Background Rosemary extract(RE)has been reported to exert antioxidant property.However,the application of RE in late-phase laying hens on egg quality,intestinal barrier and microbiota,and oviductal function has not be...Background Rosemary extract(RE)has been reported to exert antioxidant property.However,the application of RE in late-phase laying hens on egg quality,intestinal barrier and microbiota,and oviductal function has not been systematically studied.This study was investigated to detect the potential effects of RE on performance,egg quality,serum parameters,intestinal heath,cecal microbiota and metabolism,and oviductal gene expressions in late-phase laying hens.A total of 21065-week-old“Jing Tint 6”laying hens were randomly allocated into five treatments with six replicates and seven birds per replicate and fed basal diet(CON)or basal diet supplemented with chlortetracycline at 50 mg/kg(CTC)or RE at 50 mg/kg(RE50),100 mg/kg(RE100),and 200 mg/kg(RE200).Results Our results showed that RE200 improved(P<0.05)Haugh unit and n-6/n-3 of egg yolk,serum superoxide dismutase(SOD)compared with CON.No significant differences were observed for Haugh unit and n-6/n-3 of egg yolk among CTC,RE50,RE100 and RE200 groups.Compared with CTC and RE50 groups,RE200 increased serum SOD activity on d 28 and 56.Compared with CON,RE supplementation decreased(P<0.05)total cholesterol(TC)level.CTC,RE100 and RE200 decreased(P<0.05)serum interleukin-6(IL-6)content compared with CON.CTC and RE200 increased jejunal m RNA expression of ZO-1 and Occludin compared with CON.The biomarkers of cecal microbiota and metabolite induced by RE 200,including Firmicutes,Eisenbergiella,Paraprevotella,Papillibacter,and butyrate,were closely associated with Haugh unit,n-6/n-3,SOD,IL-6,and TC.PICRUSt2 analysis indicated that RE altered carbohydrate and amino acid metabolism of cecal microbiota and increased butyrate synthesizing enzymes,including 3-oxoacid Co A-transferase and butyrate-acetoacetate Co A-transferase.Moreover,transcriptomic analysis revealed that RE200 improved gene expressions and functional pathways related to immunity and albumen formation in the oviductal magnum.Conclusions Dietary supplementation with 200 mg/kg RE could increase egg quality of late-phase laying hens via modulating intestinal barrier,cecal microbiota and metabolism,and oviductal function.Overall,RE could be used as a promising feed additive to improve egg quality of laying hens at late stage of production.展开更多
Objective:In the realm of Class I pathogens,Burkholderia pseudomallei(BP)stands out for its propensity to induce severe pathogenicity.Investigating the intricate interactions between BP and host cells is imperative fo...Objective:In the realm of Class I pathogens,Burkholderia pseudomallei(BP)stands out for its propensity to induce severe pathogenicity.Investigating the intricate interactions between BP and host cells is imperative for comprehending the dynamics of BP infection and discerning biomarkers indicative of the host cell response process.Methods:mRNA extraction from BP-infected mouse macrophages constituted the initial step of our study.Employing gene expression arrays,the extracted RNA underwent conversion into digital signals.The percentile shift method facilitated data processing,with the identification of genes manifesting significant differences accomplished through the application of the t-test.Subsequently,a comprehensive analysis involving Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway was conducted on the differentially expressed genes(DEGs).Leveraging the ESTIMATE algorithm,gene signatures were utilized to compute risk scores for gene expression data.Support vector machine analysis and gene enrichment scores were instrumental in establishing correlations between biomarkers and macrophages,followed by an evaluation of the predictive power of the identified biomarkers.Results:The functional and pathway associations of the DEGs predominantly centered around G protein-coupled receptors.A noteworthy positive correlation emerged between the blue module,consisting of 416 genes,and the StromaScore.FZD4,identified through support vector machine analysis among intersecting genes,indicated a robust interaction with macrophages,suggesting its potential as a robust biomarker.FZD4 exhibited commendable predictive efficacy,with BP infection inducing its expression in both macrophages and mouse lung tissue.Western blotting in macrophages confirmed a significant upregulation of FZD4 expression from 0.5 to 24 h post-infection.In mouse lung tissue,FZD4 manifested higher expression in the cytoplasm of pulmonary epithelial cells in BP-infected lungs than in the control group.Conclusion:Thesefindings underscore the upregulation of FZD4 expression by BP in both macrophages and lung tissue,pointing to its prospective role as a biomarker in the pathogenesis of BP infection.展开更多
