Reduced levels of retinal dopamine,a key regulator of eye development,are associated with experimental myopia in various species,but are not seen in the myopic eyes of C57BL/6 mice,which are deficient in melatonin,a n...Reduced levels of retinal dopamine,a key regulator of eye development,are associated with experimental myopia in various species,but are not seen in the myopic eyes of C57BL/6 mice,which are deficient in melatonin,a neurohormone having extensive interactions with dopamine.Here,we examined the relationship between form-deprivation myopia(FDM)and retinal dopamine levels in melatonin-proficient CBA/CaJ mice.We found that these mice exhibited a myopic refractive shift in form-deprived eyes,which was accompanied by altered retinal dopamine levels.When melatonin receptors were pharmacologically blocked,FDM could still be induced,but its magnitude was reduced,and retinal dopamine levels were no longer altered in FDM animals,indicating that melatonin-related changes in retinal dopamine levels contribute to FDM.Thus,FDM is mediated by both dopamine level-independent and melatonin-related dopamine level-dependent mechanisms in CBA/CaJ mice.The previously reported unaltered retinal dopamine levels in myopic C57BL/6 mice may be attributed to melatonin deficiency.展开更多
Objective To investigate the application of BPDE-albumin adducts as monitoring biomarkers for coke oven workers exposed to polycyclic aromatic hydrocarbons （PAHs） and to explore possible relationship between BPDE-al...Objective To investigate the application of BPDE-albumin adducts as monitoring biomarkers for coke oven workers exposed to polycyclic aromatic hydrocarbons （PAHs） and to explore possible relationship between BPDE-albumin adducts and urinary 1-hydroxypyrene （1-OHP） levels in them. Methods Thirty-seven coke oven workers from a coke plant and 47 controls without the occupational exposure to PAHs were recruited in this study. The levels of plasma BPDE-albumin adducts and urinary 1-OHP were analyzed using high performance liquid chromatography. Results The median levels of BPDE-albumin adducts （42.10 fmol/mg albumin） and urinary 1-OHP （5.46 μmol/mol creatinine） were significantly higher in coke oven workers than in controls （14.16 fmol/mg albumin, 2.96μmol/mol creatinine, respectively; P〈0.01）. Multiple logistic regression analysis showed that coke oven workers were at higher risk of having BPDE-albumin adduct levels above 25.30 μmol/mg albumin （OR=1.79, P〈0.01） and urinary 1-OHP levels above 4.13 μmol/mol creatinine （OR=2.45, P〈0.05）. There was a positive correlation between the levels of BPDE-albumin adducts and urinary 1-OHP in all subjects （rs=0.349, P〈0.01）. Conclusion BPDE-albumin adduct is a useful biomarker for monitoring long-term exposure to PAHs, and plasma BPDE-albumin adducts level is significantly correlated to urinary 1-OHP levels in coke oven workers.展开更多
Changes in water quality from source water to finished water and tap water at two conventional drinking water treatment plants(DWTPs)were monitored.Beside the routine water quality testing,Caenorhabditis elegans-based...Changes in water quality from source water to finished water and tap water at two conventional drinking water treatment plants(DWTPs)were monitored.Beside the routine water quality testing,Caenorhabditis elegans-based toxicity assays and the fluorescence excitation–emission matrices technique were also applied.Both DWTPs supplied drinking water that met government standards.Under current test conditions,both the investigated finished water and tap water samples exhibited stronger lethal,genotoxic and reprotoxic potential than the relative source water sample,and the tap water sample was more lethal but tended to be less genotoxic than the corresponding finished water sample.Meanwhile,the nearly complete removal of tryptophan-like substances and newly generated tyrosine-like substances were observed after the treatment of drinking water,and humic-like substances were identified in the tap water.Based on these findings,toxic pollutants,including genotoxic/reproductive toxicants,are produced in the drinking water treatment and/or distribution processes.Moreover,further studies are needed to clarify the potentially important roles of tyrosine-like and humic-like substances in mediating drinking water toxicity and to identify the potential sources of these contaminants.Additionally,tryptophan-like fluorescence may be adopted as a useful parameter to monitor the treatment performance of DWTPs.Our observations provided insights into the importance of utilizing biotoxicity assays and fluorescence spectroscopy as tools to complement the routine evaluation of drinking water.展开更多
