Despite demonstrating significant anti-tumor potential as an artemisinin derivative,artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity.To improve the del...Despite demonstrating significant anti-tumor potential as an artemisinin derivative,artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity.To improve the delivery efficiency,we engineered three artesunate(ART) derivatives,AC_(15)-L(linear),AC_(15)-B(branched),and AC_(15)-C(cyclic) with distinct aliphatic chain architectures.Unexpectedly,we observed that AC_(15)-C exhibited superior cytotoxicity against 4T1 breast cancer cells,and had the highest binding affinity for Lon protease 1(LONP1)(-72.6 kcal/mol).Subsequently,disulfide bond-containing lipid-PEG(DSPESS-PEG2K) modified chain architecture-engineered ART derivatives nanoassemblies(NAs) were developed to mitigate solubility-related limitations while enhancing targeting precision.Molecular docking and experimental validation demonstrated that ART derivatives inhibited LONP1 through hydrophobic interactions while preserved Fe^(2+)-mediated Fenton-like reaction activity.In vitro and in vivo evaluations demonstrated that AC_(15)-C NAs outperformed free ART and other NAs,suppressing 4T1 tumor growth via dual action:LONP1-directed mitochondrial proteostasis collapse and reactive oxygen species(ROS) amplification through Fe^(2+)-ART interactions.This study elucidated a novel anti-tumor mechanism of ART through the rational design of derivatives with spatially configured aliphatic chains,and developed reductionresponsive NAs to provide an advanced delivery strategy.展开更多
Aqueous zinc-ion batteries(AZIBs)offer promising safety and affordability,but suffer from dendritic Zn growth and parasitic side reactions at the electrode-electrolyte interface.Herein,we construct a dual-region inter...Aqueous zinc-ion batteries(AZIBs)offer promising safety and affordability,but suffer from dendritic Zn growth and parasitic side reactions at the electrode-electrolyte interface.Herein,we construct a dual-region interfacial modulation framework by molecularly reconfiguring the Helmholtz double layer via trace methyl methacrylate(MMA).Exploiting its amphiphilic and functionally asymmetric architecture,MMA enables a coordinated interfacial reconstruction that disrupts Zn^(2+)solvation in the outer Helmholtz plane,builds a chemisorbed coordination layer in the inner plane,and modulates local interfacial chemistry with spatial precision.This dualregion regulation collectively suppresses water reactivity,facilitates Zn^(2+)desolvation,and drives crystallo-graphically preferred deposition along the(101)plane,promoting lateral growth and mitigating dendrite for-mation.As a result,symmetric Zn||Zn cells exhibit over 4200 h of stable cycling at 1 mA cm^(-2) and maintain 1100 h of operation at 2 mA cm^(-2),even at 0℃.Zn||Ti half-cells achieve a Coulombic efficiency of 99.83%,while Zn||NH_(4)V_(4)O_(10) full cells deliver 93.92%capacity retention after 400 cycles at 2 A g^(-1),and preserve 85.3%after 300 cycles at 0℃.This work demonstrates a scalable,mechanism-driven electrolyte design paradigm for dendrite-free and high-performance aqueous Zn metal batteries.展开更多
目前针对恶性胶质瘤的治疗手段十分有限,本研究旨在通过揭示天然产物银杏叶提取物(Ginkgo biloba extract,GBE)的抗肿瘤机制,为恶性胶质瘤的治疗提供新的潜在治疗方案。研究发现,125μg/mL GBE处理A172胶质瘤细胞可显著抑制其活力(EC50=...目前针对恶性胶质瘤的治疗手段十分有限,本研究旨在通过揭示天然产物银杏叶提取物(Ginkgo biloba extract,GBE)的抗肿瘤机制,为恶性胶质瘤的治疗提供新的潜在治疗方案。研究发现,125μg/mL GBE处理A172胶质瘤细胞可显著抑制其活力(EC50=128.6μg/mL),TUNEL及瑞氏染色均观察到典型的细胞凋亡形态。机制上,GBE处理导致线粒体膜电位显著下降(JC-1法检测)并引发内质网扩张(ER-Tracker观察)。Western blot分析证实,GBE激活了线粒体自噬与内质网应激,表现为LC3-Ⅱ/Ⅰ比值升高以及葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78)和C/EBP同源蛋白(C/EBP homologous protein,CHOP)表达上调。与此同时,免疫荧光与Western blot结果显示,Notch同源物1(neurogenic locus notch homolog protein 1,Notch1)/转化生长因子-β1(transforming growth factor-beta1,TGF-β1)/Smad家族成员2/3(Smad family member 2/3,Smad2/3)通路被激活,且Notch1胞内结构域(Notch1 intracellular domain,NICD)发生核转位。双荧光素酶报告实验进一步揭示,Smad2/3可直接促进LC3和CHOP的转录。关键的是,使用Notch1抑制剂(DAPT)或TGF-β1抑制剂(SB431542)进行干预,可部分逆转由GBE诱导的细胞器应激并提升细胞存活率。综上所述,GBE通过激活Notch1/TGF-β1/Smad2/3通路,破坏细胞器稳态,进而诱导A172胶质瘤细胞凋亡。本研究的目的在于系统阐明GBE通过“信号通路-细胞器”互作以发挥抗癌作用的全新分子机制,其意义不仅为GBE作为潜在的胶质瘤治疗药物提供了坚实的实验证据,更揭示了Notch1/TGF-β1/Smad2/3通路可作为未来开发抗胶质瘤新药的重要靶点。展开更多
