Sepsis is characterized by a severe and life-threatening host immune response to polymicrobial infection accompanied by organ dysfunction.Studies on the therapeutic effect and mechanism of immunomodulatory drugs on th...Sepsis is characterized by a severe and life-threatening host immune response to polymicrobial infection accompanied by organ dysfunction.Studies on the therapeutic effect and mechanism of immunomodulatory drugs on the sepsis-induced hyperinflammatory or immunosuppression states of various immune cells remain limited.This study aimed to investigate the protective effects and underlying mechanism of artesunate(ART)on the splenic microenvironment of cecal ligation and puncture-induced sepsis model mice using single-cell RNA sequencing(scRNA-seq)and experimental validations.The scRNA-seq analysis revealed that ART inhibited the activation of pro-inflammatory macrophages recruited during sepsis.ART could restore neutrophils’chemotaxis and immune function in the septic spleen.It inhibited the activation of T regulatory cells but promoted the cytotoxic function of natural killer cells during sepsis.ART also promoted the differentiation and activity of splenic B cells in mice with sepsis.These results indicated that ART could alleviate the inflammatory and/or immunosuppressive states of various immune cells involved in sepsis to balance the immune homeostasis within the host.Overall,this study provided a comprehensive investigation of the regulatory effect of ART on the splenic microenvironment in sepsis,thus contributing to the application of ART as adjunctive therapy for the clinical treatment of sepsis.展开更多
Objective:Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicinal herb,Tripterygium wilfordii.This study aims to provide a scientific basis for the rational development and use of cela...Objective:Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicinal herb,Tripterygium wilfordii.This study aims to provide a scientific basis for the rational development and use of celastrol in breast cancer.Method:A quantitative chemical biology approach was used to investigate the protein targets and molecular mechanisms of celastrol in breast cancer cells.Results:Low-concentration celastrol exerted an anti-tumor effect by directly binding to hydroxysteroid dehydrogenase-like 2(HSDL2)and inhibiting its expression.Moreover,the expression of the pro-apoptotic protein,Bcl-2-associated X(BaX),increased,the level of the anti-apoptotic protein,B-cell lymphoma-2(Bcl-2),decreased,and the rate of apoptosis increased.After the transfection of cells with si-HSDL2,the apoptosis rate was similar to that observed after the administration of celastrol.However,apoptosis was reversed by the overexpression of HSDL2.Furthermore,our mass spectrometry(MS)data indicated a relationship between HSDL2 and the mitogen-activated protein kinase(MAPK)signaling pathway.We also found that the expression of HSDL2 was directly related to the degree of extracellular signal-regulated kinase(ERK)phosphorylation.Conclusion:Celastrol may promote apoptosis by suppressing the HSDL2/MAPK/ERK signaling pathway.展开更多
Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18b-GA)is a natural compound that exi...Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18b-GA)is a natural compound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18b-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18b-GA inhibited the expression of a-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon resonance,we found that 18b-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18b-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18b-GA in ameliorating hepatic fibrosis,highlighting the future development of 18b-GA as a novel therapeutic drug for hepatic fibrosis.展开更多
The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been ach...The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been achieved in elucidating the antimalarial mechanisms of ART,the most crucial target proteins and pathways of ART remain unknown.Knowledge on the exact antimalarial mechanisms of ART is urgently needed,as signs of emerging ART resistance have been observed in some regions of the world.Here,we used a combined strategy involving mass spectrometry-coupled cellular thermal shift assay(MS-CETSA)and transcriptomics profiling to identify a group of putative antimalarial targets of ART.We then conducted a series of validation experiments on five prospective protein targets,demonstrating that ART may function against malaria parasites by interfering with redox homeostasis,lipid metabolism,and protein synthesis processes.Taken together,this study provides fresh perspectives on the antimalarial mechanisms of ART and identifies several crucial proteins involved in parasite survival that can be targeted to combat malaria.展开更多
