A series of novel phenoxazinone derivatives （1-6） were designed and synthesized for evaluating their antitumor activities. The antiproliferative activities of the prepared compounds against representative human neop...A series of novel phenoxazinone derivatives （1-6） were designed and synthesized for evaluating their antitumor activities. The antiproliferative activities of the prepared compounds against representative human neoplastic cell lines were evaluated by MTF assay. The results showed that most of them inhibited cell proliferation in a submicromolar to rnicromolar range. These compounds were also evaluated against KBv200 and MCF-7/Adr cell lines, which overexpress the MDR/P-glycoprotein drug efflux pump responsible for drug resistance, and had a more potential for resisting MDR than their lead compound APO.展开更多
Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regress...Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.展开更多
Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in mul...Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.展开更多
Osteosarcoma(OS)is the most common primary malignant bone tumor in children and adolescents.Although activator of HSP90 ATPase activity 1(AHA1)is reported to be a potential oncogene,its role in osteosarcoma progressio...Osteosarcoma(OS)is the most common primary malignant bone tumor in children and adolescents.Although activator of HSP90 ATPase activity 1(AHA1)is reported to be a potential oncogene,its role in osteosarcoma progression remains largely unclear.Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis,the relationship between AHA1 and cancer metabolism is unknown.In this study,we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients.AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo.Mechanistically,AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma.Notably,we identifed that isocitrate dehydrogenase 1(IDH1)is a novel client protein of Hsp90 AHA1.Furthermore,the IDH1 protein level was positively correlated with AHA1 in osteosarcoma.And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma.Moreover,high IDH1 level was also associated with poor prognosis of osteosarcoma patients.This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis,which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.展开更多
A Rubik’s cube as a reconfigurable microfluidic system is presented in this work.Composed of physically interlocking microfluidic blocks,the microfluidic cube enables the on-site design and configuration of custom mi...A Rubik’s cube as a reconfigurable microfluidic system is presented in this work.Composed of physically interlocking microfluidic blocks,the microfluidic cube enables the on-site design and configuration of custom microfluidics by twisting the faces of the cube.The reconfiguration of the microfluidics could be done by solving an ordinary Rubik’s cube with the help of Rubik’s cube algorithms and computer programs.An O-ring-aided strategy is used to enable self-sealing and the automatic alignment of the microfluidic cube blocks.Owing to the interlocking mechanics of cube blocks,the proposed microfluidic cube exhibits good reconfigurability and robustness in versatile applications and proves to be a promising candidate for the rapid deployment of microfluidic systems in resource-limited settings.展开更多
基金support by the National Natural Science Foundation of China(No.20472117)the Science Foundation of Zhuhai(PC20041131)the Scientific Research Foundation for the Returned 0verseas Chinese Scholars.
文摘A series of novel phenoxazinone derivatives （1-6） were designed and synthesized for evaluating their antitumor activities. The antiproliferative activities of the prepared compounds against representative human neoplastic cell lines were evaluated by MTF assay. The results showed that most of them inhibited cell proliferation in a submicromolar to rnicromolar range. These compounds were also evaluated against KBv200 and MCF-7/Adr cell lines, which overexpress the MDR/P-glycoprotein drug efflux pump responsible for drug resistance, and had a more potential for resisting MDR than their lead compound APO.
基金supported by the National Natural Science Foundation of China(Nos.U21A20421,82073882,82073317,81772540 and 82272996)the Key Project of Science Technology Program of Guangzhou(No.2023B03J0029,China)+1 种基金the National Key R&D Program of China(No.2022YFE0209700)the Science and Technology Program of Guangzhou(Nos.202201010819 and 202206010081,China)。
文摘Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.
基金supported by funds from the National Key Research and Development Program of China No.2017YFA0505104(Zhi Shi)the National Natural Science Foundation of China Nos.81772540 and 82272996(Zhi Shi)+1 种基金the Science and Technology Program of Guangdong No.2019A050510023(Zhi Shi,China)the Science and Technology Program of Guangzhou No.20220-6010081(Zhi Shi,China).
文摘Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.
基金This work was supported by funds from the National Key Research and Development Program of China(No.2017YFA0505104)National Natural Science Foundation of China(Nos.81772540,81472506.81772861)+7 种基金the Science and Technology Program of Guangdong(No.2019A050510023)Guangdong Province Special Fund for Science and Technology Development(No.2017A050501015)Natural Science Foundation of Guangdong(Nos.2016A030313227,2018A030313689)the Science and Technology Program of Guangzhou(Nos.201704030008,201707010007)the Fundamental Research Funds for the Central Universities(No.19ykzd10)Cultivation of Major Projects,Sun Yat-sen University(No.80000-18823701)Cultivation of International Scientifhc Research Cooperation Platform.Sun Yat-sen University(No.800018827202)“3×3”Project,the First Afliated Hospital of Sun Yat-sen Universty(No.Y70215).
文摘Osteosarcoma(OS)is the most common primary malignant bone tumor in children and adolescents.Although activator of HSP90 ATPase activity 1(AHA1)is reported to be a potential oncogene,its role in osteosarcoma progression remains largely unclear.Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis,the relationship between AHA1 and cancer metabolism is unknown.In this study,we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients.AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo.Mechanistically,AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma.Notably,we identifed that isocitrate dehydrogenase 1(IDH1)is a novel client protein of Hsp90 AHA1.Furthermore,the IDH1 protein level was positively correlated with AHA1 in osteosarcoma.And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma.Moreover,high IDH1 level was also associated with poor prognosis of osteosarcoma patients.This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis,which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.
基金This work is supported by the National Key R&D Program of China(Nos.2018YFE0205000,2017YFA0205103)the National Natural Science Foundation of China(No.81571766)+1 种基金the Natural Science Foundation of Tianjin(No.17JCYBJC24400)the 111 Project of China(No.B07014).
文摘A Rubik’s cube as a reconfigurable microfluidic system is presented in this work.Composed of physically interlocking microfluidic blocks,the microfluidic cube enables the on-site design and configuration of custom microfluidics by twisting the faces of the cube.The reconfiguration of the microfluidics could be done by solving an ordinary Rubik’s cube with the help of Rubik’s cube algorithms and computer programs.An O-ring-aided strategy is used to enable self-sealing and the automatic alignment of the microfluidic cube blocks.Owing to the interlocking mechanics of cube blocks,the proposed microfluidic cube exhibits good reconfigurability and robustness in versatile applications and proves to be a promising candidate for the rapid deployment of microfluidic systems in resource-limited settings.