Parkinson’s disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson’s disease indu...Parkinson’s disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.However,the effect of GLP-1 on intrinsic synuclein malfunction remains unclear.In this study,we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms.Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death,reduced pathological aggregation ofα-synuclein,and decreased movement disorders in SncaA53T transgenic mice.Furthermore,Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation,reduced cerebral activation of microglia and astrocytes,and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra.Additionally,Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide,lipopolysaccharide binding protein,interleukin-1β,and interleukin-6.Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice.Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis.Collectively,our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson’s disease.展开更多
Lacto-N-neotetraose(LNn T)is a crucial neutral core human milk oligosaccharide(HMO).In this study,we established a LNn T-producing Saccharomyces cerevisiae cell factory through comprehensive metabolic engineering.Spec...Lacto-N-neotetraose(LNn T)is a crucial neutral core human milk oligosaccharide(HMO).In this study,we established a LNn T-producing Saccharomyces cerevisiae cell factory through comprehensive metabolic engineering.Specifically,the de novo biosynthetic pathway of LNn T was assembled by heterologously expressing the lactose permease(lac12)from Kluyveromyces lactis and the glycosyltransferase from Neisseria meningitidis in S.cerevisiae.Subsequently,carbon source regulation based on the glucose-sensitive GAL regulatory system was employed to optimize the expression time of heterologous genes,achieving a production of 15.61 mg/L of LNn T in shake-flask fermentation.In addition,the key rate-limiting steps involved in LNn T synthesis pathway were identified and the corresponding genes were overexpressed to enhance LNn T production,resulting in an 8-fold increase in LNn T titer compared to that of parental strain.To our knowledge,this is the first report on LNn T biosynthesis in S.cerevisiae,opening up the possibility of green production of LNn T using food-safe microorganisms.展开更多
Electrocatalytic nitric oxide(NO)reduction reaction(NORR)is a promising and sustainable process that can simultaneously realize green ammonia(NH3)synthesis and hazardous NO removal.However,current NORR performances ar...Electrocatalytic nitric oxide(NO)reduction reaction(NORR)is a promising and sustainable process that can simultaneously realize green ammonia(NH3)synthesis and hazardous NO removal.However,current NORR performances are far from practical needs due to the lack of efficient electrocatalysts.Engineering the lattice of metal-based nanomaterials via phase control has emerged as an effective strategy to modulate their intrinsic electrocatalytic properties.Herein,we realize boron(B)-insertion-induced phase regulation of rhodium(Rh)nanocrystals to obtain amorphous Rh_(4)B nanoparticles(NPs)and hexagonal close-packed(hcp)RhB NPs through a facile wet-chemical method.A high Faradaic efficiency(92.1±1.2%)and NH_(3) yield rate(629.5±11.0μmol h^(−1) cm^(−2))are achieved over hcp RhB NPs,far superior to those of most reported NORR nanocatalysts.In situ spectro-electrochemical analysis and density functional theory simulations reveal that the excellent electrocatalytic performances of hcp RhB NPs are attributed to the upshift of d-band center,enhanced NO adsorption/activation profile,and greatly reduced energy barrier of the rate-determining step.A demonstrative Zn-NO battery is assembled using hcp RhB NPs as the cathode and delivers a peak power density of 4.33 mW cm−2,realizing simultaneous NO removal,NH3 synthesis,and electricity output.展开更多