Influenza caused by influenza virus,seriously threaten human life and health.Drug treatment is one of the effective measurement.However,there are only two classes of drugs,one class is M2 blockers and another is neura...Influenza caused by influenza virus,seriously threaten human life and health.Drug treatment is one of the effective measurement.However,there are only two classes of drugs,one class is M2 blockers and another is neuraminidase(NA) inhibitors.The recent antiviral surveillance studies reported a global significant increase in M2 blocker resistance among influenza viruses,and the resistant virus strains against NA inhibitor are also reported in clinical treatment.Therefore thediscovery of new medicines with low resistance has become very urgent.As all known,traditional medicines with multi-target features and network mechanism often possess low resistance.Compound Yizhihao,which consists of radix isatidis,folium isatidis,Artemisia rupestris,is one of the famous traditional medicine for influenza treatment in China,however its mechanism of action against influenza is unclear.In this study,the multiple targets related with influenza disease and the known chemical constituents from Compound Yizhihao were collected,and multi-target QSAR(mt-QSAR) classification models were developed by Na?e Bayesian algorithm and verified by various datasets.Then the classification models were applied to predict the effective constituents and their drug targets.Finally,the constituent-target-pathway network was constructed,which revealed the effective constituents and their network mechanism in Compound Yizhihao.This study will lay important basis for the clinical uses for influenza treatment and for the further research and development of the effective constituents.展开更多
OBJECTIVE To clarify out the network pharmacology mechanism of Polygala tenuifolia against Alzheimer disease(AD).METHODS Firstly,we collected the chemical constituents from Polygala tenuifolia and key targets toward A...OBJECTIVE To clarify out the network pharmacology mechanism of Polygala tenuifolia against Alzheimer disease(AD).METHODS Firstly,we collected the chemical constituents from Polygala tenuifolia and key targets toward AD.Machine learning algorithms were applied to construct classifi.ers for predicting the effective constituents.Secondly,docking models were utilized for further evalua.tion.Finally,we built constituent-target,target-target network and target-biology pathway network.RE.SULTS 104 chemical constituents Polygala tenuifolia from were collected.Through prediction of bloodbrain penetration and validation,36 chemical constituents were selected among 100 chemical constitu.ents,their action targets mainly focused on AChE,COX-2,TNF-α,insulin-degrading enzyme and APP.Their main structure types include Polygala saponins,Polygala glycosides,Polygala shrubby ketones,polygala xanthones and sterols,which acted on AchE,APP,M-TAU,GSK3β and 5 HT1A with high fre.quency.Gene-Ontology and KEGG enrichment analysis showed that the main pathways of these con.stituents involve in neurotransmitter release,synaptic conduction and synaptic plasticity,apoptosis reg.ulation,phosphorylation pathway,Ca^(2+) signaling pathway,and so on.CONCLUSION This study uncov.ered a network mechanism of Polygala tenuifolia against Alzheimer disease,which may provide impor.tant information for the further study and new drug development.展开更多
OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targ...OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7n ACh R,ACh E and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSION DL0410 is a promising candidate for further development for AD treatment.展开更多
In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ i...In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ in structure by a single methyl group,the inhibitory effect of G1(IC50¼264 nmol/L)on AChE was 80 times stronger than that of G2(IC50¼21,210 nmol/L).Enzyme-kinetic analysis,molecular docking and molecular dynamics(MD)simulations were conducted to better understand the molecular basis for this difference.The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE.The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area(MM/GBSA)method were consistent with the experimental data.The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions(ΔEele+ΔGGB)was responsible for the binding affinities of these two inhibitors.Additionally,analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124,Glu292,Val294 and Phe338 of AChE.In conclusion,the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.展开更多