●AIM:To investigate the long-term changes of corneal densitometry(CD)and its contributing elements after small incision lenticule extraction(SMILE).●METHODS:Totally 31 eyes of 31 patients with mean spherical equival...●AIM:To investigate the long-term changes of corneal densitometry(CD)and its contributing elements after small incision lenticule extraction(SMILE).●METHODS:Totally 31 eyes of 31 patients with mean spherical equivalent of-6.46±1.50 D and mean age 28.23±7.38y were enrolled.Full-scale examinations were conducted on all patients preoperatively and during followup.Visual acuity,manifest refraction,axial length,corneal thickness,corneal higher-order aberrations,and CD were evaluated.●RESULTS:All surgeries were completed successfully without complications or adverse events.Ten-year safety index was 1.17±0.20 and efficacy 1.04±0.28.CD value of 0–6 mm zones in central layer was statistically significantly lower 10y postoperatively,compared with preoperative values(0–2 mmΔ=-1.62,2–6 mmΔ=-1.24,P<0.01).There were no correlations between CD values and factors evaluated.●CONCLUSION:SMILE is a safe and efficient procedure for myopia on a long-term basis.CD values get lower 10y postoperatively,whose mechanism is to be further discussed.展开更多
Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an i...Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an indispensable role, however, its mechanism of action(MoA) is not fully understood.Methods: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling(ABPP) and mass spectrometry-coupled cellular thermal shift assay(MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays.Results: We developed a novel clickable, photo-affinity chloroquine analog probe(CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photocrosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods.Conclusions: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled(ABPP)and label-free(MS-CETSA) methods.展开更多
Tripterygium glycosides tablet(TGT),the classical commercial drug of Tripterygium wilfordii Hook.F.has been effectively used in the treatment of rheumatoid arthritis,nephrotic syndrome,leprosy,Behcet's syndrome,le...Tripterygium glycosides tablet(TGT),the classical commercial drug of Tripterygium wilfordii Hook.F.has been effectively used in the treatment of rheumatoid arthritis,nephrotic syndrome,leprosy,Behcet's syndrome,leprosy reaction and autoimmune hepatitis.However,due to its narrow and limited treatment window,TGT-induced organ toxicity(among which liver injury accounts for about 40%of clinical reports)has gained increasing attention.The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing(scRNA-seq)technology.The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators,including alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase and total bilirubin.Using the mouse model,we identified 15 specific subtypes of cells in the liver tissue,including endothelial cells,hepatocytes,cholangiocytes,and hepatic stellate cells.Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations;led to marked inflammatory response,apoptosis and fatty acid metabolism dysfunction in hepatocytes;activated hepatic stellate cells;brought about the activation,inflammation,and phagocytosis of liver capsular macrophages cells;resulted in immune dysfunction of liver lymphocytes;disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways.Thus,these findings elaborate the mechanism underlying TGT-induced acute liver injury,provide new insights into the safe and rational applications in the clinic,and complement the identification of new biomarkers and therapeutic targets for liver protection.展开更多
In response to the awareness of limited fossil resources and environmental concerns,catalytic conversion of renewable lignocellulose biomass to value-added chemicals and fuels is of great significance and attractive f...In response to the awareness of limited fossil resources and environmental concerns,catalytic conversion of renewable lignocellulose biomass to value-added chemicals and fuels is of great significance and attractive for sustainable chemistry.Division of Biomass Conversion and Bio-Energy attached to Dalian National Laboratory for Clean Energy has devoted themselves to valorization of lignocellulose biomass since launched in 2011.Our research interests focus on breeding of biomass resources(inulin and microalgae),exploration of catalytic and biological technologies,and production of energy chemicals and fuels.Although lignocellulose biomass is renewable and abundant,the way of utilization should be reasonable according to its structural characteristics in view of efficiency and economy.In this review,to celebrate the DICP's 70 th anniversary,we will highlight the major fundamental advances in DICP about the conversion of lignocellulose to value-added chemicals and liquid fuels.Particular attention will be paid to the transformation of cellulose and its derivatives to glycols,acids and nitrogen-containing chemicals,hemicellulose-derived platform molecule furfural to jet fuels and lignin to aromatics using catalytic technologies.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
Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship.Methods A total of 100 ...Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship.Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group):four groups were treated with rhG-CSFa at 500,100,10,1 μg/kg,respectively,and one group was treated with vehicle only to serve as the control.The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks.During the course of the chronic toxicity study,the physical status,body weight,and food consumption were monitored.Half of the rats in each group (n=10) were sacrificed after the last rhG-CSFa administration,and the other half were sacrificed at five weeks after the last rhG-CSFa administration.Urinalyses,blood biochemistry,hematological analysis,histopathological examination,and immunological tests were performed for each of the rats.Results The hematological analyses revealed that the mean white blood cells count,neutrophils count,and neutrophils percentage were increased in male rats at the dose of 10 μg/kg or higher,and these were related with the biological activity of rhG-CSFa.Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 μg/kg,a dosage of 200 folds higher than the normal clinical dosage),but these abnormalities were recovered within 5-week recovery period.No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.展开更多
AIM: To investigate the one-year refractive outcomes and optical quality following PRESBYOND laser-blended vision(LBV).METHODS: This retrospective study included 20 patients who underwent PRESBYOND treatment between J...AIM: To investigate the one-year refractive outcomes and optical quality following PRESBYOND laser-blended vision(LBV).METHODS: This retrospective study included 20 patients who underwent PRESBYOND treatment between Jan 2019 and Aug 2020. The patients were asked to attend a followup outpatient visit one year after surgery. Distance and near visual acuity as well as subjective refraction were examined. Optical quality was assessed using wavefront-supported custom ablation. A questionnaire evaluating optical quality and satisfaction was completed at the last visit.RESULTS: The average patient age was 48.1±7.4 y(range, 41 to 58 y). The mean preoperative spherical equivalent was-7.59±2.39D. At the one-year follow-up, two eyes(both dominant eyes) lost one line of corrected distance visual acuity(CDVA), while the remaining eyes(38/40) maintained or gained lines of CDVA. The average binocular uncorrected distance visual acuity improved from 0.15±0.03 to 0.90±0.26(decimal vision;P<0.001). The average binocular uncorrected near visual acuity increased from 0.34±0.28 to 0.97±0.07(P<0.001). The spherical aberration was 0.04±0.06 μm in the nondominant eye and 0.09±0.09 μm in the dominant eye(P=0.02). All patients were satisfied with or accepted the outcomes of the surgery. The primary complaints were related to disturbances in night vision and relatively inferior near vision.CONCLUSION: Over the one-year observation period, PRESBYOND is a safe and effective option for presbyopia correction. The optical quality and near vision deserve further investigation.展开更多
The rapidly increasing popularity of mobile devices has changed the methods with which people access various network services and increased net-work traffic markedly.Over the past few decades,network traffic identific...The rapidly increasing popularity of mobile devices has changed the methods with which people access various network services and increased net-work traffic markedly.Over the past few decades,network traffic identification has been a research hotspot in the field of network management and security mon-itoring.However,as more network services use encryption technology,network traffic identification faces many challenges.Although classic machine learning methods can solve many problems that cannot be solved by port-and payload-based methods,manually extract features that are frequently updated is time-consuming and labor-intensive.Deep learning has good automatic feature learning capabilities and is an ideal method for network traffic identification,particularly encrypted traffic identification;Existing recognition methods based on deep learning primarily use supervised learning methods and rely on many labeled samples.However,in real scenarios,labeled samples are often difficult to obtain.This paper adjusts the structure of the auxiliary classification generation adversarial network(ACGAN)so that it can use unlabeled samples for training,and use the wasserstein distance instead of the original cross entropy as the loss function to achieve semisupervised learning.Experimental results show that the identification accuracy of ISCX and USTC data sets using the proposed method yields markedly better performance when the number of labeled samples is small compared to that of convolutional neural network(CNN)based classifier.展开更多
