Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI), including acute respiratory distress syndrome(ARDS), in patients after cardiac surgery. We previously foun...Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI), including acute respiratory distress syndrome(ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles(eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of e EVs after cardiopulmonary bypass, remains unclear. Plasma plasminogenactivated inhibitor-1(PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice(C57BL/6,Toll-like receptor 4 knockout(TLR4^(-/-))) and inducible nitric oxide synthase knockout(iNOS^(-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3(JAK2/3)-signal transducer and activator of transcription 3(STAT3)-interferon regulatory factor 1(IRF-1)pathway, along with i NOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors(AG490 or S3I-201, respectively), and was relieved in TLR4-/-and iNOS-/-mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1(FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/展开更多
Recently,a novel research led by Mallika Singh and Kenneth P.Olive^(1,2) published in Nature identified a highly selective inhibitor(RMC-7977)of the active GTP-bound forms of human RAS family(KRAS,HRAS and NRAS)with a...Recently,a novel research led by Mallika Singh and Kenneth P.Olive^(1,2) published in Nature identified a highly selective inhibitor(RMC-7977)of the active GTP-bound forms of human RAS family(KRAS,HRAS and NRAS)with affinity for both mutant and wild-type variants.Moreover,they assessed the therapeutic potential of RMC-7977 in a comprehensive range of human pancreatic ductal adenocarcinoma(PDAC)models and proved that RMC-7977 could induce apoptosis and sustained proliferative arrest,whereas normal tissues underwent only transient decreases in proliferation.Meanwhile.展开更多
Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer metabolism.Despite the therapeutic potential of NAMPT enzymatic inhibitors,their effec...Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer metabolism.Despite the therapeutic potential of NAMPT enzymatic inhibitors,their effectiveness is limited by dose-related toxicity and the inability to suppress nonenzymatic functions of extracellular NAMPT(e NAMPT).Herein,we designed and synthesized the first hydrophobic tagging NAMPT degraders.Among them,compound NH-11 selectively degraded NAMPT in leukemia cells through the ubiquitin-proteasome system.Compound NH-11 effectively induced apoptosis and showed low toxicity to normal cells,representing a promising anti-leukemia lead compound.?2024 Published by Elsevier B.V.on behalf of Chinese Chemical Society and Institute of Materia Medica,Chinese Academy of Medical Sciences.展开更多
Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which ...Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.展开更多
OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative dis⁃ease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy,weakness and paralysis.Oxida...OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative dis⁃ease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy,weakness and paralysis.Oxida⁃tive stress plays a key role in the pathogenesis of ALS,including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase 1(SOD1).Moreover,although the pathogenesis of ALS is unclear,the abnormal accumulation of TAR DNA-binding pro⁃tein of 43 ku(TDP-43)is a pathological feature that exists in almost all patients.Thus far,there is no drug that can cure ALS/FTLD.Tetramethyl⁃pyrazine nitrone(TBN)is a derivative of tetra⁃methylapyrazine,derived from the traditional Chinese medicine Ligusticum chuanxiong,which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases.TBN is currently under clinical investi⁃gation for several indications including a phaseⅡtrial of ALS.Here,we explored the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse model.METHODS In the SOD1G93A transgenic mouse model,TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits.At the same time,we unilaterally and bilaterally injected the TDP-43M337V virus into the striatum of the WT mouse,and gave the TBN treatment after the mice developed a phenotype.After administering these two models for a period of time,we con⁃ducted behavioral tests,including rotarod test,balance beam test,climbing pole test,etc,to evaluate the efficacy of TBN on SOD1G93A and TDP-43M337V models.Furthermore,we explored the possible mechanism of action of TBN in the treatment of ALS through Western blotting and immunohistochemistry/immunofluorescence staining analysis.RESULTS In the SOD1G93A transgenic mouse model,TBN slowed the pro⁃gression of motor neuron disease as evidenced by improved motor performance,reduced spinal motor neuron loss and the associated glial response,and decreased skeletal muscl展开更多
The ability to widely tune the optical properties of amorphous alloys is highly desirable especially for their potential applications in optoelectronic devices.In this work,we demonstrate that introducing oxygen into ...The ability to widely tune the optical properties of amorphous alloys is highly desirable especially for their potential applications in optoelectronic devices.In this work,we demonstrate that introducing oxygen into an amorphous alloy system of Co-Fe-Ta-B enables the formation of various amorphous derivatives ranging from metals to semiconductors,and eventually to insulators.These oxygencontaining amorphous derivatives gradually become transparent with the opened bandgaps,leading to a continuous increase in their optical transmittance.Furthermore,the reflective metal-type amorphous alloy and transparent insulator-type amorphous oxide of the system can be integrated together to realize the full-color tuning over the entire visible spectral range.This provides a new way to develop large-area color coatings with high design flexibility and full-color tunability.We envisage that the design concept proposed in this work is also applicable to many other amorphous alloy systems,from which all types of amorphous materials including alloys,semiconductors and insulators may be developed to show unprecedented optical functionalities.展开更多
