Delivering high quality dietary protein at an affordable price is a major aim of the EU-funded CHANCE project. Foods have been formulated with this aim and as part of their nutritional assessment;the bioaccessbility o...Delivering high quality dietary protein at an affordable price is a major aim of the EU-funded CHANCE project. Foods have been formulated with this aim and as part of their nutritional assessment;the bioaccessbility of nutrients following simulated gastroduodenal digestion is being investigated. Nutrimetabolomics approaches can be used to comprehensively and quantitatively analyse nutrients and metabolites. They have been applied to monitor nutrient release from ham, formulated in the CHANCE project, during in vitro digestion. SDS-PAGE analysis shows that constituent ham proteins were broken down to lower molecular weight polypeptides (Mr ≤ 10 kDa) after 120 min simulated gastric digestion which was digested further by subsequent duodenal digestion. Digestion of porteins resulted in the appearance of coalesced lipid droplets associated with the loss of the muscle protein matrix of the ham. Important nutrients, such as choline, creatine, carnosine, sucrose, cholesterol, triacylglyceride and fatty acids (saturated and unsaturated) were identified using 1H NMR. Chance ham is a good source of dietary protein and the combined approach can provide representative data on the bioaccessibility of all detectable nutrients contained in CHANCE ham to human digestive system.展开更多
Tumor vascular normalization has emerged as a promising strategy for synergistic therapy recently.Based on the strategy of“fluorescence turn on-controllable release”,a novel bifunctional candidate was con-structed b...Tumor vascular normalization has emerged as a promising strategy for synergistic therapy recently.Based on the strategy of“fluorescence turn on-controllable release”,a novel bifunctional candidate was con-structed based on previous developed vascular normalization inducer QDAU5,which could self-assemble to form functional enzyme infrared QDAU5 nanoparticles(FEIRQ NPs).Subsequently,biological evaluation demonstrated that the FEIRQ NPs could induce ferroptosis,endoplasmic reticulum stress,and antigen pre-conditioning and maturation of dendritic cells and CD8^(+)T cells,leading to excellent antitumor efficacy in the absence of cytotoxic drugs.Additionally,FEIRQ NPs show high fluorescence intensity upon expo-sure to theβ-galactosidase(β-Gal)enzyme expressed in ovarian cancer,enabling real-time monitoring of therapeutic effects.Overall,our findings suggest a prospering strategy to early diagnosis and efficient therapy for ovarian cancer without cytotoxicity.展开更多
Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of...Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of glutathione(GSH)can improve the TME.Here,we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles(FEUQ Nps)based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer,a GSH depleting agent,and an activated fluorophore.In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment.In addition,it may deplete GSH in cancer cells,thus inducing the production of reactive oxygen species(ROS)and lipid peroxide(LPO)and promoting iron toxicity.It may also lead to endoplasmic stress and release of calmodulin,which activates the immune system.Meanwhile,quenched fluorophores are turned on in the presence of galactosidase(GLU)for tumor-specific labeling.In summary,we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.展开更多
The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million s...The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.展开更多
A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identif...A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.展开更多
Dear Editor,The pandemic of COVID-19 caused by SARS-CoV-2 infection has posed a serious threat to global public health and the economy.Up to now,although several potentially effective antiviral drugs are under evaluat...Dear Editor,The pandemic of COVID-19 caused by SARS-CoV-2 infection has posed a serious threat to global public health and the economy.Up to now,although several potentially effective antiviral drugs are under evaluating in clinical trials around the world,1 there are still no specific antiviral countermeasures beyond supportive therapies have been established.We herein report that the hydrophilic compound Salvianolic acid C(Sal-C)from Danshen,a traditional Chinese medicine(TCM),potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle(6-HB)core of spike(S)protein.展开更多
The aim of this study was to investigate the effects of tomato quality and yield between different bunches and the differences between the two comprehensive evaluation methods on tomato quality ranking under water str...The aim of this study was to investigate the effects of tomato quality and yield between different bunches and the differences between the two comprehensive evaluation methods on tomato quality ranking under water stress.Two degrees of water stress including mild water stress(W1)and moderate water stress(W2),and three growth stages that water stress applied including seedling stage(S1),flowering stage(S2)and fruit expanding stage(S3)were tested in this study.The yield and quality of different bunches of tomatoes under water stress during different growth stages were determined as responses,and the comprehensive fruit quality ranking and yield of the second and third bunches were evaluated.The results showed that water stress was important for the improvement of fruit quality,but fruit yield decreased during water stress.The yield of the third tomato bunch decreased from 11.69%(W1S1)to 30.60%(W2S2)compared to control(97.57 t/hm^(2)),and the effects of mild water stress on fruit yield were minimal at the early growth stage.However,the fruit quality in terms of soluble sugar(SS),total soluble