Bromophenols are a set of natural products widely distributed in seaweed, most of which exhibit interesting and useful biological activities. To develop a reliable and efficient synthetic route to these natural bromop...Bromophenols are a set of natural products widely distributed in seaweed, most of which exhibit interesting and useful biological activities. To develop a reliable and efficient synthetic route to these natural bromophenols, three of them, 3,4-dibromo-5-(2′-bromo-3′,4′- dihydroxy-6′-methoxymethyl- benzyl)-benzene-1,2-diol (compound 9), 3,4-dibromo-5-(2′-bromo-6′-ethoxy methyl-3′,4′-dihydroxybenzyl)- benzene-1,2-diol (compound 10), and 3-bromo-4-(3′-bromo-4′,5′-dihydroxy benzyl)-5-(ethoxymethyl)- benzene-1,2-diol (compound 14), isolated from red marine algae, have been synthesized in eight steps with an overall yield of 14.4%, 14.4%, and 18.2% respectively, via a practical approach employing bromination, Wolff-Kishner-Huang reduction and a Friedel-Crafts reaction as key steps. The protein tyrosine phosphatase 1B (PTP1B) inhibitory activities of the synthetic compounds were evaluated by the colorimetric assay. The results show that these compounds are moderate PTP1B inhibitors. The synthesis of these bromophenol derivatives makes in vivo studies of their structure-activity relationships and inhibition activity against PTP1B possible.展开更多
Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we sho...Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we showed that zebrafish cdk1^(-/-)embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry,M phase progression,and cell differentiation but not in interkinetic nuclear migration.We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis.While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells,the depletion of cyclin B1 led to M phase arrest.Moreover,phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2mutants,but not in ccnb1 mutants.Furthermore,overexpression of TOP2A^(S1213D),the phosphomimetic form of human TOP2A,rescued S phase entry and alleviated the microphthalmia defects in both cdk1^(-/-)and ccna2^(-/-)embryos.Taken together,our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression.展开更多
Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, ...Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase(SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.展开更多
Objective:In this study,we used HepG2 human hepatocellular carcinoma cells to study the effects of Compound Xishu Granule(CXG)on cell proliferation,apoptosis,and the cell cycle in vitro.We also used a xenograft tumor ...Objective:In this study,we used HepG2 human hepatocellular carcinoma cells to study the effects of Compound Xishu Granule(CXG)on cell proliferation,apoptosis,and the cell cycle in vitro.We also used a xenograft tumor model to study the anti-tumor effects of CXG and related mechanisms in vivo.Methods:The effect of CXG on cell viability was measured using Cell Counting Kit-8 and a colony formation assay.The effect of CXG on apoptosis and the cell cycle was analyzed using flow cytometry.The in vivo anti-tumor effect of CXG was assessed by measuring the volume change in xenograft tumors after drug administration.The CXG anti-tumor mechanism was studied using western blotting assay to detect cell cycle and apoptotic associated proteins.Results:CXG suppressed HepG2 cell proliferation in a time-and dose-dependent manner in vitro.Colony formation experiments showed that CXG administration for 24 h significantly reduced HepG2 cell formations(P<.01).Flow cytometric analysis showed that CXG treatment for 48 h promoted apoptosis and blocked HepG2 cells in the G2/M phase.Western blotting results showed that Bax was significantly upregulated and Bcl-2 was down-regulated in graft tumor tissues and HepG2 cells after CXG administration,which increased the Bax/Bcl-2 ratio.PLK1,CDC25 C,CDK1,and Cyclin B1 expression were upregulated.CXG had a good inhibitory effect on graft tumor growth in vivo.Conclusion:CXG has good anti-tumor effects in vitro and in vivo.In vitro,CXG promoted HepG2 cell apoptosis and induced G2/M phase arrest.In vivo,CXG significantly inhibited graft tumor growth.The CXG mechanism in treating hepatocellular carcinoma may be that CXG can induce abnormal apoptotic and cell cycle associated protein expression,leading to mitotic catastrophe and apoptosis.展开更多
We isolated cucurbitacinⅡa from the rhizomes of Hemsleya pengxianensis,and tested the cytotoxicity of cucurbitacinⅡa against various cancer cell lines by the sulforhodamine B assay(SRB).At the same time,we prelimina...We isolated cucurbitacinⅡa from the rhizomes of Hemsleya pengxianensis,and tested the cytotoxicity of cucurbitacinⅡa against various cancer cell lines by the sulforhodamine B assay(SRB).At the same time,we preliminarily found that cucurbitacinⅡa has a certain inhibitory activity on kinase CDK1/cyclin B,and shows potent inhibitory activities against many cancer cell lines.The cucurbitacinⅡa was structurally characterized by specific optical rotation measurement,high-resolution mass spectroscopy and NMR spectroscopic analysis.In addition,the molecular structure of cucurbitacinⅡa was further determined by X-ray single-crystal crystallography.展开更多
