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1.
Yi Chuan ; 44(6): 466-477, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35729095

RESUMO

Cells of the aerobic metabolic organism are inevitably subjected to the damage from reactive oxygen species (ROS). ROS cause multiple forms of DNA damage, among which the oxidation product of guanine G 8-hydroxyguanine (8-oxoG) is the most frequent DNA oxidative damage, recognized by the specific glycosidase OGG1 that initiates the base excision repair pathway. If left unrepaired, 8-oxoG may pair with A instead of C, leading to a mutation of G: C to T: A during replication. Thus, the accumulation of 8-oxoG or the abnormal OGG1 repair is thought to affect gene function, which in turn leads to the development of tumor or aging-related diseases. However, a series of recent studies have shown that 8-oxoG tends to be produced in regulatory regions of the genome. 8-oxoG can be regarded as an epigenetic modification, while OGG1 is a specific reader of this information. Substrate recognition, binding or resection by OGG1 can cause DNA conformation changes or affect histone modifications, causing up-regulation or down-regulation of genes with different properties. Thus, in addition to the potential genotoxicity, the association of guanine oxidative damage with development of tumors is closely related to its aberrant initiation of gene expression through epigenetic mechanisms. In this review, we summarize the underlying mechanism of 8-oxoG and repair enzyme OGG1 in tumor development and progression, with aims to interpret the relationship between DNA oxidative damage and tumor from a new perspective, and provide new ideas and targets for tumor treatment.


Assuntos
DNA Glicosilases , Neoplasias , DNA , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Neoplasias/genética , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
2.
Acta Pharmacol Sin ; 35(4): 496-503, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24632845

RESUMO

AIM: Daidzein (4',7-dihydroxyisoflavone) is an isoflavone exiting in many herbs that has shown anti-inflammation activity. The aim of this study was to investigate the mechanism underlying its anti-inflammatory action in murine lung epithelial cells. METHODS: C57BL/6 mice were intranasally exposed to TNF-α to induce lung inflammation. The mice were injected with daidzein (400 mg/kg, ip) before TNF-α challenge, and sacrificed 12 h after TNF-α challenge, and lung tissues were collected for analyisis. In in vitro studies, murine MLE-12 epithelial cells were treated with TNF-α (20 ng/mL). The expression of pro-inflammatory chemokine Cxcl2 mRNA and NF-κB transcriptional activity were examined using real-time PCR and a dual reporter assay. Protein poly-adenosine diphosphate-ribosylation (PARylation) was detecyed using Western blotting and immunoprecipitation assays. RESULTS: Pretreatment of the mice with daidzein markedly attenuated TNF-α-induced lung inflammation, and inhibited Cxcl2 expression in lung tissues. Furthermore, daidzein (10 µmol/L) prevented TNF-α-induced increases in Cxcl2 expression and activity and NF-κB transcriptional activity, and markedly inhibited TNF-α-induced protein PARylation in MLE-12 cells in vitro. In MLE-12 cells co-transfected with the PARP-1 expression plasmid and NF-κB-luc (or Cxcl2-luc) reporter plasmid, TNF-α markedly increased NF-κB (or Cxcl2) activation, which were significantly attenuated in the presence of daidzein (or the protein PARylation inhibitor PJ 34). PARP-1 activity assay showed that daidzein (10 µmol/L) reduced the activity of PARP-1 by ∼75%. CONCLUSION: The anti-inflammatory action of daidzein in murine lung epithelial cells seems to be mediated via a direct interaction with PARP-1, which inhibits RelA/p65 protein PARylation required for the transcriptional modulation of pro-inflammatory chemokines such as Cxcl2.


Assuntos
Anti-Inflamatórios/farmacologia , Quimiocina CXCL2/metabolismo , Células Epiteliais/efeitos dos fármacos , Isoflavonas/farmacologia , Pulmão/efeitos dos fármacos , Pneumonia/prevenção & controle , Poli(ADP-Ribose) Polimerases/metabolismo , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa , Animais , Linhagem Celular , Quimiocina CXCL2/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Genes Reporter , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Transfecção
3.
Acta Pharmacol Sin ; 27(5): 617-22, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16626518

RESUMO

AIM: The interactions of selectins and their ligands initiate the process of leukocyte migrating into inflamed tissue. P-selectin glycoprotein ligand 1 (PSGL-1) is the best characterized ligand of selectins, and has been demonstrated to mediate the adhesion of leukocytes to all three selectins in vivo. PSGL-1 not only functions as an anchor molecule to capture the leukocytes to the activated endothelial cells by its interaction with selectins, but also transduces the signals to activate leukocytes. Our present work aimed to investigate the mechanism by which PSGL-1-mediated signal activates neutrophils and enhances the adhesion to the endothelial cells. METHODS: We detected the effects of the engagement of PSGL-1 with monoclonal antibodies (mAb) or P-selectin on the adhesion of neutrophils to the recombinant intercellular adhesion molecule-1 (ICAM-1), and on the expression of beta(2)-integrin. Additionally, the role of cytoskeleton in these process was studied by using inhibitor cytochalasin B. RESULTS: The engagement of PSGL-1 increased the expression of beta(2)-integrin on the surface of neutrophils and enhanced the adhesion of neutrophils to the recombinant ICAM-1. mAb against CD18 impaired the adhesion of PSGL-1-engaged neutrophils to ICAM-1. Moreover, the inhibitor cytochalasin B largely blocked the increase of CD18 expression as well as the adhesion of PSGL-1-engaged neutrophils to ICAM-1. CONCLUSION: The PSGL-1-transduced signals can enhance beta(2)-integrin-involved adhesion of neutrophils to the recombinant ICAM-1, and this process depends on the dynamics of cytoskeleton.


Assuntos
Antígenos CD18/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Glicoproteínas de Membrana/farmacologia , Neutrófilos/metabolismo , Antígenos CD18/fisiologia , Adesão Celular , Separação Celular , Citocalasina B/farmacologia , Humanos , Ativação de Neutrófilo , Neutrófilos/imunologia
4.
Cell Immunol ; 237(1): 1-6, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16289055

RESUMO

PSGL-1, the optimal selectin ligand demonstrated by in vivo studies to date, is an essential adhesive molecule mediating the rolling of leukocytes on the endothelial cells and the recruitment of leukocytes to the inflamed tissue. Recent studies demonstrated, in addition to its direct role in capture of leukocytes from the bloodstream, PSGL-1 also functions as a signal-transducing receptor and initiates a series of intracellular signal events during the activation of leukocytes. Our present work showed antibody engagement of PSGL-1 upregulated the transcriptional activity of CSF-1 promotor and increased the endogenous expression of CSF-1 mRNA in Jurkat cell. Overexpression of wild-typed non-receptor tyrosine kinase Syk, but not kinase dead mutant of Syk, promoted the upregulation of the transcriptional activity of CSF-1 promoter caused by antibody engagement of PSGL-1. Additionally, special inhibitor of Syk Piceatannol suppressed the increase of CSF-1 mRNA caused by the engagement of PSGL-1. The results suggest that signal transducted by PSGL-1 upregulate the transcriptional activity of CSF-1, and non-receptor tyrosine kinase Syk participates in this pathway.


Assuntos
Precursores Enzimáticos/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/imunologia , Precursores Enzimáticos/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células Jurkat , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/imunologia , Glicoproteínas de Membrana/imunologia , Regiões Promotoras Genéticas , Proteínas Tirosina Quinases/imunologia , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Quinase Syk , Transcrição Gênica , Regulação para Cima
5.
Acta Biochim Biophys Sin (Shanghai) ; 37(7): 440-6, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15999204

RESUMO

Brg- or hBrm-associated factor (BAF) complexes, a chromatin-remodeling complex family of mammalian cells, facilitate transcriptional activity by remodeling nucleosome structure. Brg1 is the core subunit of Brg-associated factor complexes. In the present study, we investigated the spatial relationship between Brg1 and nuclear factor 1 (NF1/CTF) and RNA polymerase II (RNAP II) upon gene transcriptional activation in vivo by employing immuno-gold labeling. The data showed that Brg1 was closely co-localized with NF1/CTF and RNAP II in HeLa cells. Moreover, the co-immunoprecipitation assay further revealed that Brg1 can be isolated together with NF1/CTF and RNAP II in the ConA-stimulated, but not the resting, T lymphocyte. The combined results suggested that BAF complexes can interact with NF1/CTF and RNAP II, and this interaction is closely dependent on the activation of gene transcription.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Proteínas Nucleares/fisiologia , RNA Polimerase II/fisiologia , Fatores de Transcrição/fisiologia , Ativação Transcricional , Animais , DNA Helicases , Células HeLa , Humanos , Imuno-Histoquímica/métodos , Células Jurkat , Camundongos , Fatores de Transcrição NFI , Linfócitos T/metabolismo
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