Objective:To investigate the network pharmacology of anti-tumor Chinese medicinal formulae and explain the synergistic mechanism of various active ingredients of Chinese medicinal formulae.Methods:We collected the ant...Objective:To investigate the network pharmacology of anti-tumor Chinese medicinal formulae and explain the synergistic mechanism of various active ingredients of Chinese medicinal formulae.Methods:We collected the anti?tumor Chinese medicinal formulae and chose several single herbs with the top frequency for further study.The chemical constituents of these herbs were downloaded from databases CNPC and Traditional Chinese Medicine Systems Pharmacology and were analyzed to set up the anti-tumor material basis.The genes regulated by these constituents were retrieved in Traditional Chinese Medicine integrated database and Comparative Toxicogenomics database.Results:We collected 65 anti-tumor Chinese medicinal formulae,and 4 single herbs were selected,including Licorice,Radix astragali,Panax ginseng,and Radix scutellariae,which consist of 172,70,293,and 92 known constituents,respectively.The constituent–gene network,protein–protein interaction network,gene–pathway enrichment network,and gene–disease network were constructed.Moreover,molecular docking was employed to clarify the interactions between active constituents and key drug targets(PTG2,epidermal growth factor receptor,peroxisome proliferator?activated receptor gamma,estrogen receptor 1,mammalian target of rapamycin,AKT1,mitogen-activated protein kinase 1 [MAPK1],peroxisome proliferator-activated receptor alpha,and MAPK8).Most of the constituents could act on multiple targets,whose structures mainly belong to alkaloids,flavonoids,and their glycosides,organic acids,or dianthrone,and their representative chemical constituents include narcissus glycosides,rutin,dauricine,scutellarin,baicalin,isoschaftoside,and leucovorin.Conclusion:The network mechanism of the effective constituents from traditional Chinese medicines(TCMs) for anti-tumor therapy was partially uncovered by using statistical methods,network pharmacology methods,and molecular docking methods.This study will provide important information for new drug design with multiple targets for anti-tumor therapy.展开更多
基金supported by the National Natural Science Foundation of China(81790640,82070993,31571072,32070989,31872766,31571075,81430007,and 81470661)the Ministry of Science and Technology of China(2011CB504602 and 2015AA020512)+2 种基金a Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab,Shanghai Center for Brain Science and Brain-Inspired Technology,Sanming Project of Medicine in Shenzhen(SZSM202011015)Anhui Medical University Research Foundation(2020xkj003),China.
文摘Reduced levels of retinal dopamine,a key regulator of eye development,are associated with experimental myopia in various species,but are not seen in the myopic eyes of C57BL/6 mice,which are deficient in melatonin,a neurohormone having extensive interactions with dopamine.Here,we examined the relationship between form-deprivation myopia(FDM)and retinal dopamine levels in melatonin-proficient CBA/CaJ mice.We found that these mice exhibited a myopic refractive shift in form-deprived eyes,which was accompanied by altered retinal dopamine levels.When melatonin receptors were pharmacologically blocked,FDM could still be induced,but its magnitude was reduced,and retinal dopamine levels were no longer altered in FDM animals,indicating that melatonin-related changes in retinal dopamine levels contribute to FDM.Thus,FDM is mediated by both dopamine level-independent and melatonin-related dopamine level-dependent mechanisms in CBA/CaJ mice.The previously reported unaltered retinal dopamine levels in myopic C57BL/6 mice may be attributed to melatonin deficiency.
基金This study was supported by National Key Basic Research and Development Program of China (No.2002CB512905)National Natural Science Foundation of China (No.30371204).
文摘Objective To investigate the application of BPDE-albumin adducts as monitoring biomarkers for coke oven workers exposed to polycyclic aromatic hydrocarbons （PAHs） and to explore possible relationship between BPDE-albumin adducts and urinary 1-hydroxypyrene （1-OHP） levels in them. Methods Thirty-seven coke oven workers from a coke plant and 47 controls without the occupational exposure to PAHs were recruited in this study. The levels of plasma BPDE-albumin adducts and urinary 1-OHP were analyzed using high performance liquid chromatography. Results The median levels of BPDE-albumin adducts （42.10 fmol/mg albumin） and urinary 1-OHP （5.46 μmol/mol creatinine） were significantly higher in coke oven workers than in controls （14.16 fmol/mg albumin, 2.96μmol/mol creatinine, respectively; P〈0.01）. Multiple logistic regression analysis showed that coke oven workers were at higher risk of having BPDE-albumin adduct levels above 25.30 μmol/mg albumin （OR=1.79, P〈0.01） and urinary 1-OHP levels above 4.13 μmol/mol creatinine （OR=2.45, P〈0.05）. There was a positive correlation between the levels of BPDE-albumin adducts and urinary 1-OHP in all subjects （rs=0.349, P〈0.01）. Conclusion BPDE-albumin adduct is a useful biomarker for monitoring long-term exposure to PAHs, and plasma BPDE-albumin adducts level is significantly correlated to urinary 1-OHP levels in coke oven workers.
