A bicyclic depsipeptide, chromopeptide A(1), was isolated from a deep-sea-derived bacterium Chromobacterium sp. HS-13-94. Its structure was determined by extensive spectroscopic analysis and by comparison with a relat...A bicyclic depsipeptide, chromopeptide A(1), was isolated from a deep-sea-derived bacterium Chromobacterium sp. HS-13-94. Its structure was determined by extensive spectroscopic analysis and by comparison with a related known compound. The absolute configuration of chromopeptide A was established by X-ray diffraction analysis employing graphite monochromated Mo K_α radiation(λ ? 0.71073 ?) with small Flack parameter 0.03. Chromopeptide A suppressed the proliferation of HL-60, K-562, and Ramos cells with average IC_(50) values of 7.7, 7.0, and 16.5 nmol/L, respectively.展开更多
Histone acetylation is a critical process in the regulation of chromatin structure and gene expression.Histone deacetylases(HDACs)remove the acetyl group,leading to chromatin condensation and transcriptional repressio...Histone acetylation is a critical process in the regulation of chromatin structure and gene expression.Histone deacetylases(HDACs)remove the acetyl group,leading to chromatin condensation and transcriptional repression.HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects.This paper describes our work on the structural determination and structure-activity relationship(SAR)optimization of tetrahydroisoquinoline compounds as HDAC inhibitors.These compounds were tested for their ability to inhibit HDAC 1,3,6 and for their ability to inhibit the proliferation of a panel of cancer cell lines.Among these,compound 82 showed the greatest inhibitory activity toward HDAC 1,3,6 and strongly inhibited growth of the cancer cell lines,with results clearly superior to those of the reference compound,vorinostat(SAHA).Compound 82 increased the acetylation of histones H3,H4 and tubulin in a concentration-dependent manner,suggesting that it is a broad inhibitor of HDACs.展开更多
Main observation and conclusion As part of our continuing efforts toward the discovery of the biologically active diterpenoids from medicinal plants,six new C-ring aromatized abietane diterpenoids,clerodenoids A-F(1-6...Main observation and conclusion As part of our continuing efforts toward the discovery of the biologically active diterpenoids from medicinal plants,six new C-ring aromatized abietane diterpenoids,clerodenoids A-F(1-6),were isolated from Clerodendrum chinense.展开更多
Dear Editor,Recently,the novel coronavirus disease(COVID-19)has broken out worldwide,1 with rapid increase of infected patients.COVID-19 dominantly leads to pneumonia.2 Among these COVID-19 patients,some appears to be...Dear Editor,Recently,the novel coronavirus disease(COVID-19)has broken out worldwide,1 with rapid increase of infected patients.COVID-19 dominantly leads to pneumonia.2 Among these COVID-19 patients,some appears to be severe symptoms with acute respiratory distress syndrome,organ failure,2 and further present a poor outcome.展开更多
Medulloblastoma(MB)is a common yet highly heterogeneous childhood malignant brain tumor,however,clinically effective molecular targeted therapy is lacking.Modulation of hedgehog(HH)signaling by epigenetically targetin...Medulloblastoma(MB)is a common yet highly heterogeneous childhood malignant brain tumor,however,clinically effective molecular targeted therapy is lacking.Modulation of hedgehog(HH)signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4(BRD4)has recently spurred new interest as potential treatment of HH-driven MB.Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog(GLI)protein,the BRD4 inhibitor 2 was selected as the lead for further structural optimization,which led to the identification of compounds 25 and 35 as the high potency HH inhibitors.Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI,and were equally potent against the clinical resistant mutants and the wild type of smoothened(SMO)receptor with IC50 values around 1 nmol/L.In the resistant MB allograft mice,compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg(TGI=83.3%)and 10 mg/kg(TGI=87.6%)doses.Although further modification is needed to improve the pharmacokinetic(PK)parameters,compound 25 represents an efficacious lead compound of GLI inhibitors,possessing optimal safety and tolerance to fight against HH-driven MB.展开更多
This study aims to demonstrate that blocking the receptor-interacting protein2(Rip2)expression can decrease inflammatory cytokine production by macrophage and protect mice from endotoxin lethality.Murine Rip2 small in...This study aims to demonstrate that blocking the receptor-interacting protein2(Rip2)expression can decrease inflammatory cytokine production by macrophage and protect mice from endotoxin lethality.Murine Rip2 small interfering RNA(siRNA)plasmids were constructed and transfected into macrophage and Rip2 expression was detected with reverse transcription-polymerase chain reaction(RT-PCR)and western blot.Cell proliferation was assayed withMTT.TNF-a concentration was assayed with ELISA and high-mobility group box 1 protein(HMGB1)level with semi-quantitative western blot after lipopolysaccharide(LPS)stimulation.LPS challenge was given after the plasmids were injected into mice and the survival rate was calculated.Rip2 siRNA plasmid could block the mRNA and protein expression of Rip2 and promote cell proliferation.Blocking Rip2 could attenuate LPS-induced TNF-a and HMGB1 production.The HMGB1 expression in the liver decreased to(40.21±11.03)pg/g,and serum TNF-a level decreased to(300.43±59.26)ng/L(P<0.05).The survival rate of mice from endotoxemia was also improved(P<0.05).The results demonstrate that Rip2 siRNA plasmid can block the expression of Rip2,decrease the production of TNF-a and HMGB1 and protect mice from fatal endotoxemia.展开更多
基金financially supported by the National Marine ‘863’ Project (Nos. 2012AA092105 and 2013AA092902)the National Natural Science Foundation of China (No. 81273430)
文摘A bicyclic depsipeptide, chromopeptide A(1), was isolated from a deep-sea-derived bacterium Chromobacterium sp. HS-13-94. Its structure was determined by extensive spectroscopic analysis and by comparison with a related known compound. The absolute configuration of chromopeptide A was established by X-ray diffraction analysis employing graphite monochromated Mo K_α radiation(λ ? 0.71073 ?) with small Flack parameter 0.03. Chromopeptide A suppressed the proliferation of HL-60, K-562, and Ramos cells with average IC_(50) values of 7.7, 7.0, and 16.5 nmol/L, respectively.