solids(TSS),vitamin C(VC),and firmness(F)improved under water stress compared to control.The combined effects of water stress and its application period significantly affected SS and TSS.Water stress significantly improved the content of SS and TSS in the later growth period compared to seedling and flowering stages.Meanwhile,there was a significant difference in tomato quality between the second and third bunches of fruit,especially in the content of SS,organic acid(OA)and lycopene(L).Principal Component Analysis(PCA)and Grey Relational Analysis(GRA)were used to evaluate comprehensive fruit quality,and the best treatment in terms of the fruit quality was W1S3 for both bunches.The rank-sum ratio(RSR)method was used to evaluate fruit quality and yield,the results showed that W1S3 ranked first based on PCA and W1S1 ranked first based on GRA.Water stress enhanced tomato quality but inevitably reduced its yield during each growth stage.The application of mild water stress during the fruit expanding stage(W1S3)was considered to be the best treatment to provide satisfactory fruit quality and yield based on RSR.展开更多
In November 2021,a new SARS-CoV-2 variant emerged in South Africa and was designated the fifth variant of concern and named Omicron.It was detected in more than 26 countries worldwide,including China.The Omicron varia...In November 2021,a new SARS-CoV-2 variant emerged in South Africa and was designated the fifth variant of concern and named Omicron.It was detected in more than 26 countries worldwide,including China.The Omicron variant is highly transmissible and has extensive morbidity,which has raised concerns related to antiviral therapy.Recent reports have revealed that the Omicron variant exhibits a longer cycle of viral shedding and a decreased replication capacity and results in substantially attenuated lung pathology,indicating that the pathogenic ability of the Omicron variant is lower than that of previous variants.1Omicron has the largest number(>30)of substitutions,deletions,or insertions,with a mutation frequency of higher than 1%in the spike(S)protein.Mutation studies of the spike protein receptor-binding domain have provided a plausible explanation for the increased transmissibility and antibody resistance of this variant.However,the molecular basis for its attenuated pathogenicity and replication capacity remains elusive.展开更多
文摘Delivering high quality dietary protein at an affordable price is a major aim of the EU-funded CHANCE project. Foods have been formulated with this aim and as part of their nutritional assessment;the bioaccessbility of nutrients following simulated gastroduodenal digestion is being investigated. Nutrimetabolomics approaches can be used to comprehensively and quantitatively analyse nutrients and metabolites. They have been applied to monitor nutrient release from ham, formulated in the CHANCE project, during in vitro digestion. SDS-PAGE analysis shows that constituent ham proteins were broken down to lower molecular weight polypeptides (Mr ≤ 10 kDa) after 120 min simulated gastric digestion which was digested further by subsequent duodenal digestion. Digestion of porteins resulted in the appearance of coalesced lipid droplets associated with the loss of the muscle protein matrix of the ham. Important nutrients, such as choline, creatine, carnosine, sucrose, cholesterol, triacylglyceride and fatty acids (saturated and unsaturated) were identified using 1H NMR. Chance ham is a good source of dietary protein and the combined approach can provide representative data on the bioaccessibility of all detectable nutrients contained in CHANCE ham to human digestive system.
基金supported by the National Natural Science Foundation of China(NSFC,Nos.82373793,82173742)the Science Fund for Distinguished Young Scholars of Shaanxi Province(No.2022JC-54)the Key Research and Development Program of Shaanxi Province(No.2023-YBSF-131).
文摘Tumor vascular normalization has emerged as a promising strategy for synergistic therapy recently.Based on the strategy of“fluorescence turn on-controllable release”,a novel bifunctional candidate was con-structed based on previous developed vascular normalization inducer QDAU5,which could self-assemble to form functional enzyme infrared QDAU5 nanoparticles(FEIRQ NPs).Subsequently,biological evaluation demonstrated that the FEIRQ NPs could induce ferroptosis,endoplasmic reticulum stress,and antigen pre-conditioning and maturation of dendritic cells and CD8^(+)T cells,leading to excellent antitumor efficacy in the absence of cytotoxic drugs.Additionally,FEIRQ NPs show high fluorescence intensity upon expo-sure to theβ-galactosidase(β-Gal)enzyme expressed in ovarian cancer,enabling real-time monitoring of therapeutic effects.Overall,our findings suggest a prospering strategy to early diagnosis and efficient therapy for ovarian cancer without cytotoxicity.
基金supported by the National Natural Science Foundation of China(NSFC,No.82173742)the Science Fund for Distinguished Young Scholars of Shaanxi Province(No.2022JC-54)the Key Research and Development Program of Shaanxi Province(No.2023-YBSF-131).
文摘Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of glutathione(GSH)can improve the TME.Here,we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles(FEUQ Nps)based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer,a GSH depleting agent,and an activated fluorophore.In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment.In addition,it may deplete GSH in cancer cells,thus inducing the production of reactive oxygen species(ROS)and lipid peroxide(LPO)and promoting iron toxicity.It may also lead to endoplasmic stress and release of calmodulin,which activates the immune system.Meanwhile,quenched fluorophores are turned on in the presence of galactosidase(GLU)for tumor-specific labeling.In summary,we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.
