Objective: To investigate the differential expression of miRNA and related biological functions and signaling pathways after the intervention of the THP-1-derived foam cell model with the drug-containing serum of Yima...Objective: To investigate the differential expression of miRNA and related biological functions and signaling pathways after the intervention of the THP-1-derived foam cell model with the drug-containing serum of Yimaijiangzhi Decoction. Methods: The experiment was divided into macrophage group, foam cell model group and Yimaijiangzhi drug-containing serum group. THP-1 cells were induced into macrophages by Fopol ester, and induced differentiated macrophages were given ox-LDL to establish foam cell model, and Yimaijiangzhi decoction rat serum was used to intervene the foam cells. Total RNA was extracted from cells in each group for miRNA sequencing, differential expression of miRNA was screened, and relevant target genes were predicted for GO analysis and KEGG analysis, protein interaction network and miRNA-target gene interaction network were established, and RT-qPCR was used to verify the possible signaling pathways for improving atherosclerosis. Result: The difference miRNA between blank group and model group was hsa-miR-302c-3p, hsa-miR-302d-3p, hsa- mir-30d-3p, hsa-mir-3189-3p, hsa-mir-374b-5p, hsa-mir-423-5p, hsa-mir-423-5p, and hsa- mir-4781-3p, hsa-mir-663a;The miRNAs of model group and Yimaijiangzhi drug-containing serum group were hsa-mir-3150a-3p, hsa-mir-7704, hsa-mir-887-3p, hsa-mir-150-5p, hsa- mir-423-5p, hsa-mir-374c-3p, hsa-mir-374c-3p, hsa-mir-374b-5p;The difference of miRNAs prediction target genes between model group and Yimaijiangzhi drug-containing serum group showed that the miRNA prediction target genes were mainly enriched in MAPK signaling pathway, ErbB signaling pathway, Hippo signaling pathway, Wnt signaling pathway and other signaling pathways. SCN1A, PRKACA, MECP2, EIF4E, SRSF1, MBNL1, PRKCA, PPARGC1A may be the potential key targets for the effect of the drug-containing serum of Yimaijiangzhi Decoction on THP-1-derived foam cells. Conclusion: hsa-mir-374c-3p, hsa- mir-423-5p, and hsa-mir-374b-5p are important miRNAs that the drug-containing serum of Yimaijiangzhi Decoction acts on foam cells. The significantly differentially expressed mirnas and significantly enriched related signaling pathways may provide new ideas for the diagnosis and treatment of atherosclerosis.展开更多
Atherosclerosis is a chronic,inflammatory disorder characterized by the deposition of excess lipids in the arterial intima.The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of...Atherosclerosis is a chronic,inflammatory disorder characterized by the deposition of excess lipids in the arterial intima.The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis.Lipid homeostasis,especially cho-lesterol homeostasis,plays a crucial role during the formation of foam cells.Recently,lipid droplet-associated proteins,including PAT and CIDE family proteins,have been shown to control the development of athero-sclerosis by regulating the formation,growth,stabiliza-tion and functions of lipid droplets in macrophage-derived foam cells.This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins.Understanding the process of foam cell for-mation will aid in the future discovery of novel thera-peutic interventions for atherosclerosis.展开更多
Accumulation of macrophage"foam"cells,laden with cholesterol and cholesteryl ester,within the intima of large arteries,is a hallmark of early"fatty streak"lesions which can progress to complex,mult...Accumulation of macrophage"foam"cells,laden with cholesterol and cholesteryl ester,within the intima of large arteries,is a hallmark of early"fatty streak"lesions which can progress to complex,multicellular atheromatous plaques,involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response.Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway.Within the arterial intima,however,this mechanism is overwhelmed,leading to distinct changes in macrophage phenotype and inflammatory status.Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function,and in particular the importance of small non-coding micro-RNA(miRNA)sequences in this context.This review identifies some of the miRNA sequences which play a key role in regulating"foam"cell formation and atherogenesis,highlighting sequences involved in cholesterol accumulation,those influencing inflammation in sterol-loaded cells,and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.展开更多