基金supported financially by the National Science & Technology Major Project ‘Key New Drug Creation and Manufacturing Program’ of China(Grant No.2014ZX09507002)the National Marine ‘863’ Project(No.2013AA092902)
文摘Histone acetylation is a critical process in the regulation of chromatin structure and gene expression.Histone deacetylases(HDACs)remove the acetyl group,leading to chromatin condensation and transcriptional repression.HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects.This paper describes our work on the structural determination and structure-activity relationship(SAR)optimization of tetrahydroisoquinoline compounds as HDAC inhibitors.These compounds were tested for their ability to inhibit HDAC 1,3,6 and for their ability to inhibit the proliferation of a panel of cancer cell lines.Among these,compound 82 showed the greatest inhibitory activity toward HDAC 1,3,6 and strongly inhibited growth of the cancer cell lines,with results clearly superior to those of the reference compound,vorinostat(SAHA).Compound 82 increased the acetylation of histones H3,H4 and tubulin in a concentration-dependent manner,suggesting that it is a broad inhibitor of HDACs.
基金This study was supported by the National Natural Science Foundation of China(Nos.81872758 and 21772213)the Shanghai Rising-Star program Foundation(SCST,Nos.19QA1410800)the Youth Innovation Promotion Association,Chinese Academy of Sciences.
文摘Main observation and conclusion As part of our continuing efforts toward the discovery of the biologically active diterpenoids from medicinal plants,six new C-ring aromatized abietane diterpenoids,clerodenoids A-F(1-6),were isolated from Clerodendrum chinense.
基金supported by grants from the Emergency Prevention and Control of COVID-19 Project of Henan Province(No.201100310900)the National Natural Science Foundation of China(No.91942314,U1804281,and 81602024).
文摘Dear Editor,Recently,the novel coronavirus disease(COVID-19)has broken out worldwide,1 with rapid increase of infected patients.COVID-19 dominantly leads to pneumonia.2 Among these COVID-19 patients,some appears to be severe symptoms with acute respiratory distress syndrome,organ failure,2 and further present a poor outcome.
基金supported by grants from National Natural Science Foundation(Grants Nos.81773565,81703327,81430080,81573452,and 81773767)Supporting grants from the Key Program of the Frontier Science(Grant No.160621,China)of the Chinese Academy of Sciences+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA12020374,China)support from the State Key Laboratory of Esophageal Cancer Prevention and Treatment,Ministry of Education of China,Zhengzhou University(Grant No.K2020-0012,China)
文摘Medulloblastoma(MB)is a common yet highly heterogeneous childhood malignant brain tumor,however,clinically effective molecular targeted therapy is lacking.Modulation of hedgehog(HH)signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4(BRD4)has recently spurred new interest as potential treatment of HH-driven MB.Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog(GLI)protein,the BRD4 inhibitor 2 was selected as the lead for further structural optimization,which led to the identification of compounds 25 and 35 as the high potency HH inhibitors.Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI,and were equally potent against the clinical resistant mutants and the wild type of smoothened(SMO)receptor with IC50 values around 1 nmol/L.In the resistant MB allograft mice,compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg(TGI=83.3%)and 10 mg/kg(TGI=87.6%)doses.Although further modification is needed to improve the pharmacokinetic(PK)parameters,compound 25 represents an efficacious lead compound of GLI inhibitors,possessing optimal safety and tolerance to fight against HH-driven MB.
文摘This study aims to demonstrate that blocking the receptor-interacting protein2(Rip2)expression can decrease inflammatory cytokine production by macrophage and protect mice from endotoxin lethality.Murine Rip2 small interfering RNA(siRNA)plasmids were constructed and transfected into macrophage and Rip2 expression was detected with reverse transcription-polymerase chain reaction(RT-PCR)and western blot.Cell proliferation was assayed withMTT.TNF-a concentration was assayed with ELISA and high-mobility group box 1 protein(HMGB1)level with semi-quantitative western blot after lipopolysaccharide(LPS)stimulation.LPS challenge was given after the plasmids were injected into mice and the survival rate was calculated.Rip2 siRNA plasmid could block the mRNA and protein expression of Rip2 and promote cell proliferation.Blocking Rip2 could attenuate LPS-induced TNF-a and HMGB1 production.The HMGB1 expression in the liver decreased to(40.21±11.03)pg/g,and serum TNF-a level decreased to(300.43±59.26)ng/L(P<0.05).The survival rate of mice from endotoxemia was also improved(P<0.05).The results demonstrate that Rip2 siRNA plasmid can block the expression of Rip2,decrease the production of TNF-a and HMGB1 and protect mice from fatal endotoxemia.
