Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 24(6)2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36982956

RESUMO

Rheumatoid arthritis (RA) is an autoimmune polyarthritis in which synovial fibroblasts (SFs) play a major role in cartilage and bone destruction through tumor-like proliferation, migration, and invasion. Circular RNAs (circRNAs) have emerged as vital regulators for tumor progression. However, the regulatory role, clinical significance, and underlying mechanisms of circRNAs in RASF tumor-like growth and metastasis remain largely unknown. Differentially expressed circRNAs in synovium samples from patients with RA and patients with joint trauma were identified via RNA sequencing. Subsequently, in vitro and in vivo experiments were performed to investigate the functional roles of circCDKN2B-AS_006 in RASF proliferation, migration, and invasion. CircCDKN2B-AS_006 was upregulated in synovium samples from patients with RA and promoted the tumor-like proliferation, migration, and invasion of RASFs. Mechanistically, circCDKN2B-AS_006 was shown to regulate the expression of runt-related transcription factor 1 (RUNX1) by sponging miR-1258, influencing the Wnt/ß-catenin signaling pathway, and promoting the epithelial-to-mesenchymal transition (EMT) in RASFs. Moreover, in the collagen-induced arthritis (CIA) mouse model, intra-articular injection of lentivirus-shcircCDKN2B-AS_006 was capable of alleviating the severity of arthritis and inhibiting the aggressive behaviors of SFs. Furthermore, the correlation analysis results revealed that the circCDKN2B-AS_006/miR-1258/RUNX1 axis in the synovium was correlated with the clinical indicators of RA patients. CircCDKN2B-AS_006 promoted the proliferation, migration, and invasion of RASFs by modulating the miR-1258/RUNX1 axis.


Assuntos
Artrite Reumatoide , MicroRNAs , Neoplasias , Animais , Camundongos , RNA Circular/genética , RNA Circular/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Artrite Reumatoide/metabolismo , Membrana Sinovial/patologia , Neoplasias/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fibroblastos/metabolismo , Proliferação de Células/genética , Células Cultivadas
2.
Biochem Pharmacol ; 210: 115458, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36803956

RESUMO

Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-PrkdcscidIl2rgem1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34+ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3-ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical downstream process of FLT3-ITD in AML and a potential target for FLT3-ITD+ AML patients.


Assuntos
Leucemia Mieloide Aguda , Humanos , Camundongos , Animais , Camundongos Endogâmicos NOD , Leucemia Mieloide Aguda/metabolismo , Células Cultivadas , Antígenos CD34 , Purinas , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Mutação , Fator de Transcrição E2F1/genética
3.
J Transl Med ; 20(1): 561, 2022 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463203

RESUMO

BACKGROUND: Destruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis (RA). Acid-sensing ion channel 1a (ASIC1a) is a key molecule that mediates the destruction of RA articular cartilage. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear. METHODS: We treated rat articular chondrocytes with an acidic environment, analyzed the expression levels of mitochondrial stress protein HSP10, ClpP, LONP1 by q-PCR and immunofluorescence staining. Transmission electron microscopy was used to analyze the mitochondrial morphological changes. Laser confocal microscopy was used to analyze the Ca2+, mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) level. Moreover, ASIC1a specific inhibitor Psalmotoxin 1 (Pctx-1) and Ethylene Glycol Tetraacetic Acid (EGTA) were used to observe whether acid stimulation damage mitochondrial function through Ca2+ influx mediated by ASIC1a and whether pretreatment with estrogen could counteract these phenomena. Furthermore, the ovariectomized (OVX) adjuvant arthritis (AA) rat model was treated with estrogen to explore the effect of estrogen on disease progression. RESULTS: Our results indicated that HSP10, ClpP, LONP1 protein and mRNA expression and mitochondrial ROS level were elevated in acid-stimulated chondrocytes. Moreover, acid stimulation decreased mitochondrial membrane potential and damaged mitochondrial structure of chondrocytes. Furthermore, ASIC1a specific inhibitor PcTx-1 and EGTA inhibited acid-induced mitochondrial abnormalities. In addition, estrogen could protect acid-stimulated induced mitochondrial stress by regulating the activity of ASIC1a in rat chondrocytes and protects cartilage damage in OVX AA rat. CONCLUSIONS: Extracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the damage of rat articular chondrocytes. Estrogen antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. Our study provides new insights into the protective effect and mechanism of action of estrogen in RA.


Assuntos
Canais Iônicos Sensíveis a Ácido , Artrite Reumatoide , Condrócitos , Estrogênios , Mitocôndrias , Animais , Ratos , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Artrite Experimental , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ácido Egtázico/metabolismo , Ácido Egtázico/toxicidade , Estrogênios/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia
4.
Lab Invest ; 102(8): 859-871, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35292759

RESUMO

Nesfatin-1, a newly identified energy-regulating peptide, has been reported to possess antioxidant, anti-inflammatory, and antiapoptotic properties; however, to date, its effect on rheumatoid arthritis (RA) has not been previously explored in detail. We previously showed that activation of acid-sensing ion channel 1a (ASIC1a) by acidosis plays an important role in RA pathogenesis. Therefore, in this study, we evaluated the effects of nesfatin-1 on acidosis-stimulated chondrocyte injury in vitro and in vivo and examined the involvement of ASIC1a and the mechanism underlying the effects of nesfatin-1 on RA. Acid-stimulated articular chondrocytes were used to examine one of the several possible mechanisms underlying RA pathogenesis in vitro. The mRNA expression profile of acid-induced chondrocytes treated or not treated with nesfatin-1 was investigated by RNA sequencing. The effects of nesfatin-1 on oxidative stress, inflammation, and apoptosis in acid-induced chondrocytes were measured. The mechanistic effect of nesfatin-1 on ASIC1a expression and intracellular Ca2+ in acid-stimulated chondrocytes was studied. Rats with adjuvant-induced arthritis (AA) were used for in vivo analysis of RA pathophysiology. Cartilage degradation and ASIC1a expression in chondrocytes were detected in rats with AA after intraarticular nesfatin-1 injection. The in vitro experiments showed that nesfatin-1 decreased acidosis-induced cytotoxicity and elevation of intracellular Ca2+ levels in chondrocytes. Moreover, it attenuated acid-induced oxidative stress, inflammation, and apoptosis in chondrocytes. Nesfatin-1 decreased ASIC1a protein levels in acid-stimulated chondrocytes via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and nuclear factor kappa-B (NF-κB) signaling pathways. In vivo analysis showed that nesfatin-1 ameliorated cartilage degradation and decreased ASIC1a expression in the chondrocytes of rats with AA. Collectively, nesfatin-1 suppressed acidosis-induced oxidative stress, inflammation, and apoptosis in acid-stimulated chondrocytes and alleviated arthritis symptoms in rats with AA, and its mechanism may be related to its ability to decrease ASIC1a protein levels via the MAPK/ERK and NF-κB pathways.


Assuntos
Canais Iônicos Sensíveis a Ácido , Acidose , Artrite Experimental , Cartilagem Articular , Nucleobindinas , Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/metabolismo , Acidose/patologia , Animais , Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Nucleobindinas/metabolismo , Ratos , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA