RESUMO
The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) etâ al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compoundsâ 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43â nM and 47.71â nM, respectively, which were stronger than that of ISRIB (IC50=67.90â nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70â nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.
Assuntos
Fator 4 Ativador da Transcrição , Desenho de Fármacos , Fator de Iniciação 2B em Eucariotos , Humanos , Fator 4 Ativador da Transcrição/metabolismo , Células HeLa , Relação Estrutura-Atividade , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/antagonistas & inibidores , Estrutura Molecular , Relação Dose-Resposta a Droga , Oxidiazóis/farmacologia , Oxidiazóis/química , Oxidiazóis/síntese químicaRESUMO
Comprehending the structure and function of rhizobacteria components and their regulation are crucial for sustainable agricultural management. However, obtaining comprehensive species information for most bacteria in the natural environment, particularly rhizobacteria, presents a challenge using traditional culture methods. To obtain diverse and pure cultures of rhizobacteria, this study primarily reviews the evolution of rhizobacteria culturomics and associated culture methods. Furthermore, it explores new strategies for enhancing the application of culturomics, providing valuable insights into efficiently enriching and isolate target bacterial strains/groups from the environment. The findings will help improve rhizobacteria's culturability and enrich the functional bacterial library.