OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in hu...OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.展开更多
Background Coronary artery calcification is a well-known marker of atherosclerotic plaque burden.High-resolution intravascular optical coherence tomography(OCT)imaging has shown the potential to characterize the detai...Background Coronary artery calcification is a well-known marker of atherosclerotic plaque burden.High-resolution intravascular optical coherence tomography(OCT)imaging has shown the potential to characterize the details of coronary calcification in vivo.In routine clinical practice,it is a time-consuming and laborious task for clinicians to review the over 250 images in a single pullback.Besides,the imbalance label distribution within the entire pullbacks is another problem,which could lead to the failure of the classifier model.Given the success of deep learning methods with other imaging modalities,a thorough understanding of calcified plaque detection using Convolutional Neural Networks(CNNs)within pullbacks for future clinical decision was required.Methods All 33 IVOCT clinical pullbacks of 33 patients were taken from Affiliated Drum Tower Hospital,Nanjing University between December 2017 and December 2018.For ground-truth annotation,three trained experts determined the type of plaque that was present in a B-Scan.The experts assigned the labels'no calcified plaque','calcified plaque'for each OCT image.All experts were provided the all images for labeling.The final label was determined based on consensus between the experts,different opinions on the plaque type were resolved by asking the experts for a repetition of their evaluation.Before the implement of algorithm,all OCT images was resized to a resolution of 300×300,which matched the range used with standard architectures in the natural image domain.In the study,we randomly selected 26 pullbacks for training,the remaining data were testing.While,imbalance label distribution within entire pullbacks was great challenge for various CNNs architecture.In order to resolve the problem,we designed the following experiment.First,we fine-tuned twenty different CNNs architecture,including customize CNN architectures and pretrained CNN architectures.Considering the nature of OCT images,customize CNN architectures were designed that the layers were fewer than 25 layers.Then,three with good performance were selected and further deep fine-tuned to train three different models.The difference of CNNs was mainly in the model architecture,such as depth-based residual networks,width-based inception networks.Finally,the three CNN models were used to majority voting,the predicted labels were from the most voting.Areas under the receiver operating characteristic curve(ROC AUC)were used as the evaluation metric for the imbalance label distribution.Results The imbalance label distribution within pullbacks affected both convergence during the training phase and generalization of a CNN model.Different labels of OCT images could be classified with excellent performance by fine tuning parameters of CNN architectures.Overall,we find that our final result performed best with an accuracy of 90%of'calcified plaque'class,which the numbers were less than'no calcified plaque'class in one pullback.Conclusions The obtained results showed that the method is fast and effective to classify calcific plaques with imbalance label distribution in each pullback.The results suggest that the proposed method could be facilitating our understanding of coronary artery calcification in the process of atherosclerosis andhelping guide complex interventional strategies in coronary arteries with superficial calcification.展开更多
Plaque erosion,together with plaque rupture,is a common cause for acute coronary syndrome(ACS).Plaque erosion alone is responsible for about one third of the patients with ACS.Eroded plaque is defined as thrombosed,en...Plaque erosion,together with plaque rupture,is a common cause for acute coronary syndrome(ACS).Plaque erosion alone is responsible for about one third of the patients with ACS.Eroded plaque is defined as thrombosed,endothelium-absent and non-ruptured but often-inflamed plaques based on histological findings.Even though there is efficient imaging technologies to detect the eroded plaque in vivo and tailored treatment strategy has also