This study was conducted to elucidate the potential key candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension.Methods Expression profiles GSE2378 and GSE758 including 27 react...This study was conducted to elucidate the potential key candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension.Methods Expression profiles GSE2378 and GSE758 including 27 reactive optic nerve head astrocytes(ONHAs)by hypertensions and 26 normal controls,were integrated and deeply analyzed.Differentially expressed genes(DEGs)were sorted and candidate genes and pathways enrichment were analyzed.DEGs-associated protein-protein interaction network(PPI)was performed.Results A total of 119 consistently expressed genes were identified from 281 commonly changed DEGs,including 68 up-regulated genes and 51 down-regulated genes.PPI network complex filtered 75 DEGs(43 up-regulated and 32 down-regulated genes)of the 119 consistently altered DEGs and developed 117 edges,and 10 hub genes were identified.The most significant 3 modules were filtered from PPI,pathway enrichment analysis showed that module 1 was associated with extracellular exosome.Module 2 was mainly associated with antibody-dependent cellular cytotoxicity(ADCC)and module 3 was mainly associated with Hippo signaling pathway.Conclusion Taken above,using integrated bioinformatical analysis,we have identified DEGs candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension,which could improve our understanding of the cause and underlying molecular events,and these candidate genes and pathways could be therapeutic targets for glaucoma.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
基金supported by the China Postdoctoral Science Foundation(2022M723370)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA23080603)。
文摘Background Rosemary extract(RE)has been reported to exert antioxidant property.However,the application of RE in late-phase laying hens on egg quality,intestinal barrier and microbiota,and oviductal function has not been systematically studied.This study was investigated to detect the potential effects of RE on performance,egg quality,serum parameters,intestinal heath,cecal microbiota and metabolism,and oviductal gene expressions in late-phase laying hens.A total of 21065-week-old“Jing Tint 6”laying hens were randomly allocated into five treatments with six replicates and seven birds per replicate and fed basal diet(CON)or basal diet supplemented with chlortetracycline at 50 mg/kg(CTC)or RE at 50 mg/kg(RE50),100 mg/kg(RE100),and 200 mg/kg(RE200).Results Our results showed that RE200 improved(P<0.05)Haugh unit and n-6/n-3 of egg yolk,serum superoxide dismutase(SOD)compared with CON.No significant differences were observed for Haugh unit and n-6/n-3 of egg yolk among CTC,RE50,RE100 and RE200 groups.Compared with CTC and RE50 groups,RE200 increased serum SOD activity on d 28 and 56.Compared with CON,RE supplementation decreased(P<0.05)total cholesterol(TC)level.CTC,RE100 and RE200 decreased(P<0.05)serum interleukin-6(IL-6)content compared with CON.CTC and RE200 increased jejunal m RNA expression of ZO-1 and Occludin compared with CON.The biomarkers of cecal microbiota and metabolite induced by RE 200,including Firmicutes,Eisenbergiella,Paraprevotella,Papillibacter,and butyrate,were closely associated with Haugh unit,n-6/n-3,SOD,IL-6,and TC.PICRUSt2 analysis indicated that RE altered carbohydrate and amino acid metabolism of cecal microbiota and increased butyrate synthesizing enzymes,including 3-oxoacid Co A-transferase and butyrate-acetoacetate Co A-transferase.Moreover,transcriptomic analysis revealed that RE200 improved gene expressions and functional pathways related to immunity and albumen formation in the oviductal magnum.Conclusions Dietary supplementation with 200 mg/kg RE could increase egg quality of late-phase laying hens via modulating intestinal barrier,cecal microbiota and metabolism,and oviductal function.Overall,RE could be used as a promising feed additive to improve egg quality of laying hens at late stage of production.
基金The study was supported by Yuying Program Incubation Project of General Hospital of Center Theater(ZZYFH202104)Wuhan Young and Middle-Aged Medical Backbone Talent Project 2020(2020-55)Logistics Research Program Project 2019(CLB19J029).