The increasing prevalence of antibiotic norfloxacin(NOR)residues in aquatic environments necessitates the research of high-efficiency and eco-friendly photocatalysts for their degradation.In this study,plasma-treated{...The increasing prevalence of antibiotic norfloxacin(NOR)residues in aquatic environments necessitates the research of high-efficiency and eco-friendly photocatalysts for their degradation.In this study,plasma-treated{010}-faceted BiVO_(4)(denoted as BiVO_(4)-010-P)with abundant oxygen vacancies(V_(O))and plasmonic Bi nanoparticles was strategically employed to achieve efficient NOR degradation via peroxymonosulfate(PMS)activation.Compared with pristine BiVO_(4),BiVO_(4)-010-P exhibits significantly enhanced photocatalytic PMS activation performance,achieving approximately 95%NOR removal within 80 min under white LED irradiation.Experimental and theoretical calculations prove that metallic Bi particles not only enhanced its light-absorption capacity,generating more hot electrons,but also accelerate electrons transfer from metallic Bi to BiVO_(4)-010-V_(O).Meanwhile,the generation V_(O) not only enhances PMS adsorption,but also facilitates charge transfer between BiVO_(4)-010-V_(O) and PMS.These synergistic effects collectively contribute to enhanced photocatalytic activity.This study proposes an innovative surface engineering strategy for designing efficient photocatalyst materials for addressing antibiotic pollutants in wastewater treatment systems.展开更多
基金financially supported by the Liaoning Revitalization Talents Program (No.XLYC2403107)the Excellent Youth Science Foundation of Liaoning Province (No.2024JH3/10200046)the Basic Scientific Research Project of Liaoning Provincial Department of Education (No.LJ212410163015)。
文摘Despite demonstrating significant anti-tumor potential as an artemisinin derivative,artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity.To improve the delivery efficiency,we engineered three artesunate(ART) derivatives,AC_(15)-L(linear),AC_(15)-B(branched),and AC_(15)-C(cyclic) with distinct aliphatic chain architectures.Unexpectedly,we observed that AC_(15)-C exhibited superior cytotoxicity against 4T1 breast cancer cells,and had the highest binding affinity for Lon protease 1(LONP1)(-72.6 kcal/mol).Subsequently,disulfide bond-containing lipid-PEG(DSPESS-PEG2K) modified chain architecture-engineered ART derivatives nanoassemblies(NAs) were developed to mitigate solubility-related limitations while enhancing targeting precision.Molecular docking and experimental validation demonstrated that ART derivatives inhibited LONP1 through hydrophobic interactions while preserved Fe^(2+)-mediated Fenton-like reaction activity.In vitro and in vivo evaluations demonstrated that AC_(15)-C NAs outperformed free ART and other NAs,suppressing 4T1 tumor growth via dual action:LONP1-directed mitochondrial proteostasis collapse and reactive oxygen species(ROS) amplification through Fe^(2+)-ART interactions.This study elucidated a novel anti-tumor mechanism of ART through the rational design of derivatives with spatially configured aliphatic chains,and developed reductionresponsive NAs to provide an advanced delivery strategy.
基金supported by the National Natural Science Foundation of China(Grant Nos.52125405 and U22A20108)Thailand Science Research and Innovation Fund Chulalongkorn University,National Research Council of Thailand(NRCT)and Chulalongkorn University(N42A660383).D.D.Zhang would like to thank the financial support from the Scientific Research Fund of Liaoning Provincial Education Department of China(No.JYTQN2023289)+3 种基金Liaoning Provincial Science and Technology Joint Plan(Fund)Project(No.2023-BSBA-259)and the opening project of State Key Laboratory of Metastable Materials Science and Technology,Yanshan University(No.202404).J.Cao would like to acknowledge the support from National Natural Science Foundation of China(Grant No.52402279)China Postdoctoral Science Foundation Special Funding(Grant Nos.2025T180002,2024M751753)the opening project of State Key Laboratory of Metastable Materials Science and Technology(Yanshan University)(No.202401).