The composition of serum is extremely complex,which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis.Recently,nanoparticles have been reported to effi...The composition of serum is extremely complex,which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis.Recently,nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich lowabundance proteins in serum.Here,we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona(PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis.We identified 1,070 proteins with a median coefficient of variation of 12.56%using PC-based proteomic analysis,which was twice the number of proteins identified by direct digestion.There were also more biological processes enriched with these proteins.We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis(CIA)rat model treated with methotrexate(MTX).The bioinformatic results indicated that 485 differentially expressed proteins(DEPs)were found in CIA rats,of which 323 DEPs recovered to near normal levels after treatment with MTX.This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies,but also provide more pharmacodynamic biomarkers for disease prediction,diagnosis,and treatment.展开更多
Background:Acute respiratory distress syndrome induced by acute lung injury(ALI)is the main cause for the high mortality of coronavirus disease 2019(COVID-19).Huashi about:blank formula(HSBD)with the effects of eliminating ...Background:Acute respiratory distress syndrome induced by acute lung injury(ALI)is the main cause for the high mortality of coronavirus disease 2019(COVID-19).Huashi about:blank formula(HSBD)with the effects of eliminating dampness,clearing heat,ventilating lung,and removing toxin has been proven to be effective in the treatment of COVID-19,especially in severe cases.However,the underlying mechanism and target proteins of HSBD remain unclear.Objective:To provide evidence and decipher the mechanism of HSBD in alleviating inflammation and ALI.Materials and Methods:A mouse model of ALI was induced by lipopolysaccharide(LPS),and hematoxylin-eosin staining was used to examine the protective effects of HSBD on the model mice.The cellular thermal shift assay and proteomics analysis were used to predict the target proteins.Furthermore,the A549 cells with peroxiredoxin 5(PRDX5)knockdown were established to validate the predicted proteins.Results:Huashi about:blank formula treatment mitigated ALI and inflammatory cytokine dysfunction in LPS-induced mice,thus exerting a therapeutic effect on COVID-19.Huashi about:blank formula could serve as a therapeutic agent to alleviate inflammation and lung injury via nuclear factorκB and phosphatidylinositol 3-kinase signaling and interleukin 17 inhibition as well as targeting PRDX5,which could be one of the promising targets for treating inflammation.In the A549 cell line with PRDX5 knockdown(si-PRDX5),the anti-inflammation effects of HSBD,including reversing LPS-induced increase in the nitric oxide level and reduction in the hydrogen peroxide content,were attenuated.Thus,HSBD protected A549 cells from LPS-induced inflammation mainly by targeting PRDX5.Conclusions:Huashi about:blank formula alleviates ALI by targeting nuclear factorκB/phosphatidylinositol 3-kinase and PRDX5,as well as inhibiting the immune response induced by IL-17.展开更多
Nanocarriers have therapeutic potential to facilitate drug delivery,including biological agents,smallmolecule drugs,and nucleic acids.However,their efficiency is limited by several factors;among which,endosomal/lysoso...Nanocarriers have therapeutic potential to facilitate drug delivery,including biological agents,smallmolecule drugs,and nucleic acids.However,their efficiency is limited by several factors;among which,endosomal/lysosomal degradation after endocytosis is the most important.This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms.These strategies include promoting endosomal/lysosomal escape,using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes.On the basis of the findings of this review,we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.展开更多
Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we dev...Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we developed a novel photoaffinity probe of ART to globally capture and identify the antimalarial target proteins of ART through chemical proteomics.The results demonstrated that ART can bind to par-asite proteins by both covalent and non-covalent modification,and these may jointly contribute to the antimalarial effects.Our work enriches the research on the antimalarial targets of ART,and provides a new perspective for further exploring the antimalarial mechanism of ART.展开更多