文摘Objective:In the realm of Class I pathogens,Burkholderia pseudomallei(BP)stands out for its propensity to induce severe pathogenicity.Investigating the intricate interactions between BP and host cells is imperative for comprehending the dynamics of BP infection and discerning biomarkers indicative of the host cell response process.Methods:mRNA extraction from BP-infected mouse macrophages constituted the initial step of our study.Employing gene expression arrays,the extracted RNA underwent conversion into digital signals.The percentile shift method facilitated data processing,with the identification of genes manifesting significant differences accomplished through the application of the t-test.Subsequently,a comprehensive analysis involving Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway was conducted on the differentially expressed genes(DEGs).Leveraging the ESTIMATE algorithm,gene signatures were utilized to compute risk scores for gene expression data.Support vector machine analysis and gene enrichment scores were instrumental in establishing correlations between biomarkers and macrophages,followed by an evaluation of the predictive power of the identified biomarkers.Results:The functional and pathway associations of the DEGs predominantly centered around G protein-coupled receptors.A noteworthy positive correlation emerged between the blue module,consisting of 416 genes,and the StromaScore.FZD4,identified through support vector machine analysis among intersecting genes,indicated a robust interaction with macrophages,suggesting its potential as a robust biomarker.FZD4 exhibited commendable predictive efficacy,with BP infection inducing its expression in both macrophages and mouse lung tissue.Western blotting in macrophages confirmed a significant upregulation of FZD4 expression from 0.5 to 24 h post-infection.In mouse lung tissue,FZD4 manifested higher expression in the cytoplasm of pulmonary epithelial cells in BP-infected lungs than in the control group.Conclusion:Thesefindings underscore the upregulation of FZD4 expression by BP in both macrophages and lung tissue,pointing to its prospective role as a biomarker in the pathogenesis of BP infection.
文摘●AIM:To investigate the long-term changes of corneal densitometry(CD)and its contributing elements after small incision lenticule extraction(SMILE).●METHODS:Totally 31 eyes of 31 patients with mean spherical equivalent of-6.46±1.50 D and mean age 28.23±7.38y were enrolled.Full-scale examinations were conducted on all patients preoperatively and during followup.Visual acuity,manifest refraction,axial length,corneal thickness,corneal higher-order aberrations,and CD were evaluated.●RESULTS:All surgeries were completed successfully without complications or adverse events.Ten-year safety index was 1.17±0.20 and efficacy 1.04±0.28.CD value of 0–6 mm zones in central layer was statistically significantly lower 10y postoperatively,compared with preoperative values(0–2 mmΔ=-1.62,2–6 mmΔ=-1.24,P<0.01).There were no correlations between CD values and factors evaluated.●CONCLUSION:SMILE is a safe and efficient procedure for myopia on a long-term basis.CD values get lower 10y postoperatively,whose mechanism is to be further discussed.
基金suppor ted by the National Key Research and Development Program of China(2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202002)+2 种基金the National Natural Science Foundation of China(82074098,82003814)the CACMS Innovation Fund(CI2021A05101)the Fundamental Research Funds for the Central public welfare research institutes(ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-ND-010,ZZ15-ND-10 and ZZ14-FL-002)。
文摘Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an indispensable role, however, its mechanism of action(MoA) is not fully understood.Methods: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling(ABPP) and mass spectrometry-coupled cellular thermal shift assay(MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays.Results: We developed a novel clickable, photo-affinity chloroquine analog probe(CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photocrosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods.Conclusions: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled(ABPP)and label-free(MS-CETSA) methods.
基金supported by the National Key Research and Development Program of China(Grant Nos.:2020YFA0908000,2022YFC2303600)the Establishment of Sino-Austria“Belt and Road”Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(Grant No.:2020YFE0205100)+13 种基金the National Natural Science Foundation of China(Grant Nos.:82104480,82004248,82141001,82274182,82074098,82173914)the Fundamental Research Funds for the Central public welfare research institutes(Grant Nos.:ZZ14-YQ-055,ZZ14-YQ-059,ZZ14-YQ-060,ZXKT19018,ZXKT19021,ZXKT19022,ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010,ZZ15-ND-10,ZZ16-ND-10-19)the Beijing Municipal Natural Science Foundation(Grant No.:7214287)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-C-202002)the Young Elite Scientists Sponsorship Program by CACM(Grant No.:2021QNRC2B29)the CACMS Innovation Fund(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(Grant No.:JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)Shenzhen Governmental Sustainable Development Fund(Grant No.:KCXFZ20201221173612034)Shenzhen key Laboratory of Kidney Diseases(Grant No.:ZDSYS201504301616234)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(Grant No.:SZGSP001)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(Grant No.:CW202002)the State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process Open Fund(Grant No.:SKL2020Z0302).
