Bone defects have serious economic and clinical impacts;however,despite improvements in bone defect management,the range of clinical outcomes remains limited.A variety of biomaterials have been used to treat complex b...Bone defects have serious economic and clinical impacts;however,despite improvements in bone defect management,the range of clinical outcomes remains limited.A variety of biomaterials have been used to treat complex bone defects.However,final bone repair outcomes may be adversely affected by poor osteogenic capacity and risk of infection.Consequently,therapeutic methods are required that reduce bacterial contamination and increase the use of osteogenic biomaterials.Herein,we report the preparation of poly(lactic acid-coglycolic acid)(PLGA)microspheres coloaded with magnesium(Mg^(2+))and gallium(Ga^(3+))ions(Mg-Ga@PLGA),which can fill irregular bone defects and show good biosafety.During in vitro testing,Mg-Ga@PLGA not only showed a synergistic effect on promoting osteogenic differentiation but also inhibited osteoclastic differentiation.Moreover,we found that Mg-Ga@PLGA demonstrated an antibacterial effect.During in vivo testing,Mg Ga@PLGA exhibited strong in situ osteogenic ability.In conclusion,Mg-Ga@PLGA has good potential for treating bone defects at risk of infection.展开更多
Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficac...Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.Methods:After observing epithelial-mesenchymal transformation(EMT)changes in HepG2 and HepG2/Sorafenib cells,we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC.Subsequently,specific inhibitors of c-Jun N-terminal kinase(JNK,SP600125)and extracellular signal-regulated kinase(ERK,PD98059)were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor(EGFR)/JNK/ERK signaling pathway in vitro and in vivo.Biological behavior changes were assessed through cell counting kit-8(CCK-8),colony formation,transwell,and immunofluorescence tests.Simultaneously,Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.Results:The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells,and sorafenib-resistant HCC was characterized by EMT changes.Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells,with minimal impact on HepG2 cells.Additionally,apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells.Furthermore,there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups.Notably,SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.Conclusion:Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.展开更多
Cu-Fe composite oxides were prepared by co-precipitation method and tested for higher alcohol synthesis from syngas. The selectivity to C2＋OH and C6＋OH in alcohol distribution was very high while the methane product...Cu-Fe composite oxides were prepared by co-precipitation method and tested for higher alcohol synthesis from syngas. The selectivity to C2＋OH and C6＋OH in alcohol distribution was very high while the methane product fraction in hydrocarbon distribution was rather low, demonstrating a promising potential in higher alcohols synthesis from syngas. The distribution of alcohols and hydrocarbons approximately obeyed Anderson-Schulz-Flory distribution with similar chain growth probability, indicating alcohols and hydrocarbons derived from the same intermediates. The effects of Cu/Fe molar ratio, reaction temperature and gas hourly space velocity （GHSV） on catalytic performance were studied in detail. The sample with a Cu/Fe molar ratio of 10/1 exhibited the best catalytic performance. Higher reaction temperature accelerated water-gas-shift reaction and led to lower total alcohols selectivity. GHSV showed great effect on catalytic performance and higher GHSV increased the total alcohol selectivity, indicating there existed visible dehydration reaction of alcohol into hydrocarbon.展开更多
Co2C‐based catalysts with SiO2,γ‐Al2O3,and carbon nanotubes(CNTs)as support materials were prepared and evaluated for the Fischer‐Tropsch to olefin(FTO)reaction.The combination of catalytic performance and structu...Co2C‐based catalysts with SiO2,γ‐Al2O3,and carbon nanotubes(CNTs)as support materials were prepared and evaluated for the Fischer‐Tropsch to olefin(FTO)reaction.The combination of catalytic performance and structure characterization indicates that the cobalt‐support interaction has a great influence on the Co2C morphology and catalytic performance.The CNT support facilitates the formation of a CoMn composite oxide during calcination,and Co2C nanoprisms were observed in the spent catalysts,resulting in a product distribution that greatly deviates from the classical Anderson‐Schulz‐Flory(ASF)distribution,where only 2.4 C%methane was generated.The Co3O4 phase for SiO2‐andγ‐Al2O3‐supported catalysts was observed in the calcined sample.After reduction,CoO,MnO,and low‐valence CoMn composite oxide were generated in theγ‐Al2O3‐supported sample,and both Co2C nanospheres and nanoprisms were identified in the corresponding spent catalyst.However,only separated phases of CoO and MnO were found in the reduced sample supported by SiO2,and Co2C nanospheres were detected in the spent catalyst without the evidence of any Co2C nanoprisms.The Co2C nanospheres led to a relatively high methane selectivity of 5.8 C%and 12.0 C%of theγ‐Al2O3‐and SiO2‐supported catalysts,respectively.These results suggest that a relatively weak cobalt‐support interaction is necessary for the formation of the CoMn composite oxide during calcination,which benefits the formation of Co2C nanoprisms with promising catalytic performance for the sustainable production of olefins via syngas.展开更多
Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and d...Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored.This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC,we used small interfering RNA(siRNA)to knock down LAMC2 to further observe the changes in the signaling pathway.Furthermore,we used cell proliferation assays,Transwell invasion assays,and wound-healing assays to observe the changes in OSCC proliferation,invasion,and metastasis.RFP-LC3 was used to detect the level of autophagy intensity.A cell line-derived xenograft(CDX)model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC.The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation,invasion,and metastasis via inhibiting the PI3K/AKT/mTOR pathway.Moreover,autophagy has a dual effect on OSCC,and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration,invasion,and proliferation.展开更多
Specific features of tile access patterns can be applied in a cache replacement strategy to a limited distributed high-speed cache for the cloud-based networked geographic information services(NGISs),aiming to adapt t...Specific features of tile access patterns can be applied in a cache replacement strategy to a limited distributed high-speed cache for the cloud-based networked geographic information services(NGISs),aiming to adapt to changes in the access distribution of hotspots.By taking advantage of the spatiotemporal locality,the sequential features in tile access patterns,and the cache reading performance in the burst mode,this article proposes a tile sequence replacement method,which involves structuring a Least Recently Used(LRU)stack into three portions for the different functions in cache replacement and deriving an expression for the temporal locality and popularity of the relevant tile to facilitate the replacement process.Based on the spatial characteristics of both the tiles and the cache burst mode with regard to reading data,the proposed method generates multiple tile sequences to reflect spatiotemporal locality in tile access patterns.Then,we measure the caching value by a technique based on a weighted-based method.This technique draws on the recent access popularity and low caching costs of tile sequences,with the aim of balancing the temporal and spatial localities in tile access.It ranks tile sequences in a replacement queue to adapt to the changes in accessed hotspots while reducing the replacement frequency.Experimental results show that the proposed method effectively improves the hit rate and utilization rate for a limited distributed cache while achieving satisfactory response performance and high throughput for users in an NGIS.Therefore,it can be adapted to handle numerous data access requests in NGISs in a cloud-based environment.展开更多
Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the...Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the replenishment pathway to maintain the tricarboxylic acid cycle ensuring energy supply,therefore inducing ineffective interruption of metabolic.Herein,we designed glutamine transporter antagonist L-γ-glutamyl-p-nitroanilide(GPNA)loaded and 4T1 cancer cell membrane coated iridium oxide nanoparticles(IrO_(2)-GPNA@CCM)to realize a comprehensive inhibition of tumor energy supply which synergistically mediated by glycolysis and glutamine cycle.IrO_(2)NPs were used to catalyze the O_(2)generation by facilitating the decomposition of endogenous H_(2)O_(2)in tumor cells,which further downregulated the expression of HIF-1αand PI3K/pAKT to interrupt the generation of lactate.Meanwhile,the loaded GPNA was released under NIR irradiation to bind to alanine-serine-cysteine transporter(ASCT2)for glutamine uptake suppression,therefore realizing the comprehensive dysfunction of cell metabolism.Moreover,both in vitro and in vivo results convinced the thorough energy inhibition effect based on Ir O_(2)-GPNA@CCM NPs,which provided an inspiring strategy for future construction of tumor therapeutic regimen.展开更多