been developed for ACScaused by erosion in clinics,the pathogenesis mechanisms that cause plaque erosion are not fully understood.It is widely postulated that thrombus formation and endothelial apoptosis(the precursors of plaque erosion)have closed association with biomechanical conditions in the coronary vessel.Revealing of the mechanical conditions in the eroded plaque could advance our knowledge in understanding the formation of plaque erosion.To this end,patient-specific OCT-based fluid-structure interaction(FSI)models were developed to investigate the plaque biomechanical conditions and investigate the impact of erosioninduced inflammation on biomechanical conditions.In vivo OCTand Biplane X-ray angiographic data of eroded coronary plaque were acquired from one male patient(age:64). OCT images were segmented manually with external elastic membrane contour and the trailing edge of the lipid-rich necrotic core(lipid)assumed to have positive remodeling ratio 1.1.Locations with luminal surface having direct contact with intraluminal thrombus on OCT images were identified erosion sites.Fusion of OCT and biplane X-ray angiographic data were performed to obtain the 3D coronary geometry.OCT-based FSI models with pre-shrink-stretch process and anisotropic material properties were constructed following previously established procedures.To reflect tissue weakening caused by erosion-induced inflammation,the material stiffness of plaque intima at the erosion site was adjust to one tenth of un-eroded fibrous plaque tissue.Three FSI models were constructed to investigate the impacts of inflammation and lipid component on plaque biomechanics:M1,without erosion(this means plaque intima at the erosion sites were not softened)and without inclusion of lipid component;M2,with erosion but no lipid;M3,with erosion and inclusion of lipid.FSI models were solved by ADINA to obtain the biomechanical conditions at peak blood pressure including plaque wall stress/strain(PWS/PWSn)and flow wall shear stress(WSS).The average values of three biomechanical conditions at the erosion sites and at the fibrous cap overlaying lipid component were calculated from three models for analysis.The results of M1 and M2 were compared to investigate the impact of erosion-induced inflammation on plaque biomechanics.Mean PWS value decreases from 49.98 kPa to 18.83 kPa(62.32%decrease)while Mean PWSn value increases from 0.123 1 to 0.138 4(12%increase)as the material stiffness becomes 10times soft.Comparing M2 and M3 at the cap sites,M3(with inclusion of lipid)will elevates mean PWS and PWSn values by48.59%and 16.09%,respectively.The impacts of erosion and lipid on flow shear stress were limited(<2%).To conclude,erosion-induced inflammation would lead to lower stress distribution but larger strain distribution,while lipid would elevate both stress and strain conditions.This shows the influence of erosion and lipid component has impacts on stress/strain cal-culations which are closely related to plaque assessment.展开更多
Aim Salidroside （SAL） is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density li...Aim Salidroside （SAL） is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor - deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Method Six-week old apoE-/- male mice were fed a high-fat diet for 8 weeks and then were ad- ministered with SAL for another 8 weeks. Atherosclerotic lesion and vascular function were analyzed. Primary cul- tured human umbilical vein endothelial cells （HUVECs） were prepared. Superoxide anion （O2^-）, NO produc- tion, mitochondrial membrane potential （△ψm） and intracellular ATP and AMP levels were measured. Expression of eNOS and AMPK were analyzed by Western blot. Result SAL significantly improved endothelial function asso- ciated with increasing eNOS activation thus reduced the atherosclerotic lesion area. SAL increased eNOS-Serl177 phosphorylation and decreased eNOS-Thr495 phosphorylation. SAL significantly activated AMP-activated protein ki- nase （AMPK）. Both AMPK inhibitor and AMPK small interfering RNA （siRNA） abolished SAL-induced Akt- Ser473 and eNOS-Serl177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. SAL decreased cellular ATP content and increased the cel- lular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease A^m, which is likely consequence of reduced ATP production. Conclusion The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide （NO） production, which was associated with mitochondria depolarization and subsequent activation of the AMPK/PI3 IC/ Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.展开更多