基金supported by the National High Technology Research and Development Program(863 Program) of China(No.2013AA065204)the Fundamental Research Funds for the Central Universities in China(No.2015TS103)
文摘Changes in water quality from source water to finished water and tap water at two conventional drinking water treatment plants(DWTPs)were monitored.Beside the routine water quality testing,Caenorhabditis elegans-based toxicity assays and the fluorescence excitation–emission matrices technique were also applied.Both DWTPs supplied drinking water that met government standards.Under current test conditions,both the investigated finished water and tap water samples exhibited stronger lethal,genotoxic and reprotoxic potential than the relative source water sample,and the tap water sample was more lethal but tended to be less genotoxic than the corresponding finished water sample.Meanwhile,the nearly complete removal of tryptophan-like substances and newly generated tyrosine-like substances were observed after the treatment of drinking water,and humic-like substances were identified in the tap water.Based on these findings,toxic pollutants,including genotoxic/reproductive toxicants,are produced in the drinking water treatment and/or distribution processes.Moreover,further studies are needed to clarify the potentially important roles of tyrosine-like and humic-like substances in mediating drinking water toxicity and to identify the potential sources of these contaminants.Additionally,tryptophan-like fluorescence may be adopted as a useful parameter to monitor the treatment performance of DWTPs.Our observations provided insights into the importance of utilizing biotoxicity assays and fluorescence spectroscopy as tools to complement the routine evaluation of drinking water.
基金supported by National Natural Science Foundation of China(81673480) Project of Urumqi science and Technology Bureau of the Xinjiang Uygur Autonomous Region(Y151310010)
文摘Influenza caused by influenza virus,seriously threaten human life and health.Drug treatment is one of the effective measurement.However,there are only two classes of drugs,one class is M2 blockers and another is neuraminidase(NA) inhibitors.The recent antiviral surveillance studies reported a global significant increase in M2 blocker resistance among influenza viruses,and the resistant virus strains against NA inhibitor are also reported in clinical treatment.Therefore thediscovery of new medicines with low resistance has become very urgent.As all known,traditional medicines with multi-target features and network mechanism often possess low resistance.Compound Yizhihao,which consists of radix isatidis,folium isatidis,Artemisia rupestris,is one of the famous traditional medicine for influenza treatment in China,however its mechanism of action against influenza is unclear.In this study,the multiple targets related with influenza disease and the known chemical constituents from Compound Yizhihao were collected,and multi-target QSAR(mt-QSAR) classification models were developed by Na?e Bayesian algorithm and verified by various datasets.Then the classification models were applied to predict the effective constituents and their drug targets.Finally,the constituent-target-pathway network was constructed,which revealed the effective constituents and their network mechanism in Compound Yizhihao.This study will lay important basis for the clinical uses for influenza treatment and for the further research and development of the effective constituents.
基金supported by National Natural Science Foundation of China(81673480) National Population and Health Scientific Data Sharing Service Platform(2016NCMIZX05+1 种基金NCMI-AGD05-201709) CAMS Initiative for Innovative Medicine(CAMS-I2M,2016-I2M-3-007)
文摘OBJECTIVE To clarify out the network pharmacology mechanism of Polygala tenuifolia against Alzheimer disease(AD).METHODS Firstly,we collected the chemical constituents from Polygala tenuifolia and key targets toward AD.Machine learning algorithms were applied to construct classifi.ers for predicting the effective constituents.Secondly,docking models were utilized for further evalua.tion.Finally,we built constituent-target,target-target network and target-biology pathway network.RE.SULTS 104 chemical constituents Polygala tenuifolia from were collected.Through prediction of bloodbrain penetration and validation,36 chemical constituents were selected among 100 chemical constitu.ents,their action targets mainly focused on AChE,COX-2,TNF-α,insulin-degrading enzyme and APP.Their main structure types include Polygala saponins,Polygala glycosides,Polygala shrubby ketones,polygala xanthones and sterols,which acted on AchE,APP,M-TAU,GSK3β and 5 HT1A with high fre.quency.Gene-Ontology and KEGG enrichment analysis showed that the main pathways of these con.stituents involve in neurotransmitter release,synaptic conduction and synaptic plasticity,apoptosis reg.ulation,phosphorylation pathway,Ca^(2+) signaling pathway,and so on.CONCLUSION This study uncov.ered a network mechanism of Polygala tenuifolia against Alzheimer disease,which may provide impor.tant information for the further study and new drug development.
