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1.
Exp Biol Med (Maywood) ; 248(1): 52-60, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36151748

RESUMO

The calcific aortic valve disease (CAVD) develops as an aortic valve sclerosis and progresses to an advanced form of stenosis. In many biological fields, bioinformatics becomes a fundamental component. The key mechanisms involved in CAVD are discovered with the use of bioinformatics to investigate gene function and pathways. We downloaded the original data (GSE51472) from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). After standardization, 2978 differentially expressed genes (DEGs) were identified from the data sets GSE51472 containing samples from normal, calcified, and sclerotic aortic valves. Analysis of DEGs based on the series test of clusters (STCs) revealed the two most significant patterns. Based on the result of the STC, the functional enrichment analysis of gene ontology (GO) was conducted to investigate the molecular function (MF), biological process (BP), and cell compound (CC) of the DEGs. With a p value of 0.01, DEGs associated with "chronic inflammation," "T-cell receptor complexes," and "antigen binding" had the highest significance within BP, CC, and MF. DEG enrichment in signaling pathways was analyzed using KEGG pathway enrichment. Using a p < 0.05 level of significance, the most enriched biological pathways related to CAVD were "Chemokine signaling pathway," "Cytokine-cytokine receptor interaction," "Tuberculosis," "PI3K-Akt signaling pathway," and "Transcriptional misregulation in cancer." Finally, the construction of gene co-expression networks and pathway networks illustrated the pathogensis of CAVD. TLR2, CD86, and TYROBP were identified as hub genes for the development of CAVD. Moreover, "MAPK signaling pathway," "Apoptosis," and "Pathways in cancer" were regarded as the core pathways among the samples of normal, sclerotic and calcified aortic valve samples.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Humanos , Fosfatidilinositol 3-Quinases , Estenose da Valva Aórtica/genética , Biologia Computacional , Perfilação da Expressão Gênica
3.
Med Hypotheses ; 146: 110466, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33412502

RESUMO

Alzheimer's disease (AD) is the main cause of dementia, and its pathogenesis is still not clear. Peptidyl arginine deiminases 4(PAD4) as one of the important members of PAD family, is the only protein with nuclear transfer function, it can regulate the expression of many proteins through citrullinating histone. PAD4 can also interact with many transcription factors, involved in regulating gene expression. PAD4 expression is closely related to the inflammatory factors secreted, cell autophagy, tumorigenesis and other neurodegenerative diseases. More importantly, PAD4 and its citrullinated protein were found in cortical and hippocampal neurons of AD patients. To study the expression and regulatory pathway of PAD4 in vivo and in vitro experiments on AD may be of helpful to elucidate the pathogenesis of AD. Meanwhile, detection of anti-citrullinated antibody will have potential value as novel biomarkers of AD.


Assuntos
Doença de Alzheimer , Citrulinação , Humanos , Hidrolases/genética , Hidrolases/metabolismo , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas/genética , Desiminases de Arginina em Proteínas/metabolismo
4.
Sci Rep ; 5: 9604, 2015 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-25853231

RESUMO

Inactivation of p53 and/or Rb pathways restrains osteoblasts from cell-cycle exit and terminal differentiation, which underpins osteosarcoma formation coupled with dedifferentiation. Recently, the level of p-S6K was shown to independently predict the prognosis for osteosarcomas, while the reason behind this is not understood. Here we show that in certain high-grade osteosarcomas, immature SSEA-4(+) tumor cells represent a subset of tumor-initiating cells (TICs) whose pool size is maintained by mTORC1 activity. mTORC1 supports not only SSEA-4(+) cell self-renewal through S6K but also the regeneration of SSEA-4(+) TICs by SSEA-4(-) osteosarcoma cell dedifferentiation. Mechanistically, active mTORC1 is required to prevent a likely upregulation of the cell-cycle inhibitor p27 independently of p53 or Rb activation, which otherwise effectively drives the terminal differentiation of SSEA-4(-) osteosarcoma cells at the expense of dedifferentiation. Thus, mTORC1 is shown to critically regulate the retention of tumorigenicity versus differentiation in discrete differentiation phases in SSEA-4(+) TICs and their progeny.


Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Transformação Celular Neoplásica/metabolismo , Complexos Multiproteicos/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Antígenos Embrionários Estágio-Específicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Ciclo Celular/genética , Desdiferenciação Celular , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Xenoenxertos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/genética , Gradação de Tumores , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/mortalidade , Prognóstico , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Antígenos Embrionários Estágio-Específicos/genética , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
5.
Mol Cell ; 53(3): 407-19, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24412064

RESUMO

Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.


Assuntos
RNA Helicases DEAD-box/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Proto-Oncogênicas pp60(c-src)/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Sequência de Aminoácidos , Linhagem Celular Tumoral , Proteína DEAD-box 58 , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/genética , Ativação Enzimática , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Modelos Genéticos , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Receptores Imunológicos , Alinhamento de Sequência , Análise de Sequência de Proteína , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/fisiologia , Regulação para Cima
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