Neutrophils are the first line of defense in nonspecific immunity(innate immunity)and interact with other immune cells to participate in specific defense mechanisms(adaptive immunity).Studies have shown that the tumor...Neutrophils are the first line of defense in nonspecific immunity(innate immunity)and interact with other immune cells to participate in specific defense mechanisms(adaptive immunity).Studies have shown that the tumor microenvironment(TME)mediates tumor development and recruits neutrophils into tumors to become tumor-associated neutrophils(TANs),an important part of TME,and achieve extended lifespan.TANs can be differentiated into the antitumor or protumor phenotype,and play an important role in tumor occurrence,proliferation and recurrence,invasion and metastasis,angiogenesis,cell necrosis,and so on.Here,we summarize the TAN origin and subtypes found through Single-cell RNA sequencing analysis in different types of tumors in recent literature,and the molecular mechanisms underlying their antitumor and protumor effects on tumors.We focus on the interaction between TANs and immunosuppressive or immunostimulatory TME,as well as signal pathways such as transforming growth factorβ(TGF-β)associated with TAN phenotype transition.Based on the summarized mechanisms,we focus on the potential application and latest strategies of TAN-based immunotherapy,chemotherapy,and combination therapy in the preclinical study and clinical trials of tumors.The discussion on promising therapy encompasses five key areas:inhibition of the tumorpromoting effect of TANs,enhancement of the antitumor effect of TANs,targeting the interaction between TANs and the TME,reprogramming of TANs,and drug delivery carriers.Finally,we discuss the potential of TANs and their related markers as emerging biomarkers for predicting the prognosis of cancer patients.展开更多
The lack of effective charge transfer driving force and channel limits the electron directional migration in nanoclusters(NC)-based heterostructures,resulting in poor photocatalytic performance.Herein,a Z-scheme NC-ba...The lack of effective charge transfer driving force and channel limits the electron directional migration in nanoclusters(NC)-based heterostructures,resulting in poor photocatalytic performance.Herein,a Z-scheme NC-based heterojunction(Pt1Ag28-BTT/CoP,BTT=1,3,5-benzenetrithiol)with strong internal electric field is constructed via interfacial Co-S bond,which exhibits an absolutely superiority in photocatalytic performance with 24.89 mmol·h^(−1)·g−1 H_(2)production rate,25.77%apparent quantum yield at 420 nm,and~100%activity retention in stability,compared with Pt1Ag28-BDT/CoP(BDT=1,3-benzenedithiol),Ag29-BDT/CoP,and CoP.The enhanced catalytic performance is contributed by the dual modulation strategy of inner core and outer shell of NC,wherein,the center Pt single atom doping regulates the band structure of NC to match well with CoP,builds internal electric field,and then drives photogenerated electrons steering;the accurate surface S modification promotes the formation of Co-S atomic-precise interface channel for further high-efficient Z-scheme charge directional migration.This work opens a new avenue for designing NC-based heterojunction with matchable band structure and valid interfacial charge transfer.展开更多
The TEA domain(TEAD)family proteins(TEAD1-4)are essential transcription factors that control cell differentiation and organ size in the Hippo pathway.Although the sequences and structures of TEAD family proteins are h...The TEA domain(TEAD)family proteins(TEAD1-4)are essential transcription factors that control cell differentiation and organ size in the Hippo pathway.Although the sequences and structures of TEAD family proteins are highly conserved,each TEAD isoform has unique physiological and pathological functions.Therefore,the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases.Here,we identified a novel TEAD 1/3 covalent inhibitor(DC-TEADin1072)with biochemical IC50 values of 0.61±0.02 and 0.58±0.12μmol/L against TEAD1 and TEAD3,respectively.Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DCTEAD3 in03 with the IC_(50) value of 0.16±0.03μmol/L,which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling(ABPP)assays.In cells,DC-TEAD3 in03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD(1-4)reporter assays with the IC50 value of1.15μmol/L.When administered to zebrafish juveniles,experiments showed that DC-TEAD3 in03 reduced the growth rate of zebrafish caudal fins,indicating the importance of TEAD3 activity in controlling proportional growth of vertebrate appendages.展开更多
Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of m...Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of metabolites within the liver metastases of AML mice.Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics.This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle,coupled with an upregulation of the creatine metabolism.The upregulation of creatine synthetases Gatm and Gamt,as well as the creatine transporter Slc6a8,resulted in a marked accumulation of creatine within tumor foci.This process further enhances oxidative phosphorylation and glycolysis of leukemia cells,thereby boosting ATP production to foster proliferation and infiltration.Importantly,we discovered that inhibiting Slc6a8 can counter these detrimental effects,offering a new strategy for treating AML by targeting metabolic pathways.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82072999,82172285,82241049,82273320,81972665)1·3·5 project of excellent development of discipline of West China Hospital of Sichuan University(No.ZYYC24002).
