Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including...Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.展开更多
Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread.Therefore,the identification of lipids and metabolic pathways that are suitable targets for antiviral develop...Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread.Therefore,the identification of lipids and metabolic pathways that are suitable targets for antiviral development is crucial.Using a library of compounds targeting host lipid metabolic factors and testing them for their ability to block pseudorabies virus(PRV)and vesicular stomatitis virus(VSV)infection,we found that U18666A,a specific inhibitor of Niemann-Pick C1(NPC1),is highly potent in suppressing the entry of diverse viruses including pseudotyped severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).NPC1 deficiency markedly attenuates viral growth by decreasing cholesterol abundance in the plasma mem-brane,thereby inhibiting the dynamics of clathrin-coated pits(CCPs),which are indispensable for clathrin-mediated endocytosis.Significantly,exogenous cholesterol can complement the dynamics of CCPs,leading to efficient viral entry and infectivity.Administration of U18666A improves the survival and pathology of PRV-and influenza A virus-infected mice.Thus,our studies demonstrate a unique mechanism by which NPC1 inhibition achieves broad antiviral activity,indicating a potential new therapeutic strategy against SARS-CoV-2,as well as other emerging viruses.展开更多
A new strategy was proposed to improve the utilization rate of corn straw by making non-ruminant feed products.The corn straw was ball milled,and the crushed straw was subjected to solid-state fermentation.After ball ...A new strategy was proposed to improve the utilization rate of corn straw by making non-ruminant feed products.The corn straw was ball milled,and the crushed straw was subjected to solid-state fermentation.After ball milling,the particle size of corn straw decreased signifcantly from 4.85±0.07 cm to 10–100μm,the content of neutral detergent fber and acid detergent fber decreased by 1.3%and 3.5%,respectively,and the total soluble sugar content increased by 16.2 mg/g.At the same time,the straw treated by ball milling as substrate could promote the rapid growth of Pediococcus acidilactici R30,the increase of organic acid production and further improvement of other nutrients during solid-state fermentation.In conclusion,the fermented straw products after ball milling could signifcantly improve the performance of pig feed in terms of digestibility and nutritional value,and better meet the feed needs of non-ruminant animals while saving resources.展开更多
Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the A...Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.展开更多
Fusarium graminearum is one of the most common fungi infecting grains and the production of mycotoxin,deoxynivalenol(DON),poses a serious threat to human and livestock health.Chitosan coated emulsion can be used as a ...Fusarium graminearum is one of the most common fungi infecting grains and the production of mycotoxin,deoxynivalenol(DON),poses a serious threat to human and livestock health.Chitosan coated emulsion can be used as a highly effective antifungal agent.However,the poor solubility of chitosan leads to a longer ultrasonic time for preparing emulsion.In our work,hydroxypropyl chitosan with better water dispersion was prepared and used as a coating for clove oil emulsion,and the effect of hydroxypropylation on the physical properties,antifungal and mycotoxin inhibitory activities of chitosan coated clove oil emulsion was investigated.Compared with unmodified chitosan coated clove oil emulsion,hydroxypropyl chitosan coated clove oil emulsion had smaller particle size,lower viscosity,and its maximum reduction of the mycelial diameter and the minimum fungicidal concentration was 35%and 50%,respectively.These results indicated that hydroxypropylation could improve the physical properties and antifungal activity of chitosan coated clove oil emulsion to a certain extent.Surprisingly,after being cultured in barley medium for 7 d,the maximum reduction of DON and ergosterol accumulation was 87%and 86%respectively,showing that hydroxypropyl chitosan coated clove oil emulsion can inhibit the production of DON by mitigating the growth of F.graminearum.Moreover,clove oil emulsions coated with high molecular weight hydroxypropyl chitosan showed a stronger inhibitory effect on the accumulation of DON and ergosterol.This work can provide a reference for mitigating fungal growth and mycotoxin production in food by essential oil emulsions.展开更多
基金supported by the National Natural Science Foundation of China (91754102, 31771568, 31690102, 31600651, 31701030)National Key Research and Development Project of the Ministry of Science and Technology of China (2016YFA0500100)+2 种基金Shenzhen City Technology Basic Research Program (JCYJ20170818144026198)Science and Technology Department of Hubei Province (2017CFB617)the 111 Project of Ministry of Education of China (B16036)
文摘Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.