As activated hepatic stellate cells(aHSCs)play a central role in fibrogenesis,they have become key target cells for antifibrotic treatment.Nevertheless,the therapeutic efficiency is constrained by the exosomes they se...As activated hepatic stellate cells(aHSCs)play a central role in fibrogenesis,they have become key target cells for antifibrotic treatment.Nevertheless,the therapeutic efficiency is constrained by the exosomes they secrete,which are linked to energy metabolism and continuously stimulate the activation of neighboring quiescent hepatic stellate cells(qHSCs).Herein,an intercellular communication interference strategy is designed utilizing paeoniflorin(PF)loaded and hyaluronic acid(HA)coated copper-doped ZIF-8(PF@HA-Cu/ZIF-8,PF@HCZ)to reduce energy-related exosome secretion from aHSCs,thus preserving neighboring qHSCs in a quiescent state.Simultaneously,the released copper and zinc ions disrupt key enzymes involved in glycolysis to reduce bioenergy synthesis in aHSCs,thereby promoting the reversion of aHSCs to a quiescent state and further decreasing exosome secretion.Therefore,PF@HCZ can effectively sustain both aHSCs and qHSCs in a metabolically dormant state to ultimately alleviate liver fibrosis.The study provides an enlightening strategy for interrupting exosome-mediated intercellular communication and remodeling the energy metabolic status of HSCs with boosted antifibrogenic activity.展开更多
Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy.However,engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity rema...Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy.However,engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors.Herein,a rod-like biomimetic hybrid inorganic MnO2-Au nanozymes are developed,where MnO2 and ultrasmall Au nanoparticles(NPs)are successively deposited on the mesoporous silica nanorod to cooperatively improve the O2 content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging.Under the catalyzing of MnO2,the intratumoral H2O2 is decomposed to greatly accelerate O2 generation,which could boost the curative effect of radiation therapy(RT)and further enhance the Au-catalyzed glucose oxidation.Mutually,the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment,thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO2 with the self-supplied H2O2/H+.As a result,this mutual-reinforcing cycle can endow the nanoplatform with accelerated O2 generation,thus alleviating hypoxic environment and further boosting RT effect.Furthermore,acute glucose consuming can induce downregulation expression of heat shock protein(HSP),achieving starvation-promoted mild photothermal therapy.This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.31971106,BWS21L013,and 21WS09002).
文摘Bone defects have serious economic and clinical impacts;however,despite improvements in bone defect management,the range of clinical outcomes remains limited.A variety of biomaterials have been used to treat complex bone defects.However,final bone repair outcomes may be adversely affected by poor osteogenic capacity and risk of infection.Consequently,therapeutic methods are required that reduce bacterial contamination and increase the use of osteogenic biomaterials.Herein,we report the preparation of poly(lactic acid-coglycolic acid)(PLGA)microspheres coloaded with magnesium(Mg^(2+))and gallium(Ga^(3+))ions(Mg-Ga@PLGA),which can fill irregular bone defects and show good biosafety.During in vitro testing,Mg-Ga@PLGA not only showed a synergistic effect on promoting osteogenic differentiation but also inhibited osteoclastic differentiation.Moreover,we found that Mg-Ga@PLGA demonstrated an antibacterial effect.During in vivo testing,Mg Ga@PLGA exhibited strong in situ osteogenic ability.In conclusion,Mg-Ga@PLGA has good potential for treating bone defects at risk of infection.
基金supported by Natural Science Foundation of Shandong Province,No.ZR2021QH186National Natural Science Foundation of China,No.81870205+3 种基金Foundation Research Project of Qinghai Province,2021-ZJ-719National Natural Science Foundation of China,No.82000579Qinghai Provincial Health System Key Project No.2021-wjzd-06Foundation Research Project of Qinghai Province,2023-ZJ-786.
文摘Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.Methods:After observing epithelial-mesenchymal transformation(EMT)changes in HepG2 and HepG2/Sorafenib cells,we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC.Subsequently,specific inhibitors of c-Jun N-terminal kinase(JNK,SP600125)and extracellular signal-regulated kinase(ERK,PD98059)were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor(EGFR)/JNK/ERK signaling pathway in vitro and in vivo.Biological behavior changes were assessed through cell counting kit-8(CCK-8),colony formation,transwell,and immunofluorescence tests.Simultaneously,Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.Results:The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells,and sorafenib-resistant HCC was characterized by EMT changes.Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells,with minimal impact on HepG2 cells.Additionally,apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells.Furthermore,there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups.Notably,SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.Conclusion:Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.