China Cardiovascular Disease Report 2017(Summary)pointed out that at present,cardiovascular diseases(CVD)account for the highest number of deaths among urban and rural residents.In the middle or later stages of athero...China Cardiovascular Disease Report 2017(Summary)pointed out that at present,cardiovascular diseases(CVD)account for the highest number of deaths among urban and rural residents.In the middle or later stages of atherosclerosis,the plaques become increasingly unstable with high chance to rupture,which may lead acute death from coronary heart diseases.Medical imaging and image-based computational modeling have been used in recent years to quantify ather-osclerotic plaque morphological and biomechanical characteristics and predict the coronary plaque growth and rupture processes.Analyzing the vulnerability of plaques effectively could lead to better patient screening strategies and enable physicians to adopt timely and necessary intervention or conservative treatment.Earlier investigations of vulnerable plaques were mostly based on histopathological data.With the accumulation of experience in pathology and the gradual enrichment of autopsy materials,the criteria for the diagnosis of vulnerable plaques appeared in 2001,mainly manifested as the necrotic lipid nuclei,fibrous caps that are infiltrated by a large number of macrophages,and fibrous cap thickness less than 65μm.Because of the obvious importance of the thin fibrous cap in the study of plaque vulnerability,it has been a focus of attention by many investigations.Watson,M.G.et al.are concerned about the formation of early fibrous caps in recent years.The presentation of local maximum stress on plaque further confirmed the importance of thin fibrous cap.The development of medical images has greatly promoted the study of coronary atherosclerosis.Compared with autopsy ex vivo,medical image could provide plaque data under in vivo conditions and greatly promote the study of coronary atherosclerosis.Huang XY et al.used ex vivo magnetic resonance imaging(MRI)to study the relationship between plaque wall stress(PWS)and death caused by coronary artery disease.Due to technical limitations and the accessibility of the coronary artery in the body,MRI is not widely used for in vivo coronary studies.Interventional intravascular ultrasound(IVUS),with an image resolution of 150-200μm,has been used in research and clinical practice to identify plaques,quantify plaque morphology,and characterize plaque components.More recently,optical coherence tomography(OCT),with its resolution of 5-10μm,has emerged as an imaging modality which can be used to detect thin fibrous caps and improve diagnostic accuracy.It is commonly believed that mechanical forces play an important role in plaque progression and rupture.Image-based biomechanical plaque models have been developed and used to quantify plaque mechanical conditions and seek their linkage to plaque progression and vulnerability development activities.Based on recent advances in imaging and modeling,this paper attempts to provide a brief review on plaque research,including histological classification,image preparation,biomechanical modeling and analysis methods including medical imaging techniques represented by intravascular ultrasound(IVUS)and optical coherence tomography(OCT),computational modeling and their applications in plaque progression and vulnerability analyses and predictions.The clinical application and future development direction are also briefly described.We focus more on human coronary plaque modeling and mainly included results from our group for illustration purpose.We apologize in advance for our limitations.展开更多
Background Current bottleneck of patient-specific coronary plaque model construction is the resolution of in vivo medical imaging.The threshold of cap thickness of vulnerable coronary plaques is 65 microns,while the r...Background Current bottleneck of patient-specific coronary plaque model construction is the resolution of in vivo medical imaging.The threshold of cap thickness of vulnerable coronary plaques is 65 microns,while the resolution of in vivo coronary intravascular ultrasound(IVUS)images is 150-200 microns,which is not enough to identify vulnerable plaques with thin caps and construct accurate biomechanical plaque models.Optical coherence tomography(OCT)with a 15-20μm resolution has the capacity to identify thin fibrous cap.IVUS and OCT images could complement each other and provide for more accurate plaque morphology,especially,fibrous cap thickness measurements.A modeling approach combining IVUS and OCT was introduced in our previous publication for cap thickness quantification and more accurate cap stress/strain calculations.In this paper,patient baseline and follow-up IVUS and OCT data were acquired and multimodality image-based Fluidstructure interaction(FSI)models combining 3D IVUS,OCT,angiography were constructed to better quantify human coronary atherosclerotic plaque morphology and plaque stress/strain conditions and investigate the relationship of plaque vulnerability and morphological and mechanical factors.Methods Baseline and 10-Month follow-up in vivo IVUS and OCT coronary plaque data were acquired from one patient with informed consent obtained.Co-registration and segmentation of baseline and follow-up IVUS and OCT images were performed for modeling use.Baseline and follow-up 3D FSI models based on IVUS and OCT were constructed to simulate the mechanical factors which integrating plaque morphology were employed to predict plaque vulnerability.These 3D models were solved by ADINA(ADINA R&D,Watertown,MA,USA).The quantitative indices of cap thickness,lipid percentage were classified according to histological literatures and denoted as Cap Index and Lipid Index.Cap Index,Lipid Index and Morphological Plaque Vulnerability Index(MPVI)were chosen to quantify plaque vulnerability,respectively.Random forest(RF)which was based 13 extracted features including morphological and mechanical factors was used for plaque vulnerability classification and prediction.Over sampling scheme and a 5-fold crossvalidation procedure was employed in all 45 slices for training and testing sets.Single and all different combinations of morphological and mechanical risk factors were used for plaque progression prediction.Results When Cap Index was used as the measurement,minimum cap thickness(MCT)was the best single predictor which area under curve(AUC)is 0.782 0;the combination of MCT,critical plaque wall strain(CPWSn),critical wall shear stress(CWSS)and cap wall shear stress(CapWSS)was the best predictor with ACU=0.868 6.When Lipid Index was used as the measurement,the lipid percentage(LP)was the best single predictor which AUC value is 0.857 8;the combination of Mean cap thickness(MeanCT),LP,CWSS and cap plaque wall stress(CapPWS)and was the best predictor with ACU=0.9821.When MPVI was used as the measurement,MCT was the best single predictor which AUC value is 0.782 9;the combination of MCT,LP,plaque area(PA),CPWSn and CapWSS was the best predictor with ACU=0.872 9.Conclusions Combinations of morphological and mechanical risk factors had higher prediction accuracy,compared to the prediction of single factors and other combination of morphological factors.展开更多
目的基于高分辨磁共振血管壁成像(high-resolution magnetic resonance vessel wall imaging,HRMR-VWI)分析颈动脉斑块的特征并进行斑块影像报告与数据系统(Plaque Reporting And Data System,Plaque-RADS)评分,探究Plaque-RADS评分的...目的基于高分辨磁共振血管壁成像(high-resolution magnetic resonance vessel wall imaging,HRMR-VWI)分析颈动脉斑块的特征并进行斑块影像报告与数据系统(Plaque Reporting And Data System,Plaque-RADS)评分,探究Plaque-RADS评分的临床应用价值。材料与方法回顾性收集2022年1月至2023年12月行HRMR-VWI的患者85例,其中梗死组33例,非梗死组52例,采用独立样本t检验或Mann-Whitney U检验,比较责任斑块与非责任斑块的各项参数,并对斑块进行Plaque-RADS评分,通过logistic回归分析筛选斑块的独立危险因素,绘制受试者工作特征(receiver operating characteristic,ROC)曲线评估各参数的诊断效能。结果梗死组中责任斑块33个,非责任斑块29个,非梗死组中非责任斑块102个。责任斑块的最小管腔面积、纤维化组织体积占比明显小于非责任斑块(P<0.05);责任斑块的长度、斑块体积、平均管壁厚度、最小管壁厚度、最大管壁厚度、重构指数、斑块内出血(intraplaque hemorrhage,IPH)或血栓体积、IPH或血栓体积占比明显大于非责任斑块(P<0.05);与非责任斑块相比,责任斑块的斑块负荷、狭窄度、Plaque-RADS评分更大(P<0.001)。logistic回归分析显示,斑块的长度[比值比(odds ratio,OR)=1.67,95%置信区间(confidence interval,CI):1.04~1.10]、斑块负荷(OR=3.57,95%CI:1.76~7.24)、重构指数(OR=3.26,95%CI:1.62~6.59)IPH或血栓(OR=5.33,95%CI:2.27~12.52)、Plaque-RADS评分(OR=4.66,95%CI:2.35~9.24)、狭窄度(OR=3.77,95%CI:1.98~7.15),以及平均管壁厚度(OR=2.13,95%CI:1.05~4.32)为发生急性脑梗死(acute cerebral infarction,ACI)的重要风险因素;Plaque-RADS评分预测ACI的曲线下面积(area underthecurve,AUC)为0.815(95%CI:0.732~0.898),Plaque-RADS评分联合其余各项危险因素预测ACI的AUC为0.837(95%CI:0.735~0.921)。结论颈动脉斑块存在IPH或血栓,以及斑块长度、斑块负荷、重构指数、管腔狭窄度、平均管壁厚度、Plaque-RADS评分增加,均会增加同侧发生ACI发生的风险;Plaque-RADS评分可标准化评估颈动脉斑块,提示斑块的危险分层,识别出高风险患者,是发生同侧ACI的有效预测指标。展开更多