文摘Neutrophils are the first line of defense in nonspecific immunity(innate immunity)and interact with other immune cells to participate in specific defense mechanisms(adaptive immunity).Studies have shown that the tumor microenvironment(TME)mediates tumor development and recruits neutrophils into tumors to become tumor-associated neutrophils(TANs),an important part of TME,and achieve extended lifespan.TANs can be differentiated into the antitumor or protumor phenotype,and play an important role in tumor occurrence,proliferation and recurrence,invasion and metastasis,angiogenesis,cell necrosis,and so on.Here,we summarize the TAN origin and subtypes found through Single-cell RNA sequencing analysis in different types of tumors in recent literature,and the molecular mechanisms underlying their antitumor and protumor effects on tumors.We focus on the interaction between TANs and immunosuppressive or immunostimulatory TME,as well as signal pathways such as transforming growth factorβ(TGF-β)associated with TAN phenotype transition.Based on the summarized mechanisms,we focus on the potential application and latest strategies of TAN-based immunotherapy,chemotherapy,and combination therapy in the preclinical study and clinical trials of tumors.The discussion on promising therapy encompasses five key areas:inhibition of the tumorpromoting effect of TANs,enhancement of the antitumor effect of TANs,targeting the interaction between TANs and the TME,reprogramming of TANs,and drug delivery carriers.Finally,we discuss the potential of TANs and their related markers as emerging biomarkers for predicting the prognosis of cancer patients.
基金the Natural Science research project of Universities in Anhui Province(No.KJ2021ZD0001)the Natural Science Foundation of Anhui Province(No.2208085MB20)the National Natural Science Foundation of China(No.22101001).
文摘The lack of effective charge transfer driving force and channel limits the electron directional migration in nanoclusters(NC)-based heterostructures,resulting in poor photocatalytic performance.Herein,a Z-scheme NC-based heterojunction(Pt1Ag28-BTT/CoP,BTT=1,3,5-benzenetrithiol)with strong internal electric field is constructed via interfacial Co-S bond,which exhibits an absolutely superiority in photocatalytic performance with 24.89 mmol·h^(−1)·g−1 H_(2)production rate,25.77%apparent quantum yield at 420 nm,and~100%activity retention in stability,compared with Pt1Ag28-BDT/CoP(BDT=1,3-benzenedithiol),Ag29-BDT/CoP,and CoP.The enhanced catalytic performance is contributed by the dual modulation strategy of inner core and outer shell of NC,wherein,the center Pt single atom doping regulates the band structure of NC to match well with CoP,builds internal electric field,and then drives photogenerated electrons steering;the accurate surface S modification promotes the formation of Co-S atomic-precise interface channel for further high-efficient Z-scheme charge directional migration.This work opens a new avenue for designing NC-based heterojunction with matchable band structure and valid interfacial charge transfer.
基金the financial supports from the National Natural Science Foundation of China(91853205,81625022,81821005 to Cheng Luo81973166,21702218,91753207 to Bing Zhou),Wong Education to Cheng Luo and Bing Zhou+2 种基金the Department of Science and Technology of Fujian Province(2019T3029 to Cheng Luo,China)the Science and Technology Commission of Shanghai Municipality(19XD1404700 and 18431907100 to Cheng Luo,China)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(2018ZX09711002-008 to Cheng Luo,2018ZX09711002-008-005 to Huijin Feng,2018ZX09711002-006 to Bing Zhou,China)。
文摘The TEA domain(TEAD)family proteins(TEAD1-4)are essential transcription factors that control cell differentiation and organ size in the Hippo pathway.Although the sequences and structures of TEAD family proteins are highly conserved,each TEAD isoform has unique physiological and pathological functions.Therefore,the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases.Here,we identified a novel TEAD 1/3 covalent inhibitor(DC-TEADin1072)with biochemical IC50 values of 0.61±0.02 and 0.58±0.12μmol/L against TEAD1 and TEAD3,respectively.Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DCTEAD3 in03 with the IC_(50) value of 0.16±0.03μmol/L,which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling(ABPP)assays.In cells,DC-TEAD3 in03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD(1-4)reporter assays with the IC50 value of1.15μmol/L.When administered to zebrafish juveniles,experiments showed that DC-TEAD3 in03 reduced the growth rate of zebrafish caudal fins,indicating the importance of TEAD3 activity in controlling proportional growth of vertebrate appendages.
基金supported by the National Natural Science Foundation of China(No.81770124)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(RC20210190,China)。
文摘Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of metabolites within the liver metastases of AML mice.Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics.This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle,coupled with an upregulation of the creatine metabolism.The upregulation of creatine synthetases Gatm and Gamt,as well as the creatine transporter Slc6a8,resulted in a marked accumulation of creatine within tumor foci.This process further enhances oxidative phosphorylation and glycolysis of leukemia cells,thereby boosting ATP production to foster proliferation and infiltration.Importantly,we discovered that inhibiting Slc6a8 can counter these detrimental effects,offering a new strategy for treating AML by targeting metabolic pathways.