基金the State Key Fundamental Research Program(Ministry of Science and Technology of China,No.2011CBA00501)Shanghai Municipal Science and Technology Commission,China(Grant No:11DZ1200300)the Foundation of State Key Laboratory of Coal Conversion(Grant No:1112610)
文摘Cu-Fe composite oxides were prepared by co-precipitation method and tested for higher alcohol synthesis from syngas. The selectivity to C2＋OH and C6＋OH in alcohol distribution was very high while the methane product fraction in hydrocarbon distribution was rather low, demonstrating a promising potential in higher alcohols synthesis from syngas. The distribution of alcohols and hydrocarbons approximately obeyed Anderson-Schulz-Flory distribution with similar chain growth probability, indicating alcohols and hydrocarbons derived from the same intermediates. The effects of Cu/Fe molar ratio, reaction temperature and gas hourly space velocity （GHSV） on catalytic performance were studied in detail. The sample with a Cu/Fe molar ratio of 10/1 exhibited the best catalytic performance. Higher reaction temperature accelerated water-gas-shift reaction and led to lower total alcohols selectivity. GHSV showed great effect on catalytic performance and higher GHSV increased the total alcohol selectivity, indicating there existed visible dehydration reaction of alcohol into hydrocarbon.
文摘Co2C‐based catalysts with SiO2,γ‐Al2O3,and carbon nanotubes(CNTs)as support materials were prepared and evaluated for the Fischer‐Tropsch to olefin(FTO)reaction.The combination of catalytic performance and structure characterization indicates that the cobalt‐support interaction has a great influence on the Co2C morphology and catalytic performance.The CNT support facilitates the formation of a CoMn composite oxide during calcination,and Co2C nanoprisms were observed in the spent catalysts,resulting in a product distribution that greatly deviates from the classical Anderson‐Schulz‐Flory(ASF)distribution,where only 2.4 C%methane was generated.The Co3O4 phase for SiO2‐andγ‐Al2O3‐supported catalysts was observed in the calcined sample.After reduction,CoO,MnO,and low‐valence CoMn composite oxide were generated in theγ‐Al2O3‐supported sample,and both Co2C nanospheres and nanoprisms were identified in the corresponding spent catalyst.However,only separated phases of CoO and MnO were found in the reduced sample supported by SiO2,and Co2C nanospheres were detected in the spent catalyst without the evidence of any Co2C nanoprisms.The Co2C nanospheres led to a relatively high methane selectivity of 5.8 C%and 12.0 C%of theγ‐Al2O3‐and SiO2‐supported catalysts,respectively.These results suggest that a relatively weak cobalt‐support interaction is necessary for the formation of the CoMn composite oxide during calcination,which benefits the formation of Co2C nanoprisms with promising catalytic performance for the sustainable production of olefins via syngas.
基金This work was supported by the National Natural Science Foundation of China(Grant Numbers 31971106,BWS21L013,21WS09002,JK20211A010213).
文摘Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored.This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC,we used small interfering RNA(siRNA)to knock down LAMC2 to further observe the changes in the signaling pathway.Furthermore,we used cell proliferation assays,Transwell invasion assays,and wound-healing assays to observe the changes in OSCC proliferation,invasion,and metastasis.RFP-LC3 was used to detect the level of autophagy intensity.A cell line-derived xenograft(CDX)model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC.The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation,invasion,and metastasis via inhibiting the PI3K/AKT/mTOR pathway.Moreover,autophagy has a dual effect on OSCC,and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration,invasion,and proliferation.
基金This work was supported by the National Natural Science Foundation of China[grant number 41371370]the National Basic Research Program of China[grant number 2012CB719906].
文摘Specific features of tile access patterns can be applied in a cache replacement strategy to a limited distributed high-speed cache for the cloud-based networked geographic information services(NGISs),aiming to adapt to changes in the access distribution of hotspots.By taking advantage of the spatiotemporal locality,the sequential features in tile access patterns,and the cache reading performance in the burst mode,this article proposes a tile sequence replacement method,which involves structuring a Least Recently Used(LRU)stack into three portions for the different functions in cache replacement and deriving an expression for the temporal locality and popularity of the relevant tile to facilitate the replacement process.Based on the spatial characteristics of both the tiles and the cache burst mode with regard to reading data,the proposed method generates multiple tile sequences to reflect spatiotemporal locality in tile access patterns.Then,we measure the caching value by a technique based on a weighted-based method.This technique draws on the recent access popularity and low caching costs of tile sequences,with the aim of balancing the temporal and spatial localities in tile access.It ranks tile sequences in a replacement queue to adapt to the changes in accessed hotspots while reducing the replacement frequency.Experimental results show that the proposed method effectively improves the hit rate and utilization rate for a limited distributed cache while achieving satisfactory response performance and high throughput for users in an NGIS.Therefore,it can be adapted to handle numerous data access requests in NGISs in a cloud-based environment.