基金supported by the National Key R&D Program of China 2018YFA0507000(B.W,Q.Z.),2018ZX09735001(Y.J.)and 2020YFC0844500(J.L.),the National Science Foundation of China grants 31825010(B.W.),81525024(Q.Z.),81673489(J.L),the Key Research Program of Frontier Sciences,CAS grants QYZDB-SSWSMC024(B.W.)and QYZDB-SSW-SMC054(Q.Z.),Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.),Chinese Academy of Engineering and Jack Ma Foundation 2020-CMKYGG-05(J.D.),the Shanghai Science and Technology Development Funds 20431900200(J.L.)and K.C.Wong Education Foundation(J.L.),Fund of Youth Innovation Promotion Association 2018319(X.C.),and the Hubei Science and Technology Project 2020FCA003(G.X.).Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.)。
文摘The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
基金National Key R&D Program of China grants 2017YFC0840300(Z.R.)and 2020YFA0707500(H.Y.)Project of International Cooperation and Exchanges NSFC(Grant No.81520108019 to Z.R.)+3 种基金Science and Technology Commission of Shanghai Municipality(Grant No.20431900200 to H.Y.)Department of Science and Technology of Guangxi Zhuang Autonomous Region(Grant No.2020AB40007 to X.Y.)Hubei Science and Technology Project(Grant No.2020FCA003 to L.Z.)Youth Program of NSFC(Grant No.81900729 to L.S.).
文摘A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
文摘Dear Editor,The pandemic of COVID-19 caused by SARS-CoV-2 infection has posed a serious threat to global public health and the economy.Up to now,although several potentially effective antiviral drugs are under evaluating in clinical trials around the world,1 there are still no specific antiviral countermeasures beyond supportive therapies have been established.We herein report that the hydrophilic compound Salvianolic acid C(Sal-C)from Danshen,a traditional Chinese medicine(TCM),potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle(6-HB)core of spike(S)protein.
基金This study was financially supported by the 863 Program of National High-Tech R&D Program of China(2013AA103004)the Water and Technology Support Plan of Shaanxi Province,China(2014slkj-17).
文摘The aim of this study was to investigate the effects of tomato quality and yield between different bunches and the differences between the two comprehensive evaluation methods on tomato quality ranking under water stress.Two degrees of water stress including mild water stress(W1)and moderate water stress(W2),and three growth stages that water stress applied including seedling stage(S1),flowering stage(S2)and fruit expanding stage(S3)were tested in this study.The yield and quality of different bunches of tomatoes under water stress during different growth stages were determined as responses,and the comprehensive fruit quality ranking and yield of the second and third bunches were evaluated.The results showed that water stress was important for the improvement of fruit quality,but fruit yield decreased during water stress.The yield of the third tomato bunch decreased from 11.69%(W1S1)to 30.60%(W2S2)compared to control(97.57 t/hm^(2)),and the effects of mild water stress on fruit yield were minimal at the early growth stage.However,the fruit quality in terms of soluble sugar(SS),total soluble solids(TSS),vitamin C(VC),and firmness(F)improved under water stress compared to control.The combined effects of water stress and its application period significantly affected SS and TSS.Water stress significantly improved the content of SS and TSS in the later growth period compared to seedling and flowering stages.Meanwhile,there was a significant difference in tomato quality between the second and third bunches of fruit,especially in the content of SS,organic acid(OA)and lycopene(L).Principal Component Analysis(PCA)and Grey Relational Analysis(GRA)were used to evaluate comprehensive fruit quality,and the best treatment in terms of the fruit quality was W1S3 for both bunches.The rank-sum ratio(RSR)method was used to evaluate fruit quality and yield,the results showed that W1S3 ranked first based on PCA and W1S1 ranked first based on GRA.Water stress enhanced tomato quality but inevitably reduced its yield during each growth stage.The application of mild water stress during the fruit expanding stage(W1S3)was considered to be the best treatment to provide satisfactory fruit quality and yield based on RSR.
基金Fund of Distinguished Young Scholars(81825021)the Fund of Youth Innovation Promotion Association(2019285)+4 种基金the National Natural Science Foundation of China(81773707,92169202)the Lingang Lab(LG202101-01-04)the National Key Research and Development Program of China(2020YFC0842000)the project supported by the Shanghai Municipal Science and TechnologyMajor Project(Grant Nos.2018SHZDZX05,TZX022021002)and the Fund of Shanghai Science and Technology Innovation Action Plan(20ZR1474200).
文摘In November 2021,a new SARS-CoV-2 variant emerged in South Africa and was designated the fifth variant of concern and named Omicron.It was detected in more than 26 countries worldwide,including China.The Omicron variant is highly transmissible and has extensive morbidity,which has raised concerns related to antiviral therapy.Recent reports have revealed that the Omicron variant exhibits a longer cycle of viral shedding and a decreased replication capacity and results in substantially attenuated lung pathology,indicating that the pathogenic ability of the Omicron variant is lower than that of previous variants.1Omicron has the largest number(>30)of substitutions,deletions,or insertions,with a mutation frequency of higher than 1%in the spike(S)protein.Mutation studies of the spike protein receptor-binding domain have provided a plausible explanation for the increased transmissibility and antibody resistance of this variant.However,the molecular basis for its attenuated pathogenicity and replication capacity remains elusive.