文摘Aqueous zinc-ion batteries(AZIBs)offer promising safety and affordability,but suffer from dendritic Zn growth and parasitic side reactions at the electrode-electrolyte interface.Herein,we construct a dual-region interfacial modulation framework by molecularly reconfiguring the Helmholtz double layer via trace methyl methacrylate(MMA).Exploiting its amphiphilic and functionally asymmetric architecture,MMA enables a coordinated interfacial reconstruction that disrupts Zn^(2+)solvation in the outer Helmholtz plane,builds a chemisorbed coordination layer in the inner plane,and modulates local interfacial chemistry with spatial precision.This dualregion regulation collectively suppresses water reactivity,facilitates Zn^(2+)desolvation,and drives crystallo-graphically preferred deposition along the(101)plane,promoting lateral growth and mitigating dendrite for-mation.As a result,symmetric Zn||Zn cells exhibit over 4200 h of stable cycling at 1 mA cm^(-2) and maintain 1100 h of operation at 2 mA cm^(-2),even at 0℃.Zn||Ti half-cells achieve a Coulombic efficiency of 99.83%,while Zn||NH_(4)V_(4)O_(10) full cells deliver 93.92%capacity retention after 400 cycles at 2 A g^(-1),and preserve 85.3%after 300 cycles at 0℃.This work demonstrates a scalable,mechanism-driven electrolyte design paradigm for dendrite-free and high-performance aqueous Zn metal batteries.
文摘目前针对恶性胶质瘤的治疗手段十分有限,本研究旨在通过揭示天然产物银杏叶提取物(Ginkgo biloba extract,GBE)的抗肿瘤机制,为恶性胶质瘤的治疗提供新的潜在治疗方案。研究发现,125μg/mL GBE处理A172胶质瘤细胞可显著抑制其活力(EC50=128.6μg/mL),TUNEL及瑞氏染色均观察到典型的细胞凋亡形态。机制上,GBE处理导致线粒体膜电位显著下降(JC-1法检测)并引发内质网扩张(ER-Tracker观察)。Western blot分析证实,GBE激活了线粒体自噬与内质网应激,表现为LC3-Ⅱ/Ⅰ比值升高以及葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78)和C/EBP同源蛋白(C/EBP homologous protein,CHOP)表达上调。与此同时,免疫荧光与Western blot结果显示,Notch同源物1(neurogenic locus notch homolog protein 1,Notch1)/转化生长因子-β1(transforming growth factor-beta1,TGF-β1)/Smad家族成员2/3(Smad family member 2/3,Smad2/3)通路被激活,且Notch1胞内结构域(Notch1 intracellular domain,NICD)发生核转位。双荧光素酶报告实验进一步揭示,Smad2/3可直接促进LC3和CHOP的转录。关键的是,使用Notch1抑制剂(DAPT)或TGF-β1抑制剂(SB431542)进行干预,可部分逆转由GBE诱导的细胞器应激并提升细胞存活率。综上所述,GBE通过激活Notch1/TGF-β1/Smad2/3通路,破坏细胞器稳态,进而诱导A172胶质瘤细胞凋亡。本研究的目的在于系统阐明GBE通过“信号通路-细胞器”互作以发挥抗癌作用的全新分子机制,其意义不仅为GBE作为潜在的胶质瘤治疗药物提供了坚实的实验证据,更揭示了Notch1/TGF-β1/Smad2/3通路可作为未来开发抗胶质瘤新药的重要靶点。
基金supported by grants from the Jiangxi Provincial Natural Science Foundation,No.20242BAB26134(to XF)the National Natural Science Foundation of China,Nos.82060638(to TC),82060222(to XF),82460237(to XF)+1 种基金the Major Disciplines of Academic and Technical Leaders Project of Jiangxi Province,Nos.20194BCJ22032(to TC),20213BCJL22049(to XF)Science and Technology Plan of Jiangxi Health Planning Committee,No.202210390(to XF).
文摘Parkinson’s disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.However,the effect of GLP-1 on intrinsic synuclein malfunction remains unclear.In this study,we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms.Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death,reduced pathological aggregation ofα-synuclein,and decreased movement disorders in SncaA53T transgenic mice.Furthermore,Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation,reduced cerebral activation of microglia and astrocytes,and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra.Additionally,Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide,lipopolysaccharide binding protein,interleukin-1β,and interleukin-6.Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice.Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis.Collectively,our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson’s disease.
基金funded by the National Key Research and Development Program of China(2022YFF1100300)National Natural Science Foundation of China(22108097)+2 种基金Key Research and Development Program of Jiangsu Province(BE2022850)Taihu Innovation-Leading Talent of Wuxi City(1026010241230040)Cross-Integration Innovation Funding of SFST(SFST2023-KY-10).