Objective:To investigate whether glucagon like peptide-1(GLP-1)can reduce the cholesterol in foam cells derived from macrophages by affecting the expression of CD36 and acyl-CoA1(ACAT1)The content.Methods:Macrophages ...Objective:To investigate whether glucagon like peptide-1(GLP-1)can reduce the cholesterol in foam cells derived from macrophages by affecting the expression of CD36 and acyl-CoA1(ACAT1)The content.Methods:Macrophages were obtained from mice,and after corresponding treatment,they were divided into 4 groups:blank control group,experimental group,GLP-1 agitation group,GLP-1 inhibition group,and the expression of CD36,ACAT1 mRNA and protein in cells of each group was detected.Expression and levels of total cholesterol(TC),free cholesterol(FC)and cholesterol ester(CE).Results:Compared with the blank control group,the content of TC,FC,CE and the expression of CD36,ACAT1 mRNA and protein in the experimental group were significantly increased(P<0.05);compared with the experimental group,the content and content of TC,FC,CE in the GLP-1 excited group The expressions of CD36 and ACAT1 mRNA and protein were significantly decreased(P<0.05);compared with the GLP-1 agitation group,the contents of TC,FC and CE and the expression of CD36,ACAT1 mRNA and protein were significantly increased in the GLP-1 inhibition group(P<0.05).Conclusion:The expression levels of CD36 and ACAT1 can be suppressed by GLP-1,and under the indirect influence of GPL-1,the level of intracellular cholesterol will also be reduced,so that the process of macrophages to foam cells is suppressed Thereby slowing down the development of atherosclerosis.展开更多
Objective: To compare oxidized low density lipoprotein(ox LDL) levels in serum and vascular wall of Sprague-Dawley rats, identify their patterns in 8 weeks and 16 weeks of dyslipidemia induced by high fat diet, compar...Objective: To compare oxidized low density lipoprotein(ox LDL) levels in serum and vascular wall of Sprague-Dawley rats, identify their patterns in 8 weeks and 16 weeks of dyslipidemia induced by high fat diet, compare foam cells in aorta of each group and investigate lipoprotein-associated phospholipase A_2(Lp-PLA_2) role in atherosclerosis by darapladib administration.Methods: This study generated in twenty-four Sprague-Dawley rats. Rats were divided into 6 groups, which were received normal diet(normal group), high fat diet and high fat diet plus darapladib therapy for both 8 weeks and 16 weeks. Surgeries were performed at Week 8 and Week 16 to take the blood serum and aortic tissue. Level of ox LDL in serum,ox LDL aortic tissue, foam cell amount in aortic tissue, and Lp-PLA_2 expression in aortic tissue were measured.Results: There were significant differences in ox LDL level in serum, aortic tissue and foam cell amount(P < 0.05). There was no significant difference in Lp-PLA_2 expression in aortic tissue. Ox LDL in serum and aortic tissue had a very strong correlation(r2> 0.9, P < 0.05).This study also composed an equation for ox LDL level in aortic tissue prediction. Factorial ANOVA found that there was a significant difference of ox LDL level in the interactions between duration and location, location and treatment, and also duration, location and treatment(P < 0.01). Administration of darapladib was able to reduce levels of ox LDL in serum,aortic tissue and foam cell significantly(P < 0.05, P < 0.05 and P < 0.01, subsequently).Conclusions: Ox LDL level is location-dependent and duration-dependent. As a feasible early diagnosis, we can predict ox LDL level in aortic tissue by its level in serum. Though Lp-PLA_2 expression was unsignificant, Lp-PLA_2 inhibition by darapladib can reduce oxidative stress and inflammation in atherogenesis.展开更多
Atherosclerosis is a chronic disease that causes various cardiovascular complications.It has been realized that cellular and humoral immunity plays crucial roles in atherogenic lesion formation.In this study the effec...Atherosclerosis is a chronic disease that causes various cardiovascular complications.It has been realized that cellular and humoral immunity plays crucial roles in atherogenic lesion formation.In this study the effects of lipopolysaccharide(LPS)and interleukin-10(IL-10)on the formation of foam cells during the early stages of ath-erosclerosis have been investigated.Macrophage was induced by phorbol myristate acetate(PMA)treatment on THP-1 cells.The cells were further stimulated by ox-LDL,ox-LDL plus LPS,ox-LDL plus IL-10 and LPS.By using an oil red O staining technique,the formation of foam cells was evaluated by lipid granules formation in the cells.The ratio of foam cell formation was increased from(9.77±1.70)%to(16.27±2.27)%after 24 h stimulation with ox-LDL,and the increase was observed with incub-ating time.The foam cells were significantly increased in the presence of LPS in a dose-dependent manner.The max-imum increase of about 40%was observed.However,the significant elevation by LPS was abrogated when IL-10 was added.These results indicated that IL-10 can effectively prevent the formation of foam cells induced by ox-LDL with or without LPS.This study demonstrates that ox-LDL can cause foam cell formation from macrophages in vitro.LPS can significantly accelerate this event.IL-10,an anti-inflammatory cytokine,can inhibit the effect of ox-LDL and LPS.These results indicate that inflammatory effects in blood vessels can speed up foam cell formation.The inhibitive effect of IL-10 is an important factor for delaying atherosclerosis processes.展开更多