Introduction Stroke or heart attack,the leading cause of death and disability worldwide,is usually caused by rupture of atheromatous plaque.Therefore,the identification of vulnerable atheroma pre rupture has become ex...Introduction Stroke or heart attack,the leading cause of death and disability worldwide,is usually caused by rupture of atheromatous plaque.Therefore,the identification of vulnerable atheroma pre rupture has become extremely important for patient risk stratification.Previous studies have shown that the vulnerable plaque,i.e.one that is prone to rupture with thromboembolic complications,is often associated with a thin fibrous cap,a large lipid core and a high inflammatory burden.The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap by enzymes secreted by activa-展开更多
Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of ...Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of α3- nAChR in the inflammatory responses of atherosclerosis. Methods The inflammatory indicators were detected in mouse macrophage, adipocytes and mouse aortic endothelial cells （MAECs） after the α3-nAChR was antagonized or after the α3-nAChR gene was silenced. Meanwhile, atherogenesis was induced in the apolipoprotein E knock-out （ ApoE^ -/- ） mice after fed with an atherogenic high-fat diet for 7 weeks. Results In MAECs, the lipopolysaccha- ride （LPS）-stimulated secretions of the adhesion molecules and inflammatory cytokines were significantly enhanced （30%± 80% ） after pretreatment with α-Conotoxin MII （an antagonist for α3-nAChR） or after knock-down with α3-nAChR gene. In adipocytes, the knock-down of α3 gene promoted the generations of the proin？ ammatory adi- pokines or cytokines but decreased the production of adiponectin, an anti-inflammatory adipokine, by 29.29 ± 9.43%. In macrophage silenced with α3-nAChR gene, the M1 （classical） activation was predominantly stimula- ted, whereas the M2 （alternative） activation was suppressed. In addition, the amount of the atherosclerotic lesions and the infiltration of the M1 type activated macrophages into the arterial wall were markedly elevated in the α- Conotoxin MII-treated ApoE -/- mice. Conclusion The α3-nAChR may play a pivotal role in regulating the atherogenesis through influencing the inflammatory responses of ECs, macrophages and adipocytes. The mecha- nisms involve the regulations of multiple cell signaling pathways.展开更多
Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. The aim of this study was to investigate the effects of a novel compound ZBM30 on atherosclerosis in ApoE-...Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. The aim of this study was to investigate the effects of a novel compound ZBM30 on atherosclerosis in ApoE- deficient mice and its associated mechanism. ApoE-deficient mice （6 weeks old）, fed an atherogenic high-fat and high cholesterol diet for 8 weeks, were divided into three groups. Two groups were orally administrated ZBM30 （10, 30 nag ~ kg-1） daily for 12 weeks, while the control group was administered saline. Atherosclerotic lesions with en face aortas were evaluated by Sudan IV staining, and lesion areas in aortic sinuses were evaluated by oil red O staining. Necrotic core areas and fibrous cap areas in the lesion were evaluated by henaatoxylin and eosin （HE） staining and Masson＇ s trichronae staining in the aorta sinuses. The effects of ZBM30 on cholesterol accumulation in naacrophages and cholesterol transporters： ATP binding cassette A1 （ABCA1） and ATP binding cassette G1 （AB- CG1） were evaluated by oil red O assay, 3H-cholesterol efflux assay, Western blot, and real-time PCR on macro- phage cell lines： Raw 264.7 and THP-1. Inanauno-fluoresces was used to determine the ABCA1 expression in naac- rophage in aorta sinuses. Luciferase reporters of wild type and mutant types of ABCA1 promoter were constructed to determine the regulatory domain of ZBM30 on ABCA1 promoter. Results showed that, compared with the control group, en face lesions in ZBM30 group （ 10, 30 mg · kg^-1 ） were reduced 54.96 ± 10.06% and 71.50 ± 15.37% respectively, and aorta sinus lesions were reduced 41.85 ± 11.21% and 82.23 ± 8.25% respectively. Necrotic core areas in the ZBM30 group were markedly reduced