基金supported by the National Natural Science Foundation of China(Nos.82273873,31971106,81372124)National Key Research and Development Program of China(Nos.2020YFC1512304,2020YFC1512301)+2 种基金the Applied Basic Research Project of Tianjin(No.21JCYBJC00660)the Young Elite Scientists Sponsorship Program by Tianjin(No.0701320001)the Major Special Projects of Tianjin(No.0402080005)。
文摘Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the replenishment pathway to maintain the tricarboxylic acid cycle ensuring energy supply,therefore inducing ineffective interruption of metabolic.Herein,we designed glutamine transporter antagonist L-γ-glutamyl-p-nitroanilide(GPNA)loaded and 4T1 cancer cell membrane coated iridium oxide nanoparticles(IrO_(2)-GPNA@CCM)to realize a comprehensive inhibition of tumor energy supply which synergistically mediated by glycolysis and glutamine cycle.IrO_(2)NPs were used to catalyze the O_(2)generation by facilitating the decomposition of endogenous H_(2)O_(2)in tumor cells,which further downregulated the expression of HIF-1αand PI3K/pAKT to interrupt the generation of lactate.Meanwhile,the loaded GPNA was released under NIR irradiation to bind to alanine-serine-cysteine transporter(ASCT2)for glutamine uptake suppression,therefore realizing the comprehensive dysfunction of cell metabolism.Moreover,both in vitro and in vivo results convinced the thorough energy inhibition effect based on Ir O_(2)-GPNA@CCM NPs,which provided an inspiring strategy for future construction of tumor therapeutic regimen.
基金supported by the National Natural Science of China(82273873 and 31971106,China)the Youth Science and Technology Talent Program by Tianjin(QN20230215,China)+2 种基金the National Key Research and Development Program of China(2020YFC1512304 and 2020YFC1512301,China)the Tianjin Natural Science Foundation(24JCZDJC01110 China)the Major Special Projects(0402080005,China).
文摘As activated hepatic stellate cells(aHSCs)play a central role in fibrogenesis,they have become key target cells for antifibrotic treatment.Nevertheless,the therapeutic efficiency is constrained by the exosomes they secrete,which are linked to energy metabolism and continuously stimulate the activation of neighboring quiescent hepatic stellate cells(qHSCs).Herein,an intercellular communication interference strategy is designed utilizing paeoniflorin(PF)loaded and hyaluronic acid(HA)coated copper-doped ZIF-8(PF@HA-Cu/ZIF-8,PF@HCZ)to reduce energy-related exosome secretion from aHSCs,thus preserving neighboring qHSCs in a quiescent state.Simultaneously,the released copper and zinc ions disrupt key enzymes involved in glycolysis to reduce bioenergy synthesis in aHSCs,thereby promoting the reversion of aHSCs to a quiescent state and further decreasing exosome secretion.Therefore,PF@HCZ can effectively sustain both aHSCs and qHSCs in a metabolically dormant state to ultimately alleviate liver fibrosis.The study provides an enlightening strategy for interrupting exosome-mediated intercellular communication and remodeling the energy metabolic status of HSCs with boosted antifibrogenic activity.
基金This work was supported by Young Elite Scientists Sponsorship Program by Tianjin(No.0701320001)this work was partially supported by the grants of the National Natural Science Foundation of China(Nos.31971106 and 81372124).
文摘Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy.However,engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors.Herein,a rod-like biomimetic hybrid inorganic MnO2-Au nanozymes are developed,where MnO2 and ultrasmall Au nanoparticles(NPs)are successively deposited on the mesoporous silica nanorod to cooperatively improve the O2 content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging.Under the catalyzing of MnO2,the intratumoral H2O2 is decomposed to greatly accelerate O2 generation,which could boost the curative effect of radiation therapy(RT)and further enhance the Au-catalyzed glucose oxidation.Mutually,the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment,thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO2 with the self-supplied H2O2/H+.As a result,this mutual-reinforcing cycle can endow the nanoplatform with accelerated O2 generation,thus alleviating hypoxic environment and further boosting RT effect.Furthermore,acute glucose consuming can induce downregulation expression of heat shock protein(HSP),achieving starvation-promoted mild photothermal therapy.This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.