Background and Aims:The clinicopathological features and long-term outcomes of patients with vanishing bile duct syndrome(VBDS)have yet to be elucidated.The study aims to investigate these features and identify factor...Background and Aims:The clinicopathological features and long-term outcomes of patients with vanishing bile duct syndrome(VBDS)have yet to be elucidated.The study aims to investigate these features and identify factors associated with poor prognosis.Methods:This multicenter retrospective study recruited patients with liver biopsy-proven VBDS who were followed up at five hospitals in northern China from January 2003 to April 2022.Clinical and pathological data at time of biopsy were reviewed.Clinical outcomes including cirrhosis,decompensation events,liver transplantation(LT),and liver-related death were recorded.Cox regression analysis was used to identify the risk factors associated with poor outcomes.Results:A total of 183 patients were included.The median age was 47 years,with 77.6%being women.During a median follow-up of 4.8 years,88 patients developed compensated or decompensated cirrhosis,27 died,and 15 received LT.Multivariate Cox regression analysis showed that hepatocellular cholestasis(HR 2.953,95%CI:1.437–6.069),foam cells(HR 2.349,95%CI:1.092–5.053),and advanced fibrosis(HR 2.524,95%CI:1.313–4.851)were independent predictors of LT or liver-related deaths.A nomogram formulated with the above factors showed good consistency with a concordance index of 0.746(95%CI:0.706–0.785).Conclusions:Nearly half of VBDS patients studied progressed to end-stage liver disease and 23%of them had LT or liver-related death within two years of diagnosis.Hepatocellular cholestasis,foam cells and advanced fibrosis rather than the degree of bile duct loss or underlying etiologies were independently associated with poor prognosis in VBDS patients.展开更多
基金Guangxi Natural Science Foundation(No.2020GXNSFAA297158)The Fifth Batch of National Clinical Excellent Talent Training Projects[Guozhong Pharmaceutical Education(2022)No.1]+1 种基金Guangxi Youth Qihuang Scholar Training Program[Guizhong Medical Science and Education Development(2022)No.13]Guangxi Graduate Education Innovation Program Project(No.YCSW2022340)。
文摘Objective: To investigate the differential expression of miRNA and related biological functions and signaling pathways after the intervention of the THP-1-derived foam cell model with the drug-containing serum of Yimaijiangzhi Decoction. Methods: The experiment was divided into macrophage group, foam cell model group and Yimaijiangzhi drug-containing serum group. THP-1 cells were induced into macrophages by Fopol ester, and induced differentiated macrophages were given ox-LDL to establish foam cell model, and Yimaijiangzhi decoction rat serum was used to intervene the foam cells. Total RNA was extracted from cells in each group for miRNA sequencing, differential expression of miRNA was screened, and relevant target genes were predicted for GO analysis and KEGG analysis, protein interaction network and miRNA-target gene interaction network were established, and RT-qPCR was used to verify the possible signaling pathways for improving atherosclerosis. Result: The difference miRNA between blank group and model group was hsa-miR-302c-3p, hsa-miR-302d-3p, hsa- mir-30d-3p, hsa-mir-3189-3p, hsa-mir-374b-5p, hsa-mir-423-5p, hsa-mir-423-5p, and hsa- mir-4781-3p, hsa-mir-663a;The miRNAs of model group and Yimaijiangzhi drug-containing serum group were hsa-mir-3150a-3p, hsa-mir-7704, hsa-mir-887-3p, hsa-mir-150-5p, hsa- mir-423-5p, hsa-mir-374c-3p, hsa-mir-374c-3p, hsa-mir-374b-5p;The difference of miRNAs prediction target genes between model group and Yimaijiangzhi drug-containing serum group showed that the miRNA prediction target genes were mainly enriched in MAPK signaling pathway, ErbB signaling pathway, Hippo signaling pathway, Wnt signaling pathway and other signaling pathways. SCN1A, PRKACA, MECP2, EIF4E, SRSF1, MBNL1, PRKCA, PPARGC1A may be the potential key targets for the effect of the drug-containing serum of Yimaijiangzhi Decoction on THP-1-derived foam cells. Conclusion: hsa-mir-374c-3p, hsa- mir-423-5p, and hsa-mir-374b-5p are important miRNAs that the drug-containing serum of Yimaijiangzhi Decoction acts on foam cells. The significantly differentially expressed mirnas and significantly enriched related signaling pathways may provide new ideas for the diagnosis and treatment of atherosclerosis.