and fibrous cap areas were not changed. Oil red O staining and 3 H-cholesterol efflux assays on Raw 264.7 cell line revealed that ZBM30 significantly attenuated the cholesterol accumulation in naacrophages by enhancing apolipoprotein AI and HDL mediated cholesterol efflux. Furthermore, ZBM30 induced the protein and naRNA expression of cholesterol transporters such as ABCA1 and ABCG1. Inanauno- fluoresces experiment revealed that ZBM30 induced the ABCA1 expression in naacrophage in the lesion, which is consistent with the results in vitro. Luciferase reporter assay revealed that ZBM30 exerted its effect on ABCA1 via liver X receptor （LXR） binding domain. In conclusion, ZBM30 suppresses atherosclerosis through up-regulating cholesterol efflux via ABCA1 and ABCG1 transporters in ApoE-deficient mice.展开更多
OBJECTIVE ~1H-NMR-based metabolomics approach was conducted to holistically explore the effect and mechanisms of Cydonia oblanga Mill flavonoids(COMF) on high-fat diet induced Atherosclerosis(AS) apoE-/-mice.METHODS A...OBJECTIVE ~1H-NMR-based metabolomics approach was conducted to holistically explore the effect and mechanisms of Cydonia oblanga Mill flavonoids(COMF) on high-fat diet induced Atherosclerosis(AS) apoE-/-mice.METHODS AS model was established on the apolipoprotein e knockout mice by high-fat diet.The ApoE-/-mice were split into 6 groups including control group,AS model group,COMF High dose(COMF-H) group,COMF medium dose(COMF-M) group,COMF Low dose(COMF-L) group and Simvastatin group as the positive control group.Serum samples from all groups were analyzed by ~1H-NMR technology and the OPLS-DA was conducted to distinguish the metabolic phenotypes.RESULTS Compared to the control group,serum levels of cholesterol,VLDL,leucine,isoleucine,valine,blood lipid,citrulline,methylamine,glucose,glycine,glycerol,myo-inositol,fructose,phenylalanine,unsaturated lipid,urea and other metabolites content significantly increased,while HDL,lactate,alanine,glutamate,glutamine,pyruvate,carnitine,citrate,choline content signifi.cantly decreased and the difference was statistically significant(P<0.05).The trend of metabolites in serum samples of COMF low,medium and high group was opposite to that of atherosclerosis model group and the difference was statistically significant(P<0.05).CONCLUSION Through functional analysis of these biomakers,amino acid metabolism,lipid metabolism,cholesterol metabolism,energy metabolism and inflammation reaction were considered as the most relevant pathological biomakers in the serum of AS mice.This study also demonstrates that COMF had the therapeutic effectiveness on AS through partly reversing the lipid,cholesterol,amino acid,energy metabolism and Inflammation reaction.展开更多
OBJECTIVE To explore the biomarkers and molecular mechanism of Huanglianjiedu decoction(HJD) on high fat diet-induced experimental atherosclerosis in rats.METHODS SD male rats were randomly dividedinto five groups(n=8...OBJECTIVE To explore the biomarkers and molecular mechanism of Huanglianjiedu decoction(HJD) on high fat diet-induced experimental atherosclerosis in rats.METHODS SD male rats were randomly dividedinto five groups(n=8):normal control group,model group,and three dosage groups(1.5,3 and 6 g crude drug per kilogram of body weight).Atherosclerosis was induced by the combination of regular intraperitoneal injection of vitamin D3 and high fat diet for 8 weeks.HJD was administered by oral gavage from the third week once per day and until the end of the study.After the final administration,the blood samples were collected for biochemical analyses [total cholesterol(TC),triglycerides(TG),highdensity lipoprotein(HDL-C),low-density cholesterol(LDL-C)] and blood gas analyses(PaO_2,PaCO_2,pH,ctHb,etc);the abdominal aorta sections were stained with hematoxylin and eosin for histopathology;the liver homogenate were determined for MDA,SOD,OX-LDL,MCP-1 and VCAM-1.The plasma samples were detected using ultraper formance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS).The data of endogenous compounds were preliminarily preprocessed by software Progenesis QI and then analyzed by multivari.ate statistical analysis software EZinfo 2.0 to screen the distinguished biomarkers and the metabolic pathways were analyzed through website http://www.metaboanalyst.ca/.RESULTS Compared with the normal control group,the content of