on the capacity of these cells to home to the right organ(s). Skin delivery has shown high potency for immunotherapeutic administration. However, an adequate in vivo model of human skin immunity is still a critical bottleneck. We demonstrated here that the skin of human immune system mice is colonized by human hematopoietic cells, mainly human T cells and that complementation with human antigen-presenting cells at the vaccination site allowed the induction of an immune response.


Assuntos
Antígeno HLA-A2/genética , Células-Tronco Hematopoéticas/metabolismo , Modelos Animais , Pele/citologia , Pele/imunologia , Animais , Antígenos CD34/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Antígeno HLA-A2/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Transgênicos , Transplante Heterólogo
8.
Exp Dermatol ; 23(11): 850-2, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25091815

RESUMO

We developed a NOD-Scid IL2rγ(null) mouse model transplanted with human skin that brings fundamental insight on in vivo cellular mechanisms of intradermal immunization and antigen presentation by dermal dendritic and epidermal Langerhans cells for skin T-cell immunity. Indeed, T-cell immunity is a crucial checkpoint for the induction of in vivo rapid control of skin infection. With the long-term preservation of a complete human skin immune system, this model offers the unique opportunity not only to better understand mechanisms of skin immune response but also to test new compounds and devices for cutaneous routes of vaccination, as well as new therapeutics approach for skin diseases, allergies or infections.


Assuntos
Transplante de Pele/métodos , Pele/imunologia , Animais , Humanos , Sistema Imunitário , Subunidade gama Comum de Receptores de Interleucina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Transplante Heterólogo
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