基金supported by the Natural Science Foundation of China(Grant Nos.81070248,81070249,31171132,and 81100612).
文摘Atherosclerosis is a chronic,inflammatory disorder characterized by the deposition of excess lipids in the arterial intima.The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis.Lipid homeostasis,especially cho-lesterol homeostasis,plays a crucial role during the formation of foam cells.Recently,lipid droplet-associated proteins,including PAT and CIDE family proteins,have been shown to control the development of athero-sclerosis by regulating the formation,growth,stabiliza-tion and functions of lipid droplets in macrophage-derived foam cells.This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins.Understanding the process of foam cell for-mation will aid in the future discovery of novel thera-peutic interventions for atherosclerosis.
文摘Accumulation of macrophage"foam"cells,laden with cholesterol and cholesteryl ester,within the intima of large arteries,is a hallmark of early"fatty streak"lesions which can progress to complex,multicellular atheromatous plaques,involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response.Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway.Within the arterial intima,however,this mechanism is overwhelmed,leading to distinct changes in macrophage phenotype and inflammatory status.Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function,and in particular the importance of small non-coding micro-RNA(miRNA)sequences in this context.This review identifies some of the miRNA sequences which play a key role in regulating"foam"cell formation and atherogenesis,highlighting sequences involved in cholesterol accumulation,those influencing inflammation in sterol-loaded cells,and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.
基金Key R&D Project of Shanxi Province(No.201903D421071)。
文摘Objective:To investigate whether glucagon like peptide-1(GLP-1)can reduce the cholesterol in foam cells derived from macrophages by affecting the expression of CD36 and acyl-CoA1(ACAT1)The content.Methods:Macrophages were obtained from mice,and after corresponding treatment,they were divided into 4 groups:blank control group,experimental group,GLP-1 agitation group,GLP-1 inhibition group,and the expression of CD36,ACAT1 mRNA and protein in cells of each group was detected.Expression and levels of total cholesterol(TC),free cholesterol(FC)and cholesterol ester(CE).Results:Compared with the blank control group,the content of TC,FC,CE and the expression of CD36,ACAT1 mRNA and protein in the experimental group were significantly increased(P<0.05);compared with the experimental group,the content and content of TC,FC,CE in the GLP-1 excited group The expressions of CD36 and ACAT1 mRNA and protein were significantly decreased(P<0.05);compared with the GLP-1 agitation group,the contents of TC,FC and CE and the expression of CD36,ACAT1 mRNA and protein were significantly increased in the GLP-1 inhibition group(P<0.05).Conclusion:The expression levels of CD36 and ACAT1 can be suppressed by GLP-1,and under the indirect influence of GPL-1,the level of intracellular cholesterol will also be reduced,so that the process of macrophages to foam cells is suppressed Thereby slowing down the development of atherosclerosis.