文摘Lacto-N-neotetraose(LNn T)is a crucial neutral core human milk oligosaccharide(HMO).In this study,we established a LNn T-producing Saccharomyces cerevisiae cell factory through comprehensive metabolic engineering.Specifically,the de novo biosynthetic pathway of LNn T was assembled by heterologously expressing the lactose permease(lac12)from Kluyveromyces lactis and the glycosyltransferase from Neisseria meningitidis in S.cerevisiae.Subsequently,carbon source regulation based on the glucose-sensitive GAL regulatory system was employed to optimize the expression time of heterologous genes,achieving a production of 15.61 mg/L of LNn T in shake-flask fermentation.In addition,the key rate-limiting steps involved in LNn T synthesis pathway were identified and the corresponding genes were overexpressed to enhance LNn T production,resulting in an 8-fold increase in LNn T titer compared to that of parental strain.To our knowledge,this is the first report on LNn T biosynthesis in S.cerevisiae,opening up the possibility of green production of LNn T using food-safe microorganisms.
基金funding support from General Research Fund[Project No.14300525]from the Research Grants Council(RGC)of Hong Kong SAR,Chinafunding support from Natural Science Foundation of China(NSFC)Young Scientists Fund(Project No.22305203)+2 种基金NSFC Projects Nos.22309123,22422303,22303011,22033002,92261112 and U21A20328support from the Hong Kong Branch of National Precious Metals Material Engineering Research Center(NPMM)at City University of Hong Kongsupport from Young Collaborative Research Grant[Project No.C1003-23Y]support from RGC of Hong Kong SAR,China.
文摘Electrocatalytic nitric oxide(NO)reduction reaction(NORR)is a promising and sustainable process that can simultaneously realize green ammonia(NH3)synthesis and hazardous NO removal.However,current NORR performances are far from practical needs due to the lack of efficient electrocatalysts.Engineering the lattice of metal-based nanomaterials via phase control has emerged as an effective strategy to modulate their intrinsic electrocatalytic properties.Herein,we realize boron(B)-insertion-induced phase regulation of rhodium(Rh)nanocrystals to obtain amorphous Rh_(4)B nanoparticles(NPs)and hexagonal close-packed(hcp)RhB NPs through a facile wet-chemical method.A high Faradaic efficiency(92.1±1.2%)and NH_(3) yield rate(629.5±11.0μmol h^(−1) cm^(−2))are achieved over hcp RhB NPs,far superior to those of most reported NORR nanocatalysts.In situ spectro-electrochemical analysis and density functional theory simulations reveal that the excellent electrocatalytic performances of hcp RhB NPs are attributed to the upshift of d-band center,enhanced NO adsorption/activation profile,and greatly reduced energy barrier of the rate-determining step.A demonstrative Zn-NO battery is assembled using hcp RhB NPs as the cathode and delivers a peak power density of 4.33 mW cm−2,realizing simultaneous NO removal,NH3 synthesis,and electricity output.
基金support from the National Natural Science Foundation of China(52102362)Shandong Provincial Natural Science Foundation(ZR2021QB022)+2 种基金China Postdoctoral Science Foundation(2024M761557)Taishan Scholars Program of Shandong Province(tsqn202408162,ts201712030,tstp20230665)Technology Support Program for Youth Innovation Team of Shandong Universities(2023KJ225,2024KJH144).
文摘The increasing prevalence of antibiotic norfloxacin(NOR)residues in aquatic environments necessitates the research of high-efficiency and eco-friendly photocatalysts for their degradation.In this study,plasma-treated{010}-faceted BiVO_(4)(denoted as BiVO_(4)-010-P)with abundant oxygen vacancies(V_(O))and plasmonic Bi nanoparticles was strategically employed to achieve efficient NOR degradation via peroxymonosulfate(PMS)activation.Compared with pristine BiVO_(4),BiVO_(4)-010-P exhibits significantly enhanced photocatalytic PMS activation performance,achieving approximately 95%NOR removal within 80 min under white LED irradiation.Experimental and theoretical calculations prove that metallic Bi particles not only enhanced its light-absorption capacity,generating more hot electrons,but also accelerate electrons transfer from metallic Bi to BiVO_(4)-010-V_(O).Meanwhile,the generation V_(O) not only enhances PMS adsorption,but also facilitates charge transfer between BiVO_(4)-010-V_(O) and PMS.These synergistic effects collectively contribute to enhanced photocatalytic activity.This study proposes an innovative surface engineering strategy for designing efficient photocatalyst materials for addressing antibiotic pollutants in wastewater treatment systems.