Adhesion of P-type and type-1 fimbriated uropathogenic E.coli(UPEC)to uroepithelial cells initiates urinary tract infections(UTIs).This research aimed to evaluate the capacities of selected cranberry polyphenols and t...Adhesion of P-type and type-1 fimbriated uropathogenic E.coli(UPEC)to uroepithelial cells initiates urinary tract infections(UTIs).This research aimed to evaluate the capacities of selected cranberry polyphenols and their microbial metabolites to inhibit such adhesion in vitro using a modified fluorometric method.Data showed that the inhibition capacity of myricetin increased with concentration and plateaued at 70%.It had IC50 values of 13.2μM against P-type E.coli and 5.50μM against type-1 E.coli.Quercetin showed similar anti-adhesion capacities to myricetin.Procyanidin A2 and B2 had weaker anti-adhesion activities than myricetin and quercetin,with maximal inhibition capacities of 20%-30%against UPEC.Hippuric acid,a major metabolite of cranberry polyphenols in human urine,showed a maximal inhibition of 20%at 558μM against type-1 E.coli adhesion,whereas no anti-adhesion activity against P-type E.coli was detected.The fractions of cranberry fruit powder enriched with proanthocyanidin polymers showed the highest anti-adhesion activities compared to the fractions enriched with anthocyanins,flavonols,or proanthocyanidin oligomers.Overall,the anti-adhesion activities of cranberry polyphenols and metabolites depend on their structures and the types of fimbriae on E.coli.展开更多
Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recen...Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recently,accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma,though the mechanisms are poorly defined.Methods:Here,we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I(AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing(scRNA-seq)and proteomics techniques.We established the first single-cell atlas of mouse livers in response to AAI.Results:In hepatocytes,our results indicated that AAI activated NF-κB and STAT3 signaling pathways,which may contribute to the inflammatory response and apoptosis.In liver sinusoidal endothelial cells(LSECs),AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis.Importantly,AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation.Conclusions:Collectively,our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a singlecell level and suggests future treatment options for AAs associated hepatotoxicity.展开更多
基金support by the Establishment of Sino-Austria“Belt and Road”Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research,China(Grant No.:2020YFE0205100)the National Key Research and Development Program of China(Grant Nos.:2020YFA0908000,2022YFC2303600)+9 种基金the Distinguished Expert Project of Sichuan Province Tianfu Scholar(Grant No.:CW202002)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine,China(Grant No.:ZYYCXTD-C-202002)the National Natural Science Foundation of China(Grant Nos.:82141001,82274182,82074098,82173914)the China Academy of Chinese Medical Sciences(CACMS)Innovation Fund,China(Grant Nos.:CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Grant No.:CI2021B014)the Science and Technology Foundation of Shenzhen,China(Grant No.:JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen,China(Shenzhen Clinical Medical Research Center for Geriatric Diseases),the National Key R&D Program of China Key Projects for International Cooperation on Science,Technology and Innovation(Grant No.:2020YFE0205100)the Fundamental Research Funds for the Central Public Welfare Research Institutes,China(Grant Nos.:ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010,ZZ15-ND-10),Shenzhen Governmental Sustainable Development Fund,China(Grant No.:KCXFZ20201221173612034)Shenzhen key Laboratory of Kidney Diseases,China(Grant No.:ZDSYS201504301616234)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties,China(Grant No.:SZGSP001).
文摘Sepsis is characterized by a severe and life-threatening host immune response to polymicrobial infection accompanied by organ dysfunction.Studies on the therapeutic effect and mechanism of immunomodulatory drugs on the sepsis-induced hyperinflammatory or immunosuppression states of various immune cells remain limited.This study aimed to investigate the protective effects and underlying mechanism of artesunate(ART)on the splenic microenvironment of cecal ligation and puncture-induced sepsis model mice using single-cell RNA sequencing(scRNA-seq)and experimental validations.The scRNA-seq analysis revealed that ART inhibited the activation of pro-inflammatory macrophages recruited during sepsis.ART could restore neutrophils’chemotaxis and immune function in the septic spleen.It inhibited the activation of T regulatory cells but promoted the cytotoxic function of natural killer cells during sepsis.ART also promoted the differentiation and activity of splenic B cells in mice with sepsis.These results indicated that ART could alleviate the inflammatory and/or immunosuppressive states of various immune cells involved in sepsis to balance the immune homeostasis within the host.Overall,this study provided a comprehensive investigation of the regulatory effect of ART on the splenic microenvironment in sepsis,thus contributing to the application of ART as adjunctive therapy for the clinical treatment of sepsis.