基金supported by National Great Science and Technology Projects(2014ZX09507003-002,2013ZX09402203 and 2013ZX09508104001002)CAMS Initiative for Innovative Medicine(CAMS-I2M)(2016-I2M-3-007)National Natural Science Foundation of China(81673480)
文摘OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7n ACh R,ACh E and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSION DL0410 is a promising candidate for further development for AD treatment.
基金This work was funded in part of the Research Special Fund for Public Welfare Industry of Health(No.200802041)the National Great Science and Technology Projects(2012ZX09301002,2014ZX09507003-002)+1 种基金the International Collaboration Project(2011DFR31240)Institue of Chinese Materia Medica,China Academy of Chinese Medical Sciences&Peking Union Medical College graduate student innovation fund(2013-1007-18).
文摘In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ in structure by a single methyl group,the inhibitory effect of G1(IC50¼264 nmol/L)on AChE was 80 times stronger than that of G2(IC50¼21,210 nmol/L).Enzyme-kinetic analysis,molecular docking and molecular dynamics(MD)simulations were conducted to better understand the molecular basis for this difference.The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE.The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area(MM/GBSA)method were consistent with the experimental data.The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions(ΔEele+ΔGGB)was responsible for the binding affinities of these two inhibitors.Additionally,analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124,Glu292,Val294 and Phe338 of AChE.In conclusion,the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.
基金supported by the National Natural Science Foundation of China(81673480)Beijing Natural Science Foundation(7152103)+1 种基金National Population and Health Scientific Data Sharing Service Platform(2016NCMIZX05,NCMI-AGD05-201709)CAMS Initiative for Innovative Medicine(CAMS-I2M)(2016-I2M-3-007)
文摘Objective:To investigate the network pharmacology of anti-tumor Chinese medicinal formulae and explain the synergistic mechanism of various active ingredients of Chinese medicinal formulae.Methods:We collected the anti?tumor Chinese medicinal formulae and chose several single herbs with the top frequency for further study.The chemical constituents of these herbs were downloaded from databases CNPC and Traditional Chinese Medicine Systems Pharmacology and were analyzed to set up the anti-tumor material basis.The genes regulated by these constituents were retrieved in Traditional Chinese Medicine integrated database and Comparative Toxicogenomics database.Results:We collected 65 anti-tumor Chinese medicinal formulae,and 4 single herbs were selected,including Licorice,Radix astragali,Panax ginseng,and Radix scutellariae,which consist of 172,70,293,and 92 known constituents,respectively.The constituent–gene network,protein–protein interaction network,gene–pathway enrichment network,and gene–disease network were constructed.Moreover,molecular docking was employed to clarify the interactions between active constituents and key drug targets(PTG2,epidermal growth factor receptor,peroxisome proliferator?activated receptor gamma,estrogen receptor 1,mammalian target of rapamycin,AKT1,mitogen-activated protein kinase 1 [MAPK1],peroxisome proliferator-activated receptor alpha,and MAPK8).Most of the constituents could act on multiple targets,whose structures mainly belong to alkaloids,flavonoids,and their glycosides,organic acids,or dianthrone,and their representative chemical constituents include narcissus glycosides,rutin,dauricine,scutellarin,baicalin,isoschaftoside,and leucovorin.Conclusion:The network mechanism of the effective constituents from traditional Chinese medicines(TCMs) for anti-tumor therapy was partially uncovered by using statistical methods,network pharmacology methods,and molecular docking methods.This study will provide important information for new drug design with multiple targets for anti-tumor therapy.
