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1.
Hepatobiliary Pancreat Dis Int ; 23(5): 472-480, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38724321

RESUMO

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.


Assuntos
Antígenos CD19 , Linfócitos B Reguladores , Antígeno CD24 , Diferenciação Celular , Transplante de Fígado , MicroRNAs , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Antígenos CD19/metabolismo , Antígenos CD19/genética , Masculino , Antígeno CD24/metabolismo , Antígeno CD24/genética , Transdução de Sinais , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/genética , Feminino , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Pessoa de Meia-Idade , Tolerância Imunológica , Células Cultivadas , Adulto , Fenótipo , Memória Imunológica
2.
Sleep Med ; 100: 254-261, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36122507

RESUMO

PURPOSE: Whether preexisting sleep disorder is an independent risk factor for cancer remains unclear. Therefore, we performed this propensity score-matched population-based cohort study to compare the incidence rate ratios (IRRs) of specific cancers between patients with and without sleep disorders. PATIENTS AND METHODS: Patients were categorized into two groups on the basis of the presence or absence of sleep disorders and matched at a 1:1 ratio. RESULTS: Propensity score matching yielded a final cohort of 289,162 patients (i.e., 144,581 and 144,581 in the sleep disorder and nonsleep disorder groups, respectively) who were eligible for further analysis. In multivariate Cox regression analysis, the adjusted hazard ratio (aHR; 95% confidence interval [CI]) of cancer risk in the sleep disorder group compared with the nonsleep disorder group was 1.07 (1.04-1.12; P = 0.0001). Furthermore, the adjusted IRRs (95% CIs) for all cancers, breast cancer, and ovarian cancer in the patients with sleep disorders were 1.08 (1.02-1.18), 1.20 (1.08-1.32), and 1.30 (1.10-1.52), respectively. CONCLUSION: The results suggested that sleep disorders are a significant risk factor for all cancers, breast cancer, and ovarian cancer.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Transtornos do Sono-Vigília , Feminino , Humanos , Estudos de Coortes , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/epidemiologia , Fatores de Risco , Incidência , Neoplasias da Mama/epidemiologia
3.
Hepatobiliary Pancreat Dis Int ; 11(3): 278-84, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22672822

RESUMO

BACKGROUND: Glycogen synthase kinase (GSK)-3beta/beta-catenin signaling regulates ischemia-reperfusion (I/R)-induced apoptosis and proliferation, and inhibition of GSK-3beta has beneficial effects on I/R injury in the heart and the central nervous system. However, the role of this signaling in hepatic I/R injury remains unclear. The present study aimed to investigate the effects and mechanism of GSK-3beta/beta-catenin signaling in hepatic I/R injury. METHODS: Male C57BL/6 mice (weighing 22-25 g) were pretreated with either SB216763, an inhibitor of GSK-3beta, or vehicle. These mice were subjected to partial hepatic I/R. Blood was collected for test of alanine aminotransferase (ALT), and liver specimen for assays of phosphorylation at the Ser9 residue of GSK-3beta, GSK-3beta activity, axin 2 and the anti-apoptotic factors Bcl-2 and survivin, as well as the proliferative factors cyclin D1 and proliferating cell nuclear antigen, and apoptotic index (TUNEL). Real-time PCR, Western blotting and immunohistochemical staining were used. RESULTS: SB216763 increased phospho-GSK-3beta levels and suppressed GSK-3beta activity (1880+/-229 vs 3280+/-272 cpm, P<0.01). ALT peaked at 6 hours after reperfusion. Compared with control, SB216763 decreased ALT after 6 hours of reperfusion (4451+/-424 vs 7868+/-845 IU/L, P<0.01), and alleviated hepatocyte necrosis and vacuolization. GSK-3beta inhibition led to the accumulation of beta-catenin in the cytosol (0.40+/-0.05 vs 1.31+/-0.11, P<0.05) and nucleus (0.62+/-0.14 vs 1.73+/-0.12, P<0.05), beta-catenin further upregulated the expression of axin 2. Upregulation of GSK-3beta/beta-catenin signaling increased Bcl-2, survivin and cyclin D1. Serological and histological analyses showed that SB216763 alleviated hepatic I/R-induced injury by reducing apoptosis (1.4+/-0.2% vs 3.6+/-0.4%, P<0.05) and enhanced liver proliferation (56+/-8% vs 19+/-4%, P<0.05). CONCLUSION: Inhibition of GSK-3beta ameliorates hepatic I/R injury through the GSK-3beta/beta-catenin signaling pathway.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indóis/farmacologia , Fígado/efeitos dos fármacos , Maleimidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Proteína Axina/metabolismo , Western Blotting , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/metabolismo , Fígado/irrigação sanguínea , Fígado/enzimologia , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Proteínas Repressoras/metabolismo , Survivina , Fatores de Tempo
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