基金the National Key Research and Development Program of China(2020YFA0908000,2022YFC2303600)the National Natural Science Foundation of China(81903866,82274182)and the Central Public Welfare Research Institutes(ZZ13-YQ-105,ZZ15-YQ-065,ZZ14-YQ-058).
文摘Objective:Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicinal herb,Tripterygium wilfordii.This study aims to provide a scientific basis for the rational development and use of celastrol in breast cancer.Method:A quantitative chemical biology approach was used to investigate the protein targets and molecular mechanisms of celastrol in breast cancer cells.Results:Low-concentration celastrol exerted an anti-tumor effect by directly binding to hydroxysteroid dehydrogenase-like 2(HSDL2)and inhibiting its expression.Moreover,the expression of the pro-apoptotic protein,Bcl-2-associated X(BaX),increased,the level of the anti-apoptotic protein,B-cell lymphoma-2(Bcl-2),decreased,and the rate of apoptosis increased.After the transfection of cells with si-HSDL2,the apoptosis rate was similar to that observed after the administration of celastrol.However,apoptosis was reversed by the overexpression of HSDL2.Furthermore,our mass spectrometry(MS)data indicated a relationship between HSDL2 and the mitogen-activated protein kinase(MAPK)signaling pathway.We also found that the expression of HSDL2 was directly related to the degree of extracellular signal-regulated kinase(ERK)phosphorylation.Conclusion:Celastrol may promote apoptosis by suppressing the HSDL2/MAPK/ERK signaling pathway.
基金the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine,China(Grant No.:ZYYCXTD-C-202002)the National Key Research and Development Program of China,China(Grant No.:2020YFA0908000)+1 种基金the National Natural Science Foundation of China,China(Grant Nos.:81803389,81903588,32101219,81702580,82074098,81903866,and 81803456)the Fundamental Research Funds for the Central Public Welfare Research Institutes,China(Grant Nos.:ZZ14-YQ-050,ZZ14-YQ-059,ZZ15-ND-10,ZZ15-YQ-063,ZZ14-ND-010,and ZZ14-FL-002).
文摘Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18b-GA)is a natural compound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18b-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18b-GA inhibited the expression of a-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon resonance,we found that 18b-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18b-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18b-GA in ameliorating hepatic fibrosis,highlighting the future development of 18b-GA as a novel therapeutic drug for hepatic fibrosis.
基金supported by grants from the National Key Research and Development Program of China(2020YFA0908000 and 2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese-Medicine(ZYYCXTD-C-202002)+8 种基金the National Natural Science Foundation of China(82141001,82274182,82074098,82003814,and 82173914)the China Academy of Chinese Medical Sciences(CACMS)Innovation Fund(CI2021A05104 and CI2021A05101)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(CW202002)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(CI2021B014)the China Postdoctoral Science Foundation(2022M721541)the Establishment of Sino-Austria‘‘Belt and Road”Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(2020YFE0205100)the Excellent Scientific and Technological Innovation Training Program of Shenzhen(RCYX20210706092040048)the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-YQ-050,ZZ14-ND-010,and ZZ15-ND-10)the Introduce Innovative Team Projects of Jinan(202228029)。
文摘The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been achieved in elucidating the antimalarial mechanisms of ART,the most crucial target proteins and pathways of ART remain unknown.Knowledge on the exact antimalarial mechanisms of ART is urgently needed,as signs of emerging ART resistance have been observed in some regions of the world.Here,we used a combined strategy involving mass spectrometry-coupled cellular thermal shift assay(MS-CETSA)and transcriptomics profiling to identify a group of putative antimalarial targets of ART.We then conducted a series of validation experiments on five prospective protein targets,demonstrating that ART may function against malaria parasites by interfering with redox homeostasis,lipid metabolism,and protein synthesis processes.Taken together,this study provides fresh perspectives on the antimalarial mechanisms of ART and identifies several crucial proteins involved in parasite survival that can be targeted to combat malaria.
