OBJECTIVE To investigate the characteristics and regulations of medication in different stages of disease by constructing a dynamic disease network and a cellular feature network spanning from myocardial infarction to...OBJECTIVE To investigate the characteristics and regulations of medication in different stages of disease by constructing a dynamic disease network and a cellular feature network spanning from myocardial infarction to heart failure.METHODS Based on transcrip⁃tome and single-cell sequencing data from a mouse model of left anterior descending coro⁃nary artery ligation,a dynamic early-middle-late network and cellular feature network were con⁃structed by integrating differential gene expres⁃sion trends and biological functions.The robust⁃ness of the perturbation effect of traditional Chi⁃nese medicine(TCM)on the disease network was calculated based on multi-target TCM,and we acquired the foundational data by analyzing the results of effectiveness.The predictive plat⁃form was scrutinized and assessed with regards to the functional attributes of FDA approveddrugs and compound prescriptions,in order to determine the primary stages of intervention and the drug patterns actions in the progression of heart failure.RESULTS In this study,we devel⁃oped a prediction and analysis platform for assessing the efficacy of drugs using a networkbased approach.The accuracy of the system was validated by FDA approved-drugs.It was found that blood-activating drugs,heat-clearing drugs,and phlegm-expelling drugs exhibited favorable intervention effects during the early to middle stages of the disease by investigating the effects of single herbs and TCM prescriptions on disease progression.Similarly,phlegm-expelling drugs,spirit-nourishing drugs,and diuretic showed better intervention effects during the mid⁃dle to late stages.These findings were consis⁃tent with the clinical use of drugs.Analysis of the clustering heatmap results of TCM prescriptions revealed that the formulas aimed at qi stagnation and blood stasis had a strong effect in early stage,while the formulas for qi and yin deficiency and cardiorenal yang deficiency had a strong effect in the middle to late stages.Furthermore,analysis of the single-cell feature network demon⁃strated that TCM had advantages in modulating the changes in fibroblasts,myofibroblasts,endo⁃thelial cells,and granulocytes during the patho⁃logical process.Additionally,most prescriptions exhibited strong perturbation effects on the fea⁃ture network of NK-T cells,granulocytes,macro⁃phages,and myofibroblasts.CONCLUSION This platform quantitatively evaluates the primary action stages and characteristics of TCM and for⁃mulas involved in the dynamic process of myo⁃cardial infarction to heart failure based on the effective prediction of the efficacy of TCM and FDA approved-drugs.It provides reference for the precise clinical application of TCM and formu⁃las with multiple targets and multiple pathways.展开更多
OBJECTIVE The purpose of this study is to clarify the association between Cu levels and heart failure(HF)using a meta-analysis approach.METHODS We searched articles in the Pub Med,EMbase,CNKI,Wanfang,VIP and CBM Datab...OBJECTIVE The purpose of this study is to clarify the association between Cu levels and heart failure(HF)using a meta-analysis approach.METHODS We searched articles in the Pub Med,EMbase,CNKI,Wanfang,VIP and CBM Database published as of August 2016.The case control study on the relationship between serum copper levels and HF were collected and read and extracted by two independent researchers.A Meta analysis was conducted using Stata 12.0 software.RESULTS A total of twenty-one eligible articles,including 893 HF and 654 control subjects,were enrolled.The Meta analysis showed that serum copper levels in HF were higher than control group[SMD=0.881,95%CI:(0.487,1.264),Z=4.5,P<0.001].The sensitivity analysis indicated that the results were reliable.Begg′s tests did not find the existence of publication bias.CONCLUSION This metaanalysis indicates that there is a significant association between high Cu serum level and HF.展开更多
OBJECTIVE To determine the functional role of hydrogen sulfide(H_2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca^(2+)/calmodulin-dependent protein kinaseⅡ(Ca MKⅡ) us...OBJECTIVE To determine the functional role of hydrogen sulfide(H_2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca^(2+)/calmodulin-dependent protein kinaseⅡ(Ca MKⅡ) using wild type and CSE knockout mouse models.METHODS Continuous subcutaneous injection isoprenaline(7.5 mg·kg^(-1) per day),once a day for 4 weeks to induce heart failure in male C57BL/6(6-8 weeks old) mice and CSE-/-mice.150 μmol·L^(-1) H_2O_2 was used to induce oxidative stress in H9c2 cells.Echocardiograph was used to detect cardiac parameters.H&E stain and Masson stain was to observation histopathological changes.Western blot was used to detect protein expression and activity.The si RNA was used to silence protein expression.HPLC was used to detect H_2S level.Biotin assay was used to detect the level of S-sulfhydration protein.RESULTS Treatment with S-propyl-L-cysteine(SPRC) or sodium hydrosulfide(Na HS),modulators of blood H_2S levels,attenuated the development of heart failure in animals,reduced lipid peroxidation,and preserved mitochondrial function.The inhibition Ca MKⅡ phosphorylation by SPRC and Na HS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds.Interestingly,Ca MKⅡ activity was found to be elevated in CSE-/-mice as compared to wild type animals and the phosphorylation status of Ca MK Ⅱ appeared to relate to the severity of heart failure.Importantly,in wild type mice SPRC was found to promote S-sulfhydration of Ca MKⅡ leading to reduced activity of this protein however,in CSE-/-mice S-sulfhydration was abolished following SPRC treatment.CONCLUSION A novel mechanism depicting a role of S-sulfhydration in the regulation of Ca MKⅡ is presented.SPRC mediated S-sulfhydration of Ca MKⅡ was found to inhibit Ca MKⅡ activity and to preserve cardiovascular homeostasis.展开更多
基金National Science and Technology Major Project (2019YFC1708904)the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ13-YQ-048)the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZXKT21008)
文摘OBJECTIVE To investigate the characteristics and regulations of medication in different stages of disease by constructing a dynamic disease network and a cellular feature network spanning from myocardial infarction to heart failure.METHODS Based on transcrip⁃tome and single-cell sequencing data from a mouse model of left anterior descending coro⁃nary artery ligation,a dynamic early-middle-late network and cellular feature network were con⁃structed by integrating differential gene expres⁃sion trends and biological functions.The robust⁃ness of the perturbation effect of traditional Chi⁃nese medicine(TCM)on the disease network was calculated based on multi-target TCM,and we acquired the foundational data by analyzing the results of effectiveness.The predictive plat⁃form was scrutinized and assessed with regards to the functional attributes of FDA approveddrugs and compound prescriptions,in order to determine the primary stages of intervention and the drug patterns actions in the progression of heart failure.RESULTS In this study,we devel⁃oped a prediction and analysis platform for assessing the efficacy of drugs using a networkbased approach.The accuracy of the system was validated by FDA approved-drugs.It was found that blood-activating drugs,heat-clearing drugs,and phlegm-expelling drugs exhibited favorable intervention effects during the early to middle stages of the disease by investigating the effects of single herbs and TCM prescriptions on disease progression.Similarly,phlegm-expelling drugs,spirit-nourishing drugs,and diuretic showed better intervention effects during the mid⁃dle to late stages.These findings were consis⁃tent with the clinical use of drugs.Analysis of the clustering heatmap results of TCM prescriptions revealed that the formulas aimed at qi stagnation and blood stasis had a strong effect in early stage,while the formulas for qi and yin deficiency and cardiorenal yang deficiency had a strong effect in the middle to late stages.Furthermore,analysis of the single-cell feature network demon⁃strated that TCM had advantages in modulating the changes in fibroblasts,myofibroblasts,endo⁃thelial cells,and granulocytes during the patho⁃logical process.Additionally,most prescriptions exhibited strong perturbation effects on the fea⁃ture network of NK-T cells,granulocytes,macro⁃phages,and myofibroblasts.CONCLUSION This platform quantitatively evaluates the primary action stages and characteristics of TCM and for⁃mulas involved in the dynamic process of myo⁃cardial infarction to heart failure based on the effective prediction of the efficacy of TCM and FDA approved-drugs.It provides reference for the precise clinical application of TCM and formu⁃las with multiple targets and multiple pathways.
文摘OBJECTIVE The purpose of this study is to clarify the association between Cu levels and heart failure(HF)using a meta-analysis approach.METHODS We searched articles in the Pub Med,EMbase,CNKI,Wanfang,VIP and CBM Database published as of August 2016.The case control study on the relationship between serum copper levels and HF were collected and read and extracted by two independent researchers.A Meta analysis was conducted using Stata 12.0 software.RESULTS A total of twenty-one eligible articles,including 893 HF and 654 control subjects,were enrolled.The Meta analysis showed that serum copper levels in HF were higher than control group[SMD=0.881,95%CI:(0.487,1.264),Z=4.5,P<0.001].The sensitivity analysis indicated that the results were reliable.Begg′s tests did not find the existence of publication bias.CONCLUSION This metaanalysis indicates that there is a significant association between high Cu serum level and HF.
文摘OBJECTIVE To determine the functional role of hydrogen sulfide(H_2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca^(2+)/calmodulin-dependent protein kinaseⅡ(Ca MKⅡ) using wild type and CSE knockout mouse models.METHODS Continuous subcutaneous injection isoprenaline(7.5 mg·kg^(-1) per day),once a day for 4 weeks to induce heart failure in male C57BL/6(6-8 weeks old) mice and CSE-/-mice.150 μmol·L^(-1) H_2O_2 was used to induce oxidative stress in H9c2 cells.Echocardiograph was used to detect cardiac parameters.H&E stain and Masson stain was to observation histopathological changes.Western blot was used to detect protein expression and activity.The si RNA was used to silence protein expression.HPLC was used to detect H_2S level.Biotin assay was used to detect the level of S-sulfhydration protein.RESULTS Treatment with S-propyl-L-cysteine(SPRC) or sodium hydrosulfide(Na HS),modulators of blood H_2S levels,attenuated the development of heart failure in animals,reduced lipid peroxidation,and preserved mitochondrial function.The inhibition Ca MKⅡ phosphorylation by SPRC and Na HS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds.Interestingly,Ca MKⅡ activity was found to be elevated in CSE-/-mice as compared to wild type animals and the phosphorylation status of Ca MK Ⅱ appeared to relate to the severity of heart failure.Importantly,in wild type mice SPRC was found to promote S-sulfhydration of Ca MKⅡ leading to reduced activity of this protein however,in CSE-/-mice S-sulfhydration was abolished following SPRC treatment.CONCLUSION A novel mechanism depicting a role of S-sulfhydration in the regulation of Ca MKⅡ is presented.SPRC mediated S-sulfhydration of Ca MKⅡ was found to inhibit Ca MKⅡ activity and to preserve cardiovascular homeostasis.