Valeriaquinone A(1),an unprecedented anthraquinone–coumarin hybrid,was isolated from the roots of Knoxia valerianoides.Its structure was determined by extensive spectroscopic analyses and X-ray diffraction.The plausi...Valeriaquinone A(1),an unprecedented anthraquinone–coumarin hybrid,was isolated from the roots of Knoxia valerianoides.Its structure was determined by extensive spectroscopic analyses and X-ray diffraction.The plausible biosynthetic pathways for 1 were proposed.Compound 1 exhibited strong protein tyrosine phosphatase 1 B(PTP1 B)inhibition with high selectivity(>30 fold)over homologous T cell protein tyrosine phosphatase(TCPTP)potentially by binding to an allosteric site predicted by kinetic analysis and molecular docking.Moreover,compound 1 showed significant cytotoxic activities against three human hepatoma cell lines(HepG2,QGY-7703,and SMMC-7721)with half maximal inhibitory concentration(IC_(50))values of 1.39±0.2,10.34±2.09,and 5.56±0.47μmol/L,respectively.展开更多
Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
A novel sarsolenane diterpene, named secodihydrosarsolenone （1）, as a minor component was obtained from the South China Sea soft coral Sarcophyton trocheliophorum Marenzeller. Its structure was elucidated by detaile...A novel sarsolenane diterpene, named secodihydrosarsolenone （1）, as a minor component was obtained from the South China Sea soft coral Sarcophyton trocheliophorum Marenzeller. Its structure was elucidated by detailed spectroscopic analysis. Compound 1 exhibited moderate inhibitory activity （IC50= 13.7 μmol·L^-1） against protein tyrosine phosphatase 1B （PTP1B）, a key target for the treatment of type 2 diabetes, representing the first report of PTP1B inhibitory activity for sarsolenane diterpenes. This discovery promotes computational prediction of binding mode between the enzyme and the metabolite, suggesting a crucial role of the residues Tyr46, Ser216 and Arg221 in the binding action.展开更多
基金Supported by the National Major Research Program of China (No.2009ZX09103-148)the National High Technology Research and Development Program of China (863 program) (Nos.2007AA09Z410,2007AA091604)
文摘Bromophenols are a set of natural products widely distributed in seaweed, most of which exhibit interesting and useful biological activities. To develop a reliable and efficient synthetic route to these natural bromophenols, three of them, 3,4-dibromo-5-(2′-bromo-3′,4′- dihydroxy-6′-methoxymethyl- benzyl)-benzene-1,2-diol (compound 9), 3,4-dibromo-5-(2′-bromo-6′-ethoxy methyl-3′,4′-dihydroxybenzyl)- benzene-1,2-diol (compound 10), and 3-bromo-4-(3′-bromo-4′,5′-dihydroxy benzyl)-5-(ethoxymethyl)- benzene-1,2-diol (compound 14), isolated from red marine algae, have been synthesized in eight steps with an overall yield of 14.4%, 14.4%, and 18.2% respectively, via a practical approach employing bromination, Wolff-Kishner-Huang reduction and a Friedel-Crafts reaction as key steps. The protein tyrosine phosphatase 1B (PTP1B) inhibitory activities of the synthetic compounds were evaluated by the colorimetric assay. The results show that these compounds are moderate PTP1B inhibitors. The synthesis of these bromophenol derivatives makes in vivo studies of their structure-activity relationships and inhibition activity against PTP1B possible.
基金supported by grants from the National Key Research and Development Program of China (2017YFA0104600)the National Natural Science Foundation of China (31970767, 31771597 and 31571515)+1 种基金the National Basic Research Program of China (973 Program 2012CB966601 and 2013CB945300)the Ministry of Science and Technology of the People’s Republic of China (2011DFB30010)。
文摘Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we showed that zebrafish cdk1^(-/-)embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry,M phase progression,and cell differentiation but not in interkinetic nuclear migration.We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis.While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells,the depletion of cyclin B1 led to M phase arrest.Moreover,phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2mutants,but not in ccnb1 mutants.Furthermore,overexpression of TOP2A^(S1213D),the phosphomimetic form of human TOP2A,rescued S phase entry and alleviated the microphthalmia defects in both cdk1^(-/-)and ccna2^(-/-)embryos.Taken together,our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression.
基金supported b y the Na tional In stitu te o f Health(1R01CA172268)the Leukemia&Lymphoma Society(1024-14+7 种基金TRP-6024-14)the Robert A.Welch Foundation(I-1834)the Cancer Prevention and Research Institute of Texas(RP140402 and DP150056)the Innovation Program of Shanghai Municipal Education Commission(13G20)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learningthe National Natural Science Foundation of China(813706548142200181471524)
文摘Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase(SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.