基金support from the National Key Research and Development Program of China(Grant Nos.:2020YFA0908000 and 2020YFE0205100)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-C-202002)+3 种基金the National Natural Science Foundation of China(Grant Nos.:82074098,82173914,and 82141001)the CACMS Innovation Fund(Grant Nos.:CI2021A05101 and CI2021A05104)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grant Nos.:ZZ15-YQ-065,ZZ14-YQ-058,ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-ND-010,ZZ15-ND-10,and ZZ14-FL-002)the Chinese Academy of Sciences(Grant No.:YJKYYQ20210025).
文摘The composition of serum is extremely complex,which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis.Recently,nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich lowabundance proteins in serum.Here,we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona(PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis.We identified 1,070 proteins with a median coefficient of variation of 12.56%using PC-based proteomic analysis,which was twice the number of proteins identified by direct digestion.There were also more biological processes enriched with these proteins.We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis(CIA)rat model treated with methotrexate(MTX).The bioinformatic results indicated that 485 differentially expressed proteins(DEPs)were found in CIA rats,of which 323 DEPs recovered to near normal levels after treatment with MTX.This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies,but also provide more pharmacodynamic biomarkers for disease prediction,diagnosis,and treatment.
基金This research was funded by Establishment of Sino-Austria“Belt and Road”Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(2020YFE0205100)National Natural Science Foundation of China(grant/award no.82204479)+1 种基金Guangdong Basic andApplied BasicResearch Foundation(grant/award no.2021A1515110381)Fundamental Research Funds for the Central public welfare research institutes(Grant No.ZZ14-YQ-056,ZZ13-YQ-103,ZZ16-ND-10-11,ZZ16-ND-10-03).
文摘Background:Acute respiratory distress syndrome induced by acute lung injury(ALI)is the main cause for the high mortality of coronavirus disease 2019(COVID-19).Huashi about:blank formula(HSBD)with the effects of eliminating dampness,clearing heat,ventilating lung,and removing toxin has been proven to be effective in the treatment of COVID-19,especially in severe cases.However,the underlying mechanism and target proteins of HSBD remain unclear.Objective:To provide evidence and decipher the mechanism of HSBD in alleviating inflammation and ALI.Materials and Methods:A mouse model of ALI was induced by lipopolysaccharide(LPS),and hematoxylin-eosin staining was used to examine the protective effects of HSBD on the model mice.The cellular thermal shift assay and proteomics analysis were used to predict the target proteins.Furthermore,the A549 cells with peroxiredoxin 5(PRDX5)knockdown were established to validate the predicted proteins.Results:Huashi about:blank formula treatment mitigated ALI and inflammatory cytokine dysfunction in LPS-induced mice,thus exerting a therapeutic effect on COVID-19.Huashi about:blank formula could serve as a therapeutic agent to alleviate inflammation and lung injury via nuclear factorκB and phosphatidylinositol 3-kinase signaling and interleukin 17 inhibition as well as targeting PRDX5,which could be one of the promising targets for treating inflammation.In the A549 cell line with PRDX5 knockdown(si-PRDX5),the anti-inflammation effects of HSBD,including reversing LPS-induced increase in the nitric oxide level and reduction in the hydrogen peroxide content,were attenuated.Thus,HSBD protected A549 cells from LPS-induced inflammation mainly by targeting PRDX5.Conclusions:Huashi about:blank formula alleviates ALI by targeting nuclear factorκB/phosphatidylinositol 3-kinase and PRDX5,as well as inhibiting the immune response induced by IL-17.
基金the Fundamental Research Funds for the National Natural Science Foundation(nos.82204322 and 82104480)the Central Public Welfare Research Institutes(grant nos.:ZZ16-ND-10-05,ZZ16-ND10-13,ZZ16-ND-10-17,ZZ16-ND-10-19,ZZ14-YQ-050,ZZ14-YQ-055,ZZ14-YQ-059,ZZ14-YQ-060,and ZZ16-YQ-046)the Young Elite Scientists Sponsorship Program by CACM(2021QNRC2B29).
文摘Nanocarriers have therapeutic potential to facilitate drug delivery,including biological agents,smallmolecule drugs,and nucleic acids.However,their efficiency is limited by several factors;among which,endosomal/lysosomal degradation after endocytosis is the most important.This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms.These strategies include promoting endosomal/lysosomal escape,using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes.On the basis of the findings of this review,we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.
基金supported by grants from the National Key Research and Development Program of China(Nos.2020YFA0908000 and 2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202002)+10 种基金the National Natural Science Foundation of China(Nos.82141001,82274182,82074098 and 82173914)the CACMS Innovation Fund(Nos.CI2021A05101 and CI2021A05104):the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(No.CI2021B014)the Science and Technology Foundation of Shenzhen(No.JCYj20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)Establishment of Sino-Austria"Belt and Road"Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(No.2020YFE0205100)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Nos.ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010 and ZZ15-ND-10)Introduce innovative team projects of Jinan(No.202228029)Shenzhen Governmental Sustainable Development Fund(No.KCXFZ20201221173612034)Shenzhen Key Laboratory of Kidney Diseases(No.ZDSYS201504301616234)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(No.SZGSPO01).
文摘Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we developed a novel photoaffinity probe of ART to globally capture and identify the antimalarial target proteins of ART through chemical proteomics.The results demonstrated that ART can bind to par-asite proteins by both covalent and non-covalent modification,and these may jointly contribute to the antimalarial effects.Our work enriches the research on the antimalarial targets of ART,and provides a new perspective for further exploring the antimalarial mechanism of ART.
基金funded in part by University of Florida Research Foundation.TEM images were acquired by Nicole J.Machi and Rodolfo Alvarado in the Interdisciplinary Center for Biotechnology Research at University of Florida.
文摘Adhesion of P-type and type-1 fimbriated uropathogenic E.coli(UPEC)to uroepithelial cells initiates urinary tract infections(UTIs).This research aimed to evaluate the capacities of selected cranberry polyphenols and their microbial metabolites to inhibit such adhesion in vitro using a modified fluorometric method.Data showed that the inhibition capacity of myricetin increased with concentration and plateaued at 70%.It had IC50 values of 13.2μM against P-type E.coli and 5.50μM against type-1 E.coli.Quercetin showed similar anti-adhesion capacities to myricetin.Procyanidin A2 and B2 had weaker anti-adhesion activities than myricetin and quercetin,with maximal inhibition capacities of 20%-30%against UPEC.Hippuric acid,a major metabolite of cranberry polyphenols in human urine,showed a maximal inhibition of 20%at 558μM against type-1 E.coli adhesion,whereas no anti-adhesion activity against P-type E.coli was detected.The fractions of cranberry fruit powder enriched with proanthocyanidin polymers showed the highest anti-adhesion activities compared to the fractions enriched with anthocyanins,flavonols,or proanthocyanidin oligomers.Overall,the anti-adhesion activities of cranberry polyphenols and metabolites depend on their structures and the types of fimbriae on E.coli.
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0908000)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-C-202002)+3 种基金the National Natural Science Foundation of China(Grants No.82074098 and 81841001)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grants No.ZXKT18003,ZZ14-YQ-050,ZZ14-ND-010,ZZ15-ND-10,ZZ14-FL-002,ZZ14-YQ-059,and ZZ15-YQ-063)the Shenzhen Science and Technology Innovation Commission(Grants No.JCYJ20210324115800001 and JCYJ20210324114014039)the National Key R&D Program of China Key Projects for International Cooperation on Science,Technology and Innovation(Grant No.2020YFE0205100).
文摘Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recently,accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma,though the mechanisms are poorly defined.Methods:Here,we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I(AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing(scRNA-seq)and proteomics techniques.We established the first single-cell atlas of mouse livers in response to AAI.Results:In hepatocytes,our results indicated that AAI activated NF-κB and STAT3 signaling pathways,which may contribute to the inflammatory response and apoptosis.In liver sinusoidal endothelial cells(LSECs),AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis.Importantly,AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation.Conclusions:Collectively,our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a singlecell level and suggests future treatment options for AAs associated hepatotoxicity.