基金Supported by Indonesia Ministry of Research,Technology,and Higher Education with grant No.530.2/UN10.21/PG/2015
文摘Objective: To compare oxidized low density lipoprotein(ox LDL) levels in serum and vascular wall of Sprague-Dawley rats, identify their patterns in 8 weeks and 16 weeks of dyslipidemia induced by high fat diet, compare foam cells in aorta of each group and investigate lipoprotein-associated phospholipase A_2(Lp-PLA_2) role in atherosclerosis by darapladib administration.Methods: This study generated in twenty-four Sprague-Dawley rats. Rats were divided into 6 groups, which were received normal diet(normal group), high fat diet and high fat diet plus darapladib therapy for both 8 weeks and 16 weeks. Surgeries were performed at Week 8 and Week 16 to take the blood serum and aortic tissue. Level of ox LDL in serum,ox LDL aortic tissue, foam cell amount in aortic tissue, and Lp-PLA_2 expression in aortic tissue were measured.Results: There were significant differences in ox LDL level in serum, aortic tissue and foam cell amount(P < 0.05). There was no significant difference in Lp-PLA_2 expression in aortic tissue. Ox LDL in serum and aortic tissue had a very strong correlation(r2> 0.9, P < 0.05).This study also composed an equation for ox LDL level in aortic tissue prediction. Factorial ANOVA found that there was a significant difference of ox LDL level in the interactions between duration and location, location and treatment, and also duration, location and treatment(P < 0.01). Administration of darapladib was able to reduce levels of ox LDL in serum,aortic tissue and foam cell significantly(P < 0.05, P < 0.05 and P < 0.01, subsequently).Conclusions: Ox LDL level is location-dependent and duration-dependent. As a feasible early diagnosis, we can predict ox LDL level in aortic tissue by its level in serum. Though Lp-PLA_2 expression was unsignificant, Lp-PLA_2 inhibition by darapladib can reduce oxidative stress and inflammation in atherogenesis.
基金supported by the National Natural Science Foundation of China(Grant No.30671969)Tongji University Startup Grant(No.03038).
文摘Atherosclerosis is a chronic disease that causes various cardiovascular complications.It has been realized that cellular and humoral immunity plays crucial roles in atherogenic lesion formation.In this study the effects of lipopolysaccharide(LPS)and interleukin-10(IL-10)on the formation of foam cells during the early stages of ath-erosclerosis have been investigated.Macrophage was induced by phorbol myristate acetate(PMA)treatment on THP-1 cells.The cells were further stimulated by ox-LDL,ox-LDL plus LPS,ox-LDL plus IL-10 and LPS.By using an oil red O staining technique,the formation of foam cells was evaluated by lipid granules formation in the cells.The ratio of foam cell formation was increased from(9.77±1.70)%to(16.27±2.27)%after 24 h stimulation with ox-LDL,and the increase was observed with incub-ating time.The foam cells were significantly increased in the presence of LPS in a dose-dependent manner.The max-imum increase of about 40%was observed.However,the significant elevation by LPS was abrogated when IL-10 was added.These results indicated that IL-10 can effectively prevent the formation of foam cells induced by ox-LDL with or without LPS.This study demonstrates that ox-LDL can cause foam cell formation from macrophages in vitro.LPS can significantly accelerate this event.IL-10,an anti-inflammatory cytokine,can inhibit the effect of ox-LDL and LPS.These results indicate that inflammatory effects in blood vessels can speed up foam cell formation.The inhibitive effect of IL-10 is an important factor for delaying atherosclerosis processes.
基金supported by National Natural Science Foundation of China(No.82100633 to LTT).
文摘Background and Aims:The clinicopathological features and long-term outcomes of patients with vanishing bile duct syndrome(VBDS)have yet to be elucidated.The study aims to investigate these features and identify factors associated with poor prognosis.Methods:This multicenter retrospective study recruited patients with liver biopsy-proven VBDS who were followed up at five hospitals in northern China from January 2003 to April 2022.Clinical and pathological data at time of biopsy were reviewed.Clinical outcomes including cirrhosis,decompensation events,liver transplantation(LT),and liver-related death were recorded.Cox regression analysis was used to identify the risk factors associated with poor outcomes.Results:A total of 183 patients were included.The median age was 47 years,with 77.6%being women.During a median follow-up of 4.8 years,88 patients developed compensated or decompensated cirrhosis,27 died,and 15 received LT.Multivariate Cox regression analysis showed that hepatocellular cholestasis(HR 2.953,95%CI:1.437–6.069),foam cells(HR 2.349,95%CI:1.092–5.053),and advanced fibrosis(HR 2.524,95%CI:1.313–4.851)were independent predictors of LT or liver-related deaths.A nomogram formulated with the above factors showed good consistency with a concordance index of 0.746(95%CI:0.706–0.785).Conclusions:Nearly half of VBDS patients studied progressed to end-stage liver disease and 23%of them had LT or liver-related death within two years of diagnosis.Hepatocellular cholestasis,foam cells and advanced fibrosis rather than the degree of bile duct loss or underlying etiologies were independently associated with poor prognosis in VBDS patients.
