目的:对从FDA(food and drug administration)批准的1430个化合物中通过微复制子系统筛选出对发热伴血小板减少综合征病毒(severe fever with thrombocytopenia syndrome virus,SFTSV)起抑制作用的药物,并解析药物抗病毒的作用阶段。方...目的:对从FDA(food and drug administration)批准的1430个化合物中通过微复制子系统筛选出对发热伴血小板减少综合征病毒(severe fever with thrombocytopenia syndrome virus,SFTSV)起抑制作用的药物,并解析药物抗病毒的作用阶段。方法:利用SFTSV微复制子初步筛选出对SFTSV复制转录系统具有抑制作用的药物,通过药物浓度梯度抑制实验确定各药物的半数抑制浓度(IC50)。再利用SFTSV感染细胞模型,使用药物分别与病毒孵育后再感染细胞、与病毒共同和细胞孵育、在病毒与细胞孵育后作用于细胞、以及在病毒感染细胞全过程(entire stage)使用药物,并采用实时荧光定量PCR(qRT-PCR)对感染细胞上清中病毒进行定量,分析药物对病毒感染细胞的整个过程的不同阶段,包括:病毒颗粒稳定性(virion stability)、病毒感染入侵(entry stage)、病毒进入细胞后的复制过程(post-entry)的抑制作用,并与药物作用于病毒感染细胞整个过程的抑制作用相比较,初步揭示药物抑制SFTSV感染的作用机制。结果:吗替麦考酚酯、麦考酚酸、硝唑尼特、Vidofludimus 4种药物对SFTSV具有较好的抑制效果,4种药物对微复制子系统的半数抑制浓度IC50分别为0.014、0.627、1.283、0.059μmol/L;4种药物对SFTSV的抑制作用发生在病毒入侵细胞后的阶段。结论:吗替麦考酚酯、麦考酚酸、硝唑尼特、Vidofludimus具有较好的抗发热伴血小板减少综合征病毒效果。展开更多
Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two...Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two repressing marks. Using mouse embryonic stem cells, we demonstrated that KIAA1718 expression increased at the early phase of neural differentiation. Knockdown of the gene blocked neural differentiation and the effect was rescued by the wild-type human gene, and not by a catalytically inactive mutant. In addition, overexpression of KIAA1718 accelerated neural differentiation. We provide the evidence that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation. Thus, our study identified a dual-specificity histone demethylase that regulates neural differentiation through FGF4.展开更多
Transforming growth factor-β(TGF-β) is a key factor in cancer development and progression. TGF-β can suppress tumorigenesis by inhibiting cell cycle progression and stimulating apoptosis in early stages of cancer p...Transforming growth factor-β(TGF-β) is a key factor in cancer development and progression. TGF-β can suppress tumorigenesis by inhibiting cell cycle progression and stimulating apoptosis in early stages of cancer progression. However, TGF-β can modulate cancer-related processes, such as cell invasion, distant metastasis, and microenvironment modification that may be used by cancer cells to their advantage in late stages. Corresponding mechanisms include angiogenesis promotion, anti-tumor immunity suppression, and epithelial-to-mesenchymal transition(EMT) induction. The correlation between TGF-β expression and cancer prognosis has also been extensively investigated. Results suggest that TGF-β pathway can be targeted to treat cancer; as such, the feasibility of this treatment is investigated in clinical trials.展开更多
文摘目的:对从FDA(food and drug administration)批准的1430个化合物中通过微复制子系统筛选出对发热伴血小板减少综合征病毒(severe fever with thrombocytopenia syndrome virus,SFTSV)起抑制作用的药物,并解析药物抗病毒的作用阶段。方法:利用SFTSV微复制子初步筛选出对SFTSV复制转录系统具有抑制作用的药物,通过药物浓度梯度抑制实验确定各药物的半数抑制浓度(IC50)。再利用SFTSV感染细胞模型,使用药物分别与病毒孵育后再感染细胞、与病毒共同和细胞孵育、在病毒与细胞孵育后作用于细胞、以及在病毒感染细胞全过程(entire stage)使用药物,并采用实时荧光定量PCR(qRT-PCR)对感染细胞上清中病毒进行定量,分析药物对病毒感染细胞的整个过程的不同阶段,包括:病毒颗粒稳定性(virion stability)、病毒感染入侵(entry stage)、病毒进入细胞后的复制过程(post-entry)的抑制作用,并与药物作用于病毒感染细胞整个过程的抑制作用相比较,初步揭示药物抑制SFTSV感染的作用机制。结果:吗替麦考酚酯、麦考酚酸、硝唑尼特、Vidofludimus 4种药物对SFTSV具有较好的抑制效果,4种药物对微复制子系统的半数抑制浓度IC50分别为0.014、0.627、1.283、0.059μmol/L;4种药物对SFTSV的抑制作用发生在病毒入侵细胞后的阶段。结论:吗替麦考酚酯、麦考酚酸、硝唑尼特、Vidofludimus具有较好的抗发热伴血小板减少综合征病毒效果。
基金Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Anning Lin （The University of Chicago） for the critical reading of the paper, members in the Chen lab for technical help, the cell biology and molecular biology core facilities for confocal study and Q-PCR, and Shanghai Biochip Co Ltd. for microarray analysis. The H3K27me2 antibody was kindly provided by Li Tang （Fudan University） and Thomas Jenuwein （Research Institute of Molecular Pathology, The Vienna Biocenter）. This work was supported by the National Basic Research Program of China （2007CB957900, 2006CB943902, 2007CB947101, 2008KR0695, 2009CB941100, 2005CB522704）, the Chinese Academy of Sciences （KSCX2-YW-R-04）, the National Natural Science Foundation of China （90919026, 30870538,30623003, 30721065, 30830034, 90919046）, the Shanghai Pujiang Program （0757S11361）, the Shanghai Key Project of Basic Science Research （06DJ14001, 06DZ22032, 08DJ1400501）, and the Council of Shanghai Municipal Government for Science and Technology （088014199）.
文摘Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two repressing marks. Using mouse embryonic stem cells, we demonstrated that KIAA1718 expression increased at the early phase of neural differentiation. Knockdown of the gene blocked neural differentiation and the effect was rescued by the wild-type human gene, and not by a catalytically inactive mutant. In addition, overexpression of KIAA1718 accelerated neural differentiation. We provide the evidence that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation. Thus, our study identified a dual-specificity histone demethylase that regulates neural differentiation through FGF4.
基金supported by the National Natural Science Foundation of China (Grant No. 81372429)
文摘Transforming growth factor-β(TGF-β) is a key factor in cancer development and progression. TGF-β can suppress tumorigenesis by inhibiting cell cycle progression and stimulating apoptosis in early stages of cancer progression. However, TGF-β can modulate cancer-related processes, such as cell invasion, distant metastasis, and microenvironment modification that may be used by cancer cells to their advantage in late stages. Corresponding mechanisms include angiogenesis promotion, anti-tumor immunity suppression, and epithelial-to-mesenchymal transition(EMT) induction. The correlation between TGF-β expression and cancer prognosis has also been extensively investigated. Results suggest that TGF-β pathway can be targeted to treat cancer; as such, the feasibility of this treatment is investigated in clinical trials.
