RESUMO
Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.
Assuntos
Pontos de Checagem do Ciclo Celular , Diferenciação Celular , RNA Helicases DEAD-box , Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , RNA Longo não Codificante , Transdução de Sinais , Humanos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , RNA Helicases DEAD-box/efeitos dos fármacos , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , RNA Longo não Codificante/efeitos dos fármacos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tretinoína/farmacologiaRESUMO
Diabetic coronary heart disease is a global medical problem that poses a serious threat to human health, and its pathogenesis is complex and interconnected. Nicotinamide adenine dinucleotide (NAD) is an important small molecule used in the body that serves as a coenzyme in redox reactions and as a substrate for non-redox processes. NAD levels are highly controlled by various pathways, and increasing evidence has shown that NAD pathways, including NAD precursors and key enzymes involved in NAD synthesis and catabolism, exert both positive and negative effects on the pathogenesis of diabetic coronary heart disease. Thus, the mechanisms by which the NAD pathway acts in diabetic coronary heart disease require further investigation. This review first briefly introduces the current understanding of the intertwined pathological mechanisms of diabetic coronary heart disease, including insulin resistance, dyslipidemia, oxidative stress, chronic inflammation, and intestinal flora dysbiosis. Then, we mainly review the relationships between NAD pathways, such as nicotinic acid, tryptophan, the kynurenine pathway, nicotinamide phosphoribosyltransferase, and sirtuins, and the pathogenic mechanisms of diabetic coronary heart disease. Moreover, we discuss the potential of targeting NAD pathways in the prevention and treatment of diabetic coronary heart disease, which may provide important strategies to modulate its progression.