文摘Tripterygium glycosides tablet(TGT),the classical commercial drug of Tripterygium wilfordii Hook.F.has been effectively used in the treatment of rheumatoid arthritis,nephrotic syndrome,leprosy,Behcet's syndrome,leprosy reaction and autoimmune hepatitis.However,due to its narrow and limited treatment window,TGT-induced organ toxicity(among which liver injury accounts for about 40%of clinical reports)has gained increasing attention.The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing(scRNA-seq)technology.The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators,including alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase and total bilirubin.Using the mouse model,we identified 15 specific subtypes of cells in the liver tissue,including endothelial cells,hepatocytes,cholangiocytes,and hepatic stellate cells.Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations;led to marked inflammatory response,apoptosis and fatty acid metabolism dysfunction in hepatocytes;activated hepatic stellate cells;brought about the activation,inflammation,and phagocytosis of liver capsular macrophages cells;resulted in immune dysfunction of liver lymphocytes;disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways.Thus,these findings elaborate the mechanism underlying TGT-induced acute liver injury,provide new insights into the safe and rational applications in the clinic,and complement the identification of new biomarkers and therapeutic targets for liver protection.
基金supported by the National Natural Science Foundation of China(Projects 21790331,21603218,21703236 and 21872138)the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB17020300 and XDA21030400)+1 种基金the Youth Innovation Promotion Association,CAS(2018219)DICP ZZBS201811
文摘In response to the awareness of limited fossil resources and environmental concerns,catalytic conversion of renewable lignocellulose biomass to value-added chemicals and fuels is of great significance and attractive for sustainable chemistry.Division of Biomass Conversion and Bio-Energy attached to Dalian National Laboratory for Clean Energy has devoted themselves to valorization of lignocellulose biomass since launched in 2011.Our research interests focus on breeding of biomass resources(inulin and microalgae),exploration of catalytic and biological technologies,and production of energy chemicals and fuels.Although lignocellulose biomass is renewable and abundant,the way of utilization should be reasonable according to its structural characteristics in view of efficiency and economy.In this review,to celebrate the DICP's 70 th anniversary,we will highlight the major fundamental advances in DICP about the conversion of lignocellulose to value-added chemicals and liquid fuels.Particular attention will be paid to the transformation of cellulose and its derivatives to glycols,acids and nitrogen-containing chemicals,hemicellulose-derived platform molecule furfural to jet fuels and lignin to aromatics using catalytic technologies.
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 State Scientific Key Projects for New Drug Research and Development (2009ZX09102-250)High-tech Research Project for Medicine and Pharmacology of Jiangsu Province (BG20070605)
文摘Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship.Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group):four groups were treated with rhG-CSFa at 500,100,10,1 μg/kg,respectively,and one group was treated with vehicle only to serve as the control.The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks.During the course of the chronic toxicity study,the physical status,body weight,and food consumption were monitored.Half of the rats in each group (n=10) were sacrificed after the last rhG-CSFa administration,and the other half were sacrificed at five weeks after the last rhG-CSFa administration.Urinalyses,blood biochemistry,hematological analysis,histopathological examination,and immunological tests were performed for each of the rats.Results The hematological analyses revealed that the mean white blood cells count,neutrophils count,and neutrophils percentage were increased in male rats at the dose of 10 μg/kg or higher,and these were related with the biological activity of rhG-CSFa.Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 μg/kg,a dosage of 200 folds higher than the normal clinical dosage),but these abnormalities were recovered within 5-week recovery period.No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.
基金Supported by National Natural Science Foundation of China(No.81770955)National Natural Science Foundation of China for Young Scholars(No.82000929)+6 种基金Project of Shanghai Science and Technology(No.20410710100)Clinical Research Plan of SHDC(No.SHDC2020CR1043B)Project of Shanghai Xuhui District Science and Technology(No.2020-015)Project of Shanghai Xuhui District Science and Technology(No.XHLHGG202104)Shanghai Engineering Research Center of Laser and Autostereoscopic 3D for Vision Care(No.20DZ2255000)Shanghai Sailing Program(No.20YF1405000)。
文摘AIM: To investigate the one-year refractive outcomes and optical quality following PRESBYOND laser-blended vision(LBV).METHODS: This retrospective study included 20 patients who underwent PRESBYOND treatment between Jan 2019 and Aug 2020. The patients were asked to attend a followup outpatient visit one year after surgery. Distance and near visual acuity as well as subjective refraction were examined. Optical quality was assessed using wavefront-supported custom ablation. A questionnaire evaluating optical quality and satisfaction was completed at the last visit.RESULTS: The average patient age was 48.1±7.4 y(range, 41 to 58 y). The mean preoperative spherical equivalent was-7.59±2.39D. At the one-year follow-up, two eyes(both dominant eyes) lost one line of corrected distance visual acuity(CDVA), while the remaining eyes(38/40) maintained or gained lines of CDVA. The average binocular uncorrected distance visual acuity improved from 0.15±0.03 to 0.90±0.26(decimal vision;P<0.001). The average binocular uncorrected near visual acuity increased from 0.34±0.28 to 0.97±0.07(P<0.001). The spherical aberration was 0.04±0.06 μm in the nondominant eye and 0.09±0.09 μm in the dominant eye(P=0.02). All patients were satisfied with or accepted the outcomes of the surgery. The primary complaints were related to disturbances in night vision and relatively inferior near vision.CONCLUSION: Over the one-year observation period, PRESBYOND is a safe and effective option for presbyopia correction. The optical quality and near vision deserve further investigation.
基金This work is supported by the Science and Technology Project of State Grid Jiangsu Electric Power Co.,Ltd.under Grant No.J2020068.
文摘The rapidly increasing popularity of mobile devices has changed the methods with which people access various network services and increased net-work traffic markedly.Over the past few decades,network traffic identification has been a research hotspot in the field of network management and security mon-itoring.However,as more network services use encryption technology,network traffic identification faces many challenges.Although classic machine learning methods can solve many problems that cannot be solved by port-and payload-based methods,manually extract features that are frequently updated is time-consuming and labor-intensive.Deep learning has good automatic feature learning capabilities and is an ideal method for network traffic identification,particularly encrypted traffic identification;Existing recognition methods based on deep learning primarily use supervised learning methods and rely on many labeled samples.However,in real scenarios,labeled samples are often difficult to obtain.This paper adjusts the structure of the auxiliary classification generation adversarial network(ACGAN)so that it can use unlabeled samples for training,and use the wasserstein distance instead of the original cross entropy as the loss function to achieve semisupervised learning.Experimental results show that the identification accuracy of ISCX and USTC data sets using the proposed method yields markedly better performance when the number of labeled samples is small compared to that of convolutional neural network(CNN)based classifier.
基金support from the China National Natural Science Foundation Funding Project(NO.81804150)Hunan University of Chinese Medicine,National Key Discipline of TCM Diagnostics Foundation Funding Project(No.2015ZYZD02)+5 种基金The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese MedicineHunan Provincial Department of Education Innovation Platform Open Fund Project(16K065)Chinese Medicine Key Laboratory of Prevention and Treatment of Disease in Hunan Province(2017TP1018)Changsha Science and Technology Plan Project(KC1704005)Hunan Engineering Technology Research Center for the Prevention and Treatment of Otorhinolaryngologic Diseases and Protection of Visual Function with Chinese MedicineHunan Provincial Research Innovation Project for Graduate students(CX2017B426)
文摘This study was conducted to elucidate the potential key candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension.Methods Expression profiles GSE2378 and GSE758 including 27 reactive optic nerve head astrocytes(ONHAs)by hypertensions and 26 normal controls,were integrated and deeply analyzed.Differentially expressed genes(DEGs)were sorted and candidate genes and pathways enrichment were analyzed.DEGs-associated protein-protein interaction network(PPI)was performed.Results A total of 119 consistently expressed genes were identified from 281 commonly changed DEGs,including 68 up-regulated genes and 51 down-regulated genes.PPI network complex filtered 75 DEGs(43 up-regulated and 32 down-regulated genes)of the 119 consistently altered DEGs and developed 117 edges,and 10 hub genes were identified.The most significant 3 modules were filtered from PPI,pathway enrichment analysis showed that module 1 was associated with extracellular exosome.Module 2 was mainly associated with antibody-dependent cellular cytotoxicity(ADCC)and module 3 was mainly associated with Hippo signaling pathway.Conclusion Taken above,using integrated bioinformatical analysis,we have identified DEGs candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension,which could improve our understanding of the cause and underlying molecular events,and these candidate genes and pathways could be therapeutic targets for glaucoma.
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.