TC,TG,LDL-C,PaCO_2,MDA,Ox-LDL,MCP-1 and VCAM-1 were significantly increased and HDL-C,PaO_2,ctHb and SOD decreased in the atherosclerosis rats.HJD could significantly attenuated the high fat-induced atherosclerosis pathological injury and the abovementioned indexes(P<0.05).The five groups could be clearly distinguished using the metabolomics method.The administration groups profile exhibited an apparent returning trend from that of the model group and that of the normal control group.Twenty-one endogenous metabolites has been significantly changed in atherosclerosis rats.HJD could remarkably up-regulate 5-L-glutamyl-taurine,L-beta-aspartylL-glutamic acid,histidinyl-hydroxyproline,tryptophyl-alanine,4′-O-methyl-(-)-epicatechin,and downregulate protoporphyrin IX,azelaic acid,lacto-N-triaose,cinnamoylglycine and 9′-carboxy-alpha-tocotri.enol.CONCLUSION The beneficial effect of HJD in high fat-induced atherosclerosis rats may be due to anti-oxidant and anti-inflammatory.And it is suggested that HJD may affect the model rats through tryptophan metabolism,taurine and hypotaurine metabolism,histidine metabolism,lysine degradation and porphyrin and chlorophyll metabolism pathway.展开更多
基金supported by National Science Foundation of China(81402943)CAMS Major Collaborative Innovation Project(2016-I2M-1-011)PUMC Youth Fund(3332015168)
文摘OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.
基金supported in part by the National Natural Science Foundation of China ( NSFC ) ( 11772093)ARC ( FT140101152)
文摘Background Coronary artery calcification is a well-known marker of atherosclerotic plaque burden.High-resolution intravascular optical coherence tomography(OCT)imaging has shown the potential to characterize the details of coronary calcification in vivo.In routine clinical practice,it is a time-consuming and laborious task for clinicians to review the over 250 images in a single pullback.Besides,the imbalance label distribution within the entire pullbacks is another problem,which could lead to the failure of the classifier model.Given the success of deep learning methods with other imaging modalities,a thorough understanding of calcified plaque detection using Convolutional Neural Networks(CNNs)within pullbacks for future clinical decision was required.Methods All 33 IVOCT clinical pullbacks of 33 patients were taken from Affiliated Drum Tower Hospital,Nanjing University between December 2017 and December 2018.For ground-truth annotation,three trained experts determined the type of plaque that was present in a B-Scan.The experts assigned the labels'no calcified plaque','calcified plaque'for each OCT image.All experts were provided the all images for labeling.The final label was determined based on consensus between the experts,different opinions on the plaque type were resolved by asking the experts for a repetition of their evaluation.Before the implement of algorithm,all OCT images was resized to a resolution of 300×300,which matched the range used with standard architectures in the natural image domain.In the study,we randomly selected 26 pullbacks for training,the remaining data were testing.While,imbalance label distribution within entire pullbacks was great challenge for various CNNs architecture.In order to resolve the problem,we designed the following experiment.First,we fine-tuned twenty different CNNs architecture,including customize CNN architectures and pretrained CNN architectures.Considering the nature of OCT images,customize CNN architectures were designed that the layers were fewer than 25 layers.Then,three with good performance were selected and further deep fine-tuned to train three different models.The difference of CNNs was mainly in the model architecture,such as depth-based residual networks,width-based inception networks.Finally,the three CNN models were used to majority voting,the predicted labels were from the most voting.Areas under the receiver operating characteristic curve(ROC AUC)were used as the evaluation metric for the imbalance label distribution.Results The imbalance label distribution within pullbacks affected both convergence during the training phase and generalization of a CNN model.Different labels of OCT images could be classified with excellent performance by fine tuning parameters of CNN architectures.Overall,we find that our final result performed best with an accuracy of 90%of'calