RESUMO
A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 µM for PI3Kγ). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3Kγ structure active site to determine the probable binding model.
Assuntos
Imunossupressores , Oxidiazóis , Animais , Apoptose/efeitos dos fármacos , Domínio Catalítico , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Imunossupressores/síntese química , Imunossupressores/química , Imunossupressores/farmacologia , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologia , Linfócitos T/efeitos dos fármacosRESUMO
Understanding how infected cells respond to Ebola virus (EBOV) and how this response changes during the process of viral replication and transcription are very important for establishing effective antiviral strategies. In this study, we conducted a genome-wide screen to identify long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and mRNAs differentially expressed during replication and transcription using a tetracistronic transcription and replication-competent virus-like particle (trVLP) system that models the life cycle of EBOV in 293T cells. To characterize the expression patterns of these differentially expressed RNAs, we performed a series cluster analysis, and up- or down-regulated genes were selected to establish a gene co-expression network. Competing endogenous RNA (ceRNA) networks based on the RNAs responsible for the effects induced by EBOV replication and transcription in human cells, including circRNAs, lncRNAs, miRNAs, and mRNAs, were constructed for the first time. Based on these networks, the interaction details of circRNA-chr19 were explored. Our results demonstrated that circRNA-chr19 targeting miR-30b-3p regulated CLDN18 expression by functioning as a ceRNA. These findings may have important implications for further studies of the mechanisms of EBOV replication and transcription. These RNAs potentially have important functions and may be promising targets for EBOV therapy.
Assuntos
Ebolavirus/fisiologia , Perfilação da Expressão Gênica , Doença pelo Vírus Ebola/genética , Interações Hospedeiro-Patógeno/genética , RNA/genética , RNA/metabolismo , Replicação Viral/fisiologia , Ebolavirus/patogenicidade , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Doença pelo Vírus Ebola/metabolismo , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNARESUMO
A new sesquiterpenoid, 1alpha,5alpha-epoxy-4alpha-hydroxyl-4beta,10beta-dimethyl-7alphaH,10alphaH-guaia-l1(13)-en-12-oic acid (1), and four known compounds, lactucin (2), 1beta-hydroxy-7alphaH,8,11betaH-eudesm-3-en-8,12-olide (3), 13,14-seco-stigma 9(11),14(15)-dien-3alpha-ol (4), and bacosterol-3-O-beta-D-glucopyranoside (5) were isolated from Cichorium intybus L. Their structures were determined on the basis of detailed analysis of their 1D- and 2D-NMR spectroscopic and mass spectrometric data. Compounds 2 and 4 showed strong activities against the A2780 cell line with IC50 values of 1.81 and 0.07 microM, respectively.