In vitro cultures of primary cortical neurons are widely used to investigate neuronal function.However,it has yet to be fully investigated whether there are significant differences in development and function between ...In vitro cultures of primary cortical neurons are widely used to investigate neuronal function.However,it has yet to be fully investigated whether there are significant differences in development and function between cultured rodent and primate cortical neurons,and whether these differences influence the utilization of cultured cortical neurons to model pathological conditions.Using in vitro culture techniques combined with immunofluorescence and electrophysiological methods,our study found that the development and maturation of primary cerebral cortical neurons from cynomolgus monkeys were slower than those from mice.We used a microelectrode array technique to compare the electrophysiological differences in cortical neurons,and found that primary cortical neurons from the mouse brain began to show electrical activity earlier than those from the cynomolgus monkey.Although cultured monkey cortical neurons developed slowly in vitro,they exhibited typical pathological features-revealed by immunofluorescent staining-when infected with adeno-associated viral vectors expressing mutant huntingtin(HTT),the Huntington’s disease protein.A quantitative analysis of the cultured monkey cortical neurons also confirmed that mutant HTT significantly reduced the length of neurites.Therefore,compared with the primary cortical neurons of mice,cultured monkey cortical neurons have longer developmental and survival times and greater sustained physiological activity,such as electrophysiological activity.Our findings also suggest that primary cynomolgus monkey neurons cultured in vitro can simulate a cell model of human neurodegenerative disease,and may be useful for investigating time-dependent neuronal death as well as treatment via neuronal regeneration.All mouse experiments and protocols were approved by the Animal Care and Use Committee of Jinan University of China(IACUC Approval No.20200512-04)on May 12,2020.All monkey experiments were approved by the IACUC protocol(IACUC Approval No.LDACU 20190820-01)on August 23,2019 for anim展开更多
基金supported by the National Key Research and Development Program of China(2021YFA0805100)the National Natural Science Foundation of China(81830013,81770241,81970363,82000362,92268202,81170271,81370370,81490531,81670392,81600382)+6 种基金the National Natural Science Foundation of China Distinguished Young Scholar Grant(81325001)“973 Project”from the Ministry of Science and Technology of China(2009CB522104)Guangdong Basic and Applied Basic Research Foundation,China(2019B1515120092)the Science and Technology Planning Project of Guangzhou,China(202103000016)the Changjiang Scholars Program from the Ministry of Education of Chinathe Sun Yat-sen University Clinical Research 5010 Programthe Program of National Key Clinical Specialties。
文摘Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI), including acute respiratory distress syndrome(ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles(eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of e EVs after cardiopulmonary bypass, remains unclear. Plasma plasminogenactivated inhibitor-1(PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice(C57BL/6,Toll-like receptor 4 knockout(TLR4^(-/-))) and inducible nitric oxide synthase knockout(iNOS^(-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3(JAK2/3)-signal transducer and activator of transcription 3(STAT3)-interferon regulatory factor 1(IRF-1)pathway, along with i NOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors(AG490 or S3I-201, respectively), and was relieved in TLR4-/-and iNOS-/-mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1(FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/
文摘Recently,a novel research led by Mallika Singh and Kenneth P.Olive^(1,2) published in Nature identified a highly selective inhibitor(RMC-7977)of the active GTP-bound forms of human RAS family(KRAS,HRAS and NRAS)with affinity for both mutant and wild-type variants.Moreover,they assessed the therapeutic potential of RMC-7977 in a comprehensive range of human pancreatic ductal adenocarcinoma(PDAC)models and proved that RMC-7977 could induce apoptosis and sustained proliferative arrest,whereas normal tissues underwent only transient decreases in proliferation.Meanwhile.
基金supported by the National Key Research and Development Program of China(No.2022YFC3401500 to C.S.)the National Natural Science Foundation of China(No.82030105 to C.S.)and Shanghai Rising-Star Program(No.20QA1411700 to G.D.)。
文摘Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer metabolism.Despite the therapeutic potential of NAMPT enzymatic inhibitors,their effectiveness is limited by dose-related toxicity and the inability to suppress nonenzymatic functions of extracellular NAMPT(e NAMPT).Herein,we designed and synthesized the first hydrophobic tagging NAMPT degraders.Among them,compound NH-11 selectively degraded NAMPT in leukemia cells through the ubiquitin-proteasome system.Compound NH-11 effectively induced apoptosis and showed low toxicity to normal cells,representing a promising anti-leukemia lead compound.?2024 Published by Elsevier B.V.on behalf of Chinese Chemical Society and Institute of Materia Medica,Chinese Academy of Medical Sciences.
基金supported by the Science and Technology Development Fund(Grant Nos.:0007/2020/A1 and 0020/2022/A1)the State Key Laboratory of Quality Research in Chinese Medicine,University of Macao(Grant No.:SKL-QRCM(UM)-2020-2022)+4 种基金the University of Macao(Grant Nos.:MYRG2019-00002-ICMS and MYRG2020-00017-ICMS)2022 Internal Research Grant of SKLQRCM(University of Macao)(Grant No.:QRCM-IRG2022-011)the National Natural Science Foundation of China(Grant No.:22101230)the Natural Science Basic Research Program of Shaanxi(Grant No.:2021JQ-089)the Natural Science Foundation of Chongqing,China(Grant No.:cstc2021jcyj-msxmX0659).