基金the Major Innovative Drug Development Project from Ministry of Science and Technology of the People’s Republic of China(Project No.2017ZX09301011)。
文摘Objective:In this study,we used HepG2 human hepatocellular carcinoma cells to study the effects of Compound Xishu Granule(CXG)on cell proliferation,apoptosis,and the cell cycle in vitro.We also used a xenograft tumor model to study the anti-tumor effects of CXG and related mechanisms in vivo.Methods:The effect of CXG on cell viability was measured using Cell Counting Kit-8 and a colony formation assay.The effect of CXG on apoptosis and the cell cycle was analyzed using flow cytometry.The in vivo anti-tumor effect of CXG was assessed by measuring the volume change in xenograft tumors after drug administration.The CXG anti-tumor mechanism was studied using western blotting assay to detect cell cycle and apoptotic associated proteins.Results:CXG suppressed HepG2 cell proliferation in a time-and dose-dependent manner in vitro.Colony formation experiments showed that CXG administration for 24 h significantly reduced HepG2 cell formations(P<.01).Flow cytometric analysis showed that CXG treatment for 48 h promoted apoptosis and blocked HepG2 cells in the G2/M phase.Western blotting results showed that Bax was significantly upregulated and Bcl-2 was down-regulated in graft tumor tissues and HepG2 cells after CXG administration,which increased the Bax/Bcl-2 ratio.PLK1,CDC25 C,CDK1,and Cyclin B1 expression were upregulated.CXG had a good inhibitory effect on graft tumor growth in vivo.Conclusion:CXG has good anti-tumor effects in vitro and in vivo.In vitro,CXG promoted HepG2 cell apoptosis and induced G2/M phase arrest.In vivo,CXG significantly inhibited graft tumor growth.The CXG mechanism in treating hepatocellular carcinoma may be that CXG can induce abnormal apoptotic and cell cycle associated protein expression,leading to mitotic catastrophe and apoptosis.
基金supported by the National Natural Science Foundation of China(No.81903473)the Innovaton Project of Shandong Academy of Medical Sciences。
文摘We isolated cucurbitacinⅡa from the rhizomes of Hemsleya pengxianensis,and tested the cytotoxicity of cucurbitacinⅡa against various cancer cell lines by the sulforhodamine B assay(SRB).At the same time,we preliminarily found that cucurbitacinⅡa has a certain inhibitory activity on kinase CDK1/cyclin B,and shows potent inhibitory activities against many cancer cell lines.The cucurbitacinⅡa was structurally characterized by specific optical rotation measurement,high-resolution mass spectroscopy and NMR spectroscopic analysis.In addition,the molecular structure of cucurbitacinⅡa was further determined by X-ray single-crystal crystallography.
基金National Natural Science Foundation of China(No.81703391)Shandong Provincial Natural Science Foundation of China(No.ZR2020KB015)Key R&D Program of Shandong Province(No.2019JZZY011104,China)。
文摘Valeriaquinone A(1),an unprecedented anthraquinone–coumarin hybrid,was isolated from the roots of Knoxia valerianoides.Its structure was determined by extensive spectroscopic analyses and X-ray diffraction.The plausible biosynthetic pathways for 1 were proposed.Compound 1 exhibited strong protein tyrosine phosphatase 1 B(PTP1 B)inhibition with high selectivity(>30 fold)over homologous T cell protein tyrosine phosphatase(TCPTP)potentially by binding to an allosteric site predicted by kinetic analysis and molecular docking.Moreover,compound 1 showed significant cytotoxic activities against three human hepatoma cell lines(HepG2,QGY-7703,and SMMC-7721)with half maximal inhibitory concentration(IC_(50))values of 1.39±0.2,10.34±2.09,and 5.56±0.47μmol/L,respectively.
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
基金Acknowledgement This research work was financially supported by the National Natural Science Foundation of China （Nos. 41506187, 81520108028, 21672230, 41676073, 81603022）, SCTSM Project （No. 15431901000, 14431901100）, the Hunan Provincial Natural Science Foundation of China （2015JJ3176）, and the SKLDR/SIMM Projects （No. SIMMI501ZZ-03）. Linfu Liang thanks to the financial support of the China Postdoctoral Science Foundation （2016M601677）. The authors are grateful to Mr. Li-Gong Yao of State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, for his valuable work on collection of the sample.
文摘A novel sarsolenane diterpene, named secodihydrosarsolenone （1）, as a minor component was obtained from the South China Sea soft coral Sarcophyton trocheliophorum Marenzeller. Its structure was elucidated by detailed spectroscopic analysis. Compound 1 exhibited moderate inhibitory activity （IC50= 13.7 μmol·L^-1） against protein tyrosine phosphatase 1B （PTP1B）, a key target for the treatment of type 2 diabetes, representing the first report of PTP1B inhibitory activity for sarsolenane diterpenes. This discovery promotes computational prediction of binding mode between the enzyme and the metabolite, suggesting a crucial role of the residues Tyr46, Ser216 and Arg221 in the binding action.
