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1.
Curr Med Chem ; 28(20): 3964-3979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33109026

RESUMO

In December 2019, a novel respiratory coronavirus named SARS-CoV-2 appeared in China, causing the disease termed COVID-19 that has caused millions of infections worldwide. In this article, we have analyzed existing evidence on the immune response against SARS coronaviruses in order to understand the possible outcome of a vaccine for COVID-19. From our analysis, it becomes clear that there is a big difference in the immune response against SARS in children, young adults and the elderly, both at the innate and adaptive levels. Taking this information into account, we have studied the strategies that are being used for the development of COVID-19 vaccines. We discussed the perspectives for obtention and worldwide distribution of reliable vaccines using this perspective. The conclusion is that different vaccines may be protective for different age segments within the population, depending on the strategy used for their design. Therefore, it will become necessary for several vaccines to reach the finish line, not only to ensure availability, but also to guarantee an adequate immune response at the individual level.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Idoso , Criança , China , Humanos , Imunidade Inata , SARS-CoV-2
2.
Cancer Lett ; 375(1): 92-99, 2016 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-26944313

RESUMO

Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase, where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and its derivatives. NUMB is an evolutionary well-conserved protein initially described as a functional antagonist of NOTCH function. NUMB is an endocytic protein associated with receptor internalization, involved in multiple cellular functions. It has been reported that MSI2 protein, a NUMB inhibitor, is upregulated in CML blast crisis, whereas NUMB itself is downregulated. This suggest that NUMB plays a role in the malignant progression of CML. Here we have generated K562 cells (derived from CML in blast crisis) constitutively expressing a dominant negative form of NUMB (dnNUMB). We show that dnNUMB expression confers a high proliferative phenotype to the cells. Importantly, dnNUMB triggers a partial resistance to imatinib in these cells, antagonizing the apoptosis mediated by the drug. Interestingly, imatinib resistance is not linked to p53 status or NOTCH signaling, as K562 lack p53 and imatinib resistance is reproduced in the presence of NOTCH inhibitors. Taken together, our data support the hypothesis that NUMB activation could be a new therapeutic target in CML.


Assuntos
Antineoplásicos/farmacologia , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/metabolismo , Expressão Gênica , Genes Dominantes , Células HeLa , Humanos , Células K562 , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Transdução de Sinais
3.
Int Immunol ; 28(3): 127-37, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26507128

RESUMO

Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3ε that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3ε chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination.


Assuntos
Complexo CD3/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteólise , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células HEK293 , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas Oncogênicas/metabolismo , Ligação Proteica/genética , Transporte Proteico/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Deleção de Sequência/genética
4.
Blood ; 116(10): 1705-14, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-20530794

RESUMO

Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example. Here, we have explored the role of asymmetric division in thymocyte development, visualizing the differential segregation of Numb and pre-TCR in thymic precursors. Analysis of mice where Numb had been inhibited by expressing a dominant negative revealed enhanced pre-T-cell receptor (TCR) signaling and a smaller thymus. Conversely, Numb overexpression resulted in loss of asymmetric division and a larger thymus. The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected.


Assuntos
Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Timo/metabolismo , Animais , Apoptose , Western Blotting , Ciclo Celular , Diferenciação Celular , Divisão Celular , Proliferação de Células , Células Cultivadas , Endossomos/metabolismo , Citometria de Fluxo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Proteínas de Membrana/genética , Camundongos , Microscopia de Fluorescência , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Receptores Notch/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Timo/citologia , Timo/embriologia
5.
J Immunol ; 176(1): 75-84, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16365398

RESUMO

During thymocyte development, CCR9 is expressed on late CD4-CD8- (double-negative (DN)) and CD4+CD8+ (double-positive) cells, but is subsequently down-regulated as cells transition to the mature CD4+ or CD8+ (single-positive (SP)) stage. This pattern of expression has led to speculation that CCR9 may regulate thymocyte trafficking and/or export. In this study, we generated transgenic mice in which CCR9 surface expression was maintained throughout T cell development. Significantly, forced expression of CCR9 on mature SP thymocytes did not inhibit their export from the thymus, indicating that CCR9 down-regulation is not essential for thymocyte emigration. CCR9 was also expressed prematurely on immature DN thymocytes in CCR9 transgenic mice. Early expression of CCR9 resulted in a partial block of development at the DN stage and a marked reduction in the numbers of double-positive and SP thymocytes. Moreover, in CCR9-transgenic mice, CD25high DN cells were scattered throughout the cortex rather than confined to the subcapsular region of the thymus. Together, these results suggest that regulated expression of CCR9 is critical for normal development of immature thymocytes, but that down-regulation of CCR9 is not a prerequisite for thymocyte emigration.