文摘Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread.Therefore,the identification of lipids and metabolic pathways that are suitable targets for antiviral development is crucial.Using a library of compounds targeting host lipid metabolic factors and testing them for their ability to block pseudorabies virus(PRV)and vesicular stomatitis virus(VSV)infection,we found that U18666A,a specific inhibitor of Niemann-Pick C1(NPC1),is highly potent in suppressing the entry of diverse viruses including pseudotyped severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).NPC1 deficiency markedly attenuates viral growth by decreasing cholesterol abundance in the plasma mem-brane,thereby inhibiting the dynamics of clathrin-coated pits(CCPs),which are indispensable for clathrin-mediated endocytosis.Significantly,exogenous cholesterol can complement the dynamics of CCPs,leading to efficient viral entry and infectivity.Administration of U18666A improves the survival and pathology of PRV-and influenza A virus-infected mice.Thus,our studies demonstrate a unique mechanism by which NPC1 inhibition achieves broad antiviral activity,indicating a potential new therapeutic strategy against SARS-CoV-2,as well as other emerging viruses.
基金This work was supported by the National Natural Science Foundation of China(31701588)the Natural Science Foundation of Jiangsu Province(BK20170178)+2 种基金the Fundamental Research Funds for the Central Universities(JUSRP11965 and JUSRP21914)the Program of Introducing Talents of Discipline to Universities(111 project)(111-2-06)the Collaborative Innovation Center of Jiangsu Modern Industrial Fermentation and the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions.
文摘A new strategy was proposed to improve the utilization rate of corn straw by making non-ruminant feed products.The corn straw was ball milled,and the crushed straw was subjected to solid-state fermentation.After ball milling,the particle size of corn straw decreased signifcantly from 4.85±0.07 cm to 10–100μm,the content of neutral detergent fber and acid detergent fber decreased by 1.3%and 3.5%,respectively,and the total soluble sugar content increased by 16.2 mg/g.At the same time,the straw treated by ball milling as substrate could promote the rapid growth of Pediococcus acidilactici R30,the increase of organic acid production and further improvement of other nutrients during solid-state fermentation.In conclusion,the fermented straw products after ball milling could signifcantly improve the performance of pig feed in terms of digestibility and nutritional value,and better meet the feed needs of non-ruminant animals while saving resources.
基金supported by the China Postdoctoral Science Foundation Grant(2021M692478)the Ministry of Science and Technology of China(2018YFA0800703)+2 种基金the National Natural Science Foundation of China(32293203,31771568)111 Project of Ministry of Education of China(B16036)the support from the Tencent Foundation through the XPLORER PRIZE。
文摘Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.
基金financial support from the Key Research and Development Program of Jiangsu Province(BE2018308)The Key Project of Research and Development Plan of Ningxia(2020BFH02005)+1 种基金the Program of Introducing Talents of Discipline to Universities(111 Project)(111-2-06)Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Fusarium graminearum is one of the most common fungi infecting grains and the production of mycotoxin,deoxynivalenol(DON),poses a serious threat to human and livestock health.Chitosan coated emulsion can be used as a highly effective antifungal agent.However,the poor solubility of chitosan leads to a longer ultrasonic time for preparing emulsion.In our work,hydroxypropyl chitosan with better water dispersion was prepared and used as a coating for clove oil emulsion,and the effect of hydroxypropylation on the physical properties,antifungal and mycotoxin inhibitory activities of chitosan coated clove oil emulsion was investigated.Compared with unmodified chitosan coated clove oil emulsion,hydroxypropyl chitosan coated clove oil emulsion had smaller particle size,lower viscosity,and its maximum reduction of the mycelial diameter and the minimum fungicidal concentration was 35%and 50%,respectively.These results indicated that hydroxypropylation could improve the physical properties and antifungal activity of chitosan coated clove oil emulsion to a certain extent.Surprisingly,after being cultured in barley medium for 7 d,the maximum reduction of DON and ergosterol accumulation was 87%and 86%respectively,showing that hydroxypropyl chitosan coated clove oil emulsion can inhibit the production of DON by mitigating the growth of F.graminearum.Moreover,clove oil emulsions coated with high molecular weight hydroxypropyl chitosan showed a stronger inhibitory effect on the accumulation of DON and ergosterol.This work can provide a reference for mitigating fungal growth and mycotoxin production in food by essential oil emulsions.
