Arsenic compounds are widely used for the therapeutic intervention of multiple diseases.Ancient pharmacologists discovered the medicinal utility of these highly toxic substances,and modern pharmacologists have further...Arsenic compounds are widely used for the therapeutic intervention of multiple diseases.Ancient pharmacologists discovered the medicinal utility of these highly toxic substances,and modern pharmacologists have further recognized the specific active ingredients in human diseases.In particular,Arsenic trioxide(ATO),as a main component,has therapeutic effects on various tumors(including leukemia,hepatocellular carcinoma,lung cancer,etc.).However,its toxicity limits its efficacy,and controlling the toxicity has been an important issue.Interestingly,recent evidence has pointed out the pivotal roles of arsenic compounds in phase separation and membraneless organelles formation,which may determine their toxicity and therapeutic efficacy.Here,we summarize the arsenic compoundsregulating phase separation and membraneless organelles formation.We further hypothesize their potential involvement in the therapy and toxicity of arsenic compounds,highlighting potential mechanisms underlying the clinical application of arsenic compounds.展开更多
In this study,an amine-coordinated cobalt phthalocyanine(CoPc)-based anodic catalyst was fabricated by a facile process,to enhance the performance of hydrogen peroxide fuel cells(HPFCs) and enzymatic biofuel cells(EBC...In this study,an amine-coordinated cobalt phthalocyanine(CoPc)-based anodic catalyst was fabricated by a facile process,to enhance the performance of hydrogen peroxide fuel cells(HPFCs) and enzymatic biofuel cells(EBCs).For this purpose,polyethyleneimine(PEI) was added onto the reduced graphene oxide and CoPc composite(RGO/CoPc) to create abundant NH2 axial ligand groups,for anchoring the Co core within the CoPc.Owing to the PEI addition,the onset potential of the hydrogen peroxide oxidation reaction was shifted by 0.13 V in the negative direction(0.02 V) and the current density was improved by 1.92 times(1.297 mA cm^(-2)),compared to those for RGO/CoPc(0.15 V and 0.676 mA cm^(-2),respectively),due to the formation of donor-acceptor dyads and the prevention of CoPc from leaching out.The biocatalyst using glucose oxidase(GOx)([RGO/CoPc]/PEI/GOx) showed a better onset potential and catalytic activity(0.15 V and 318.7 μA cm^(-2)) than comparable structures,as well as significantly improved operational durability and long-term stability.This is also attributed to PEI,which created a favorable microenvironment for the enzyme.The maximum power densities(MPDs) and open-circuit voltages(OCVs) obtained for HPFCs and EBCs using the suggested catalyst were 105.2±1.3 μW cm^(-2)(0.317±0.003 V) and 25.4±0.9 μW cm^(-2)(0.283±0.007 V),respectively.This shows that the amine axial ligand effectively improves the performance of the actual driving HPFCs and EBCs.展开更多
Osteosarcoma(OS)is the most frequent primary bone sarcomas with high recurrence and poor prognosis.Emerging evidence indicates that membraneless organelles stress granules(SGs),whose assemblies are driven by scaffold ...Osteosarcoma(OS)is the most frequent primary bone sarcomas with high recurrence and poor prognosis.Emerging evidence indicates that membraneless organelles stress granules(SGs),whose assemblies are driven by scaffold protein G3BP1,are extensively involved in tumor,especially in OS.However,how SGs behave and communicate with organelles,particularly nucleoli and mitochondria,during drug challenges remain unknown.This study revealed that chemotherapeutic drugs activated the cysteine protease asparagine endopeptidase(AEP)to specifically cleave the SG core protein G3BP1 at N258/N309 in OS and malignant glioma.tG3BP1-Ns modulated SG dynamics by competitively binding to full-length G3BP1.Strikingly,tG3BP1-Cs,containing a conserved RNA recognition motif CCUBSCUS,sequestered mRNAs of ribosomal proteins and oxidative phosphorylation genes in the nucleoli and mitochondria to repress translation and oxidative stress.Moreover,the inhibition of AEP promoted the tumor-suppressing effect of chemotherapeutic drugs,whereas AEP-cleaved G3BP1 rescue reversed the effect in both OS and glioma models.Cancerous tissues exhibited high levels of AEP and G3BP1 truncations,which were strongly associated with poor prognosis.展开更多
Evolution has enabled living cells to adopt their structural and functional complexity by organizing intricate cellular compartments,such as membrane-bound and membraneless organelles(MLOs),for spatiotemporal catalysi...Evolution has enabled living cells to adopt their structural and functional complexity by organizing intricate cellular compartments,such as membrane-bound and membraneless organelles(MLOs),for spatiotemporal catalysis of physiochemical reactions essential for cell plasticity control.Emerging evidence and view support the notion that MLOs are built by multivalent interactions of biomolecules via phase separation and transition mechanisms.In healthy cells,dynamic chemical modifications regulate MLO plasticity,and reversible phase separation is essential for cell homeostasis.Emerging evidence revealed that aberrant phase separation results in numerous neurodegenerative disorders,cancer,and other diseases.In this review,we provide molecular underpinnings on(i)mechanistic understanding of phase separation,(ii)unifying structural and mechanistic principles that underlie this phenomenon,(iii)various mechanisms that are used by cells for the regulation of phase separation,and(iv)emerging therapeutic and other applications.展开更多
Implanting artificial organelles in living cells is capable of correcting cellular dysfunctionalities for cell repair and biomedical applications. In this work, phase-separated bienzyme-loaded coacervate microdroplets...Implanting artificial organelles in living cells is capable of correcting cellular dysfunctionalities for cell repair and biomedical applications. In this work, phase-separated bienzyme-loaded coacervate microdroplets are established as a model of artificial membraneless organelles in endothelial dysfunctional cells for the cascade enzymatic production of nitric oxide(NO) with a purpose of correcting cellular NO deficiency. We prepared the coacervate microdroplets via liquid-liquid phase separation of oppositely charged polyelectrolytes, in which glucose oxidase/horseradish peroxidase-mediated cascade reaction was compartmented. After the coacervate microdroplets were implanted in NO-deficient dysfunctional cells, the compartments maintained a phase-separated liquid droplet structure, which facilitated a significant enhancement of NO production in the dysfunctional cells. The recovery of NO production was further exploited to inhibit clot formation in blood plasma located in the cell suspension. This demonstrated a proof-of-concept design of artificial organelles in dysfunctional cells for cell repair and anticoagulation-related medical applications. Our results demonstrate an approach for the construction of coacervate droplets through phase separation for the generation of artificial membraneless organelles, which can be designed to provide an array of functionalities in living organisms that have the potential to be used in the field of cell engineering and medical therapy.展开更多
Liquid-liquid phase separation(LLPS)or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes.Mechanism study of regulating LLPS is therefore c...Liquid-liquid phase separation(LLPS)or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes.Mechanism study of regulating LLPS is therefore central to the understanding of protein aggregation and disease-relevant process.We report a fused in sarcoma protein(FUS)-derived low complexity(LC)sequence that undergoes LLPS in the presence of metal ions.The LC protein was constructed by fusing a hexhistidine-tag to the N-terminal low complexity domain(the residues 1–165 in QGSY-rich segment)of FUS.Spontaneous condensation of the intrinsic disordered protein into coacervate droplets was observed in the presence of metal ions that chelate oligohistidine moieties to form protein matrix.We demonstrate the key role of metal ion-histidine coordination in governing LLPS behaviours and the fluidity of biomolecular condensates.By taking advantage of competitive binding using chelators,we show the possibility of regulating dynamic behaviors of disease-relevant protein droplets,and developing a potential approach towards controllable biological encapsulation/release.展开更多
基金the financial support from the National Natural Science Foundation of China(Grant Nos.:31571493,81741043,31871395,and 32170841).
文摘Arsenic compounds are widely used for the therapeutic intervention of multiple diseases.Ancient pharmacologists discovered the medicinal utility of these highly toxic substances,and modern pharmacologists have further recognized the specific active ingredients in human diseases.In particular,Arsenic trioxide(ATO),as a main component,has therapeutic effects on various tumors(including leukemia,hepatocellular carcinoma,lung cancer,etc.).However,its toxicity limits its efficacy,and controlling the toxicity has been an important issue.Interestingly,recent evidence has pointed out the pivotal roles of arsenic compounds in phase separation and membraneless organelles formation,which may determine their toxicity and therapeutic efficacy.Here,we summarize the arsenic compoundsregulating phase separation and membraneless organelles formation.We further hypothesize their potential involvement in the therapy and toxicity of arsenic compounds,highlighting potential mechanisms underlying the clinical application of arsenic compounds.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(Nos.2017R1D1A1B03032033 and 2020R1C1C1010386)“Leaders in INdustry-university Cooperation+”project supported by the Ministry of Education and National Research Foundation of Korea。
文摘In this study,an amine-coordinated cobalt phthalocyanine(CoPc)-based anodic catalyst was fabricated by a facile process,to enhance the performance of hydrogen peroxide fuel cells(HPFCs) and enzymatic biofuel cells(EBCs).For this purpose,polyethyleneimine(PEI) was added onto the reduced graphene oxide and CoPc composite(RGO/CoPc) to create abundant NH2 axial ligand groups,for anchoring the Co core within the CoPc.Owing to the PEI addition,the onset potential of the hydrogen peroxide oxidation reaction was shifted by 0.13 V in the negative direction(0.02 V) and the current density was improved by 1.92 times(1.297 mA cm^(-2)),compared to those for RGO/CoPc(0.15 V and 0.676 mA cm^(-2),respectively),due to the formation of donor-acceptor dyads and the prevention of CoPc from leaching out.The biocatalyst using glucose oxidase(GOx)([RGO/CoPc]/PEI/GOx) showed a better onset potential and catalytic activity(0.15 V and 318.7 μA cm^(-2)) than comparable structures,as well as significantly improved operational durability and long-term stability.This is also attributed to PEI,which created a favorable microenvironment for the enzyme.The maximum power densities(MPDs) and open-circuit voltages(OCVs) obtained for HPFCs and EBCs using the suggested catalyst were 105.2±1.3 μW cm^(-2)(0.317±0.003 V) and 25.4±0.9 μW cm^(-2)(0.283±0.007 V),respectively.This shows that the amine axial ligand effectively improves the performance of the actual driving HPFCs and EBCs.
基金supported by the National Key R&D Program of China(grant number 2023ZD0502206,2024YFB3213200,Topic No.2024YFB3213204)National Natural Science Foundation of China(nos.82273278,82373514,82373202,82272728,82002630,81772654)+5 种基金the National Key Research and Development Program of China(grant number 2022YFC2404602)Shanghai Hospital Development Center Foundation(grant number SHDC12023108)Scientific and Technological Innovation Action Plan of Shanghai Science and Technology Committee(grant number 22Y31900103)Beijing Science and Technology Innovation Medical Development Foundation(grant number KC2021-JX-0170-9)the Shanghai Association for Science and Technology(nos.201409003000,201409002400,20YF1426200)Shanghai Science and Technology Innovation Action Plan(grant number 23Y41900100).
文摘Osteosarcoma(OS)is the most frequent primary bone sarcomas with high recurrence and poor prognosis.Emerging evidence indicates that membraneless organelles stress granules(SGs),whose assemblies are driven by scaffold protein G3BP1,are extensively involved in tumor,especially in OS.However,how SGs behave and communicate with organelles,particularly nucleoli and mitochondria,during drug challenges remain unknown.This study revealed that chemotherapeutic drugs activated the cysteine protease asparagine endopeptidase(AEP)to specifically cleave the SG core protein G3BP1 at N258/N309 in OS and malignant glioma.tG3BP1-Ns modulated SG dynamics by competitively binding to full-length G3BP1.Strikingly,tG3BP1-Cs,containing a conserved RNA recognition motif CCUBSCUS,sequestered mRNAs of ribosomal proteins and oxidative phosphorylation genes in the nucleoli and mitochondria to repress translation and oxidative stress.Moreover,the inhibition of AEP promoted the tumor-suppressing effect of chemotherapeutic drugs,whereas AEP-cleaved G3BP1 rescue reversed the effect in both OS and glioma models.Cancerous tissues exhibited high levels of AEP and G3BP1 truncations,which were strongly associated with poor prognosis.
基金supported in part by grants from the National Natural Science Foundation of China(32090040,31621002,21922706,81630080,31430054,91854203,91853115,and 31671405)the National Key Research and Development Program of China(2017YFA0503600 and 2016YFA0100500)+4 种基金the Ministry of Education of China(IRT_17R102)the Strategic Priority Research Program of Chinese Academy of Sciences(XDB19000000)the Fundamental Research Funds for the Central Universities(KB2070000023 and WK2070000194)National Institutes of Health Grants(CA164133,DK115812,and DK56292)We thank our laboratory members for stimulating discussion。
文摘Evolution has enabled living cells to adopt their structural and functional complexity by organizing intricate cellular compartments,such as membrane-bound and membraneless organelles(MLOs),for spatiotemporal catalysis of physiochemical reactions essential for cell plasticity control.Emerging evidence and view support the notion that MLOs are built by multivalent interactions of biomolecules via phase separation and transition mechanisms.In healthy cells,dynamic chemical modifications regulate MLO plasticity,and reversible phase separation is essential for cell homeostasis.Emerging evidence revealed that aberrant phase separation results in numerous neurodegenerative disorders,cancer,and other diseases.In this review,we provide molecular underpinnings on(i)mechanistic understanding of phase separation,(ii)unifying structural and mechanistic principles that underlie this phenomenon,(iii)various mechanisms that are used by cells for the regulation of phase separation,and(iv)emerging therapeutic and other applications.
基金supported by the National Natural Science Foundation of China(21735002,22177032,32101082)the Science Fund for Distinguished Young Scholars of Hunan Province(2021JJ10013)+1 种基金the Hunan Province Innovative Talent Funding for Postdoctoral Fellows(2021RC2059)the Postdoctoral Science Foundation of China(2021TQ0103,2021M690957).
文摘Implanting artificial organelles in living cells is capable of correcting cellular dysfunctionalities for cell repair and biomedical applications. In this work, phase-separated bienzyme-loaded coacervate microdroplets are established as a model of artificial membraneless organelles in endothelial dysfunctional cells for the cascade enzymatic production of nitric oxide(NO) with a purpose of correcting cellular NO deficiency. We prepared the coacervate microdroplets via liquid-liquid phase separation of oppositely charged polyelectrolytes, in which glucose oxidase/horseradish peroxidase-mediated cascade reaction was compartmented. After the coacervate microdroplets were implanted in NO-deficient dysfunctional cells, the compartments maintained a phase-separated liquid droplet structure, which facilitated a significant enhancement of NO production in the dysfunctional cells. The recovery of NO production was further exploited to inhibit clot formation in blood plasma located in the cell suspension. This demonstrated a proof-of-concept design of artificial organelles in dysfunctional cells for cell repair and anticoagulation-related medical applications. Our results demonstrate an approach for the construction of coacervate droplets through phase separation for the generation of artificial membraneless organelles, which can be designed to provide an array of functionalities in living organisms that have the potential to be used in the field of cell engineering and medical therapy.
基金financially supported by the National Natural Science Foundation of China (Nos. 22072159 and 22172007)the Fundamental Research Funds for the Central Universities(No. buctrc202015)
文摘Liquid-liquid phase separation(LLPS)or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes.Mechanism study of regulating LLPS is therefore central to the understanding of protein aggregation and disease-relevant process.We report a fused in sarcoma protein(FUS)-derived low complexity(LC)sequence that undergoes LLPS in the presence of metal ions.The LC protein was constructed by fusing a hexhistidine-tag to the N-terminal low complexity domain(the residues 1–165 in QGSY-rich segment)of FUS.Spontaneous condensation of the intrinsic disordered protein into coacervate droplets was observed in the presence of metal ions that chelate oligohistidine moieties to form protein matrix.We demonstrate the key role of metal ion-histidine coordination in governing LLPS behaviours and the fluidity of biomolecular condensates.By taking advantage of competitive binding using chelators,we show the possibility of regulating dynamic behaviors of disease-relevant protein droplets,and developing a potential approach towards controllable biological encapsulation/release.