Assuntos
Receptores de Quimiocinas/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/crescimento & desenvolvimento , Transferência Adotiva , Animais , Antígenos de Diferenciação de Linfócitos T/imunologia , Western Blotting , Quimiotaxia de Leucócito/imunologia , Regulação para Baixo , Citometria de Fluxo , Humanos , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Receptores CCR , Timo/imunologia
6.
Mol Carcinog ; 39(2): 85-90, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14750213

RESUMO

Mad proteins (Mad1, Mxi1, Mad3, Mad4, Mnt/Rox) are biochemical and biological antagonists of c-Myc oncoprotein. Mad-Max dimers repress the transcription of the same target genes activated by Myc-Max dimers. Despite the critical role of Max and Mad proteins as modulators of c-Myc functions, there are no comparative data on their regulation in vivo. We carried out a systematic analysis of c-myc, max, and mad family expression in a model of synchronized cell proliferation in vivo in adult tissues, that is, rat hepatocytes after partial hepatectomy. We confirmed the previously reported early peak of c-myc expression after hepatectomy but we show that it did not correlate with hepatocyte proliferation as it also occurred in sham-operated animals as a result of surgical stresses. A second peak of c-myc expression was observed later, at the time of the wave of DNA synthesis. No such expression was detected in sham-operated rat quiescent hepatocytes. max expression increased around 4-16 h after hepatectomy, before the peaks of c-myc and DNA synthesis. mxi1 and mad4 were slightly downregulated during liver regeneration. mnt/rox expression did not change. These expression patterns suggest a role of Myc-Max for efficient mitogenic response of hepatocytes. We also analyzed the effects of Myc and Max ectopic expression on the clonogenic growth of the rat hepatoma cells. Expression of c-Myc and Max increased clonogenic growth, whereas the reduction of c-Myc levels by an antisense vector decreased growth. The results suggest nonredundant roles for mad genes in hepatocyte proliferation and point to c-Myc as a putative target for anticancer therapy of liver cancer.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepatócitos/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras , Fatores de Transcrição , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Fatores de Transcrição de Zíper de Leucina Básica , Carcinoma Hepatocelular/metabolismo , Divisão Celular/fisiologia , Proteínas de Ligação a DNA/genética , Regeneração Hepática/genética , Regeneração Hepática/fisiologia , Masculino , Família Multigênica , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
7.
Nat Immunol ; 4(8): 756-64, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12858172

RESUMO

T cell receptor signaling is an essential factor regulating thymocyte selection, but the function of the thymic environment in this process is not clear. In mice transgenic for major histocompatibility complex class II-restricted T cell receptors, every thymocyte is potentially selectable for maturation in the CD4 lineage. To address whether selection frequency affects positive selection, we created hematopoietic chimeras with mixtures of selectable and nonselectable precursors. With increased proportions of nonselectable thymocytes, positive selection of MHC class II-specific precursors was enhanced, generating not only CD4 but also CD8 thymocytes. These results indicate that the CD4 versus CD8 fate of selectable precursors can be influenced by the selection potential of its neighbors.


Assuntos
Diferenciação Celular/fisiologia , Linhagem da Célula/imunologia , Timo/fisiologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Camundongos , Timo/citologia , Timo/imunologia
8.
Int Immunol ; 14(6): 535-44, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12039905

RESUMO

The early activation marker, CD69, is transiently expressed on activated mature T cells and on thymocytes that are undergoing positive or negative selection in the thymus. CD69 is a member of the NK gene complex family of C-type lectin-like signaling receptors; however, its function is unknown. In this report, we describe the characterization of mice that constitutively express high levels of surface CD69 on immature and mature T cells throughout development. Constitutive surface expression of CD69 did not affect T cell maturation, signaling through the TCR or thymocyte selection. However, phenotypically and functionally mature thymocytes accumulated in the medulla of CD69 transgenic mice and failed to be exported from the thymus. The retention of mature thymocytes correlated with transgene dose and CD69 surface levels. These results identify a potential role for CD69 in controlling thymocyte export, and suggest that the transient expression of CD69 on thymocytes and T cells may function to regulate thymocyte and T cell trafficking.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T/imunologia , Animais , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Diferenciação Celular , Movimento Celular/imunologia , Sobrevivência Celular , Humanos , Cinética , Lectinas Tipo C , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/fisiologia , Linfócitos T/citologia , Linfócitos T/fisiologia , Timo/citologia , Timo/imunologia
9.
Phys Rev Lett ; 88(8): 081101, 2002 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-11863949

RESUMO

Supernova (SN) explosions are one of the most energetic---and potentially lethal---phenomena in the Universe. We show that the Scorpius-Centaurus OB association, a group of young stars currently located at approximately 130 pc from the Sun, has generated 20 SN explosions during the last 11 Myr, some of them probably as close as 40 pc to our planet. The deposition on Earth of (60)Fe atoms produced by these explosions can explain the recent measurements of an excess of this isotope in deep ocean crust samples. We propose that approximately 2 Myr ago, one of the SNe exploded close enough to Earth to seriously damage the ozone layer, provoking or contributing to the Pliocene-Pleistocene boundary marine extinction.

10.
J Alzheimers Dis ; 3(2): 181-190, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12214059

RESUMO

The familial Alzheimer's disease gene products, presenilin-1 and presenilin-2 (PS1 and PS2), are involved in amyloid beta-protein precursor processing (AbetaPP), Notch receptor signaling, and programmed cell death. However, the molecular mechanisms by which presenilins regulate these processes remain unknown. Clues about the function of a protein can be obtained by seeing whether it interacts with another protein of known function. Using the yeast two-hybrid system, we identified two proteins that interact and colocalize with the presenilins. One of these newly detected presenilin-interacting proteins belongs to the FtsH family of ATP-dependent proteases, and the other one belongs to Rhomboid superfamily of membrane proteins that are highly conserved in eukaryotes, archaea and bacteria. Based on the pattern of amino acid residues conservation in the Rhomboid superfamily, we hypothesize that these proteins possess a metal-dependent enzymatic, possibly protease activity. The two putative proteases interacting with presenilins could mediate specific proteolysis of membrane proteins and contribute to the network of interactions in which presenilins are involved.

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