文摘Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.
文摘OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative dis⁃ease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy,weakness and paralysis.Oxida⁃tive stress plays a key role in the pathogenesis of ALS,including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase 1(SOD1).Moreover,although the pathogenesis of ALS is unclear,the abnormal accumulation of TAR DNA-binding pro⁃tein of 43 ku(TDP-43)is a pathological feature that exists in almost all patients.Thus far,there is no drug that can cure ALS/FTLD.Tetramethyl⁃pyrazine nitrone(TBN)is a derivative of tetra⁃methylapyrazine,derived from the traditional Chinese medicine Ligusticum chuanxiong,which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases.TBN is currently under clinical investi⁃gation for several indications including a phaseⅡtrial of ALS.Here,we explored the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse model.METHODS In the SOD1G93A transgenic mouse model,TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits.At the same time,we unilaterally and bilaterally injected the TDP-43M337V virus into the striatum of the WT mouse,and gave the TBN treatment after the mice developed a phenotype.After administering these two models for a period of time,we con⁃ducted behavioral tests,including rotarod test,balance beam test,climbing pole test,etc,to evaluate the efficacy of TBN on SOD1G93A and TDP-43M337V models.Furthermore,we explored the possible mechanism of action of TBN in the treatment of ALS through Western blotting and immunohistochemistry/immunofluorescence staining analysis.RESULTS In the SOD1G93A transgenic mouse model,TBN slowed the pro⁃gression of motor neuron disease as evidenced by improved motor performance,reduced spinal motor neuron loss and the associated glial response,and decreased skeletal muscl
基金financially supported by the National Science Fund for Excellent Young Scholars (51922053)the School of Materials Science and Engineering at Tsinghua Universitythe funding from the National Key Research and Development Program (2016YFB0700402)+2 种基金the National Natural Science Foundation of China (51822105 and 11834009)the City University of Hong Kong (9610484)the Shenzhen Research Institute, the City University of Hong Kong
文摘The ability to widely tune the optical properties of amorphous alloys is highly desirable especially for their potential applications in optoelectronic devices.In this work,we demonstrate that introducing oxygen into an amorphous alloy system of Co-Fe-Ta-B enables the formation of various amorphous derivatives ranging from metals to semiconductors,and eventually to insulators.These oxygencontaining amorphous derivatives gradually become transparent with the opened bandgaps,leading to a continuous increase in their optical transmittance.Furthermore,the reflective metal-type amorphous alloy and transparent insulator-type amorphous oxide of the system can be integrated together to realize the full-color tuning over the entire visible spectral range.This provides a new way to develop large-area color coatings with high design flexibility and full-color tunability.We envisage that the design concept proposed in this work is also applicable to many other amorphous alloy systems,from which all types of amorphous materials including alloys,semiconductors and insulators may be developed to show unprecedented optical functionalities.
基金This work was supported by the National Natural Science Foundation of China,No.81922026(to SY)the National Key Research and Development Program of China Stem Cell and Translational Research,No.2017YFA0105104(to SY)+3 种基金Key Field Research and Development Program of Guangdong Province,No.2018B030337001(to XJL)Guangdong Key Laboratory of Non-human Primate Models of Brain Diseases,No.2020B121201006(to XJL)Guangzhou Key Research Program on Brain Science,No.202007030008(to SY)the Fundamental Research Funds for the Central Universities,No.21619104(to SY).
文摘In vitro cultures of primary cortical neurons are widely used to investigate neuronal function.However,it has yet to be fully investigated whether there are significant differences in development and function between cultured rodent and primate cortical neurons,and whether these differences influence the utilization of cultured cortical neurons to model pathological conditions.Using in vitro culture techniques combined with immunofluorescence and electrophysiological methods,our study found that the development and maturation of primary cerebral cortical neurons from cynomolgus monkeys were slower than those from mice.We used a microelectrode array technique to compare the electrophysiological differences in cortical neurons,and found that primary cortical neurons from the mouse brain began to show electrical activity earlier than those from the cynomolgus monkey.Although cultured monkey cortical neurons developed slowly in vitro,they exhibited typical pathological features-revealed by immunofluorescent staining-when infected with adeno-associated viral vectors expressing mutant huntingtin(HTT),the Huntington’s disease protein.A quantitative analysis of the cultured monkey cortical neurons also confirmed that mutant HTT significantly reduced the length of neurites.Therefore,compared with the primary cortical neurons of mice,cultured monkey cortical neurons have longer developmental and survival times and greater sustained physiological activity,such as electrophysiological activity.Our findings also suggest that primary cynomolgus monkey neurons cultured in vitro can simulate a cell model of human neurodegenerative disease,and may be useful for investigating time-dependent neuronal death as well as treatment via neuronal regeneration.All mouse experiments and protocols were approved by the Animal Care and Use Committee of Jinan University of China(IACUC Approval No.20200512-04)on May 12,2020.All monkey experiments were approved by the IACUC protocol(IACUC Approval No.LDACU 20190820-01)on August 23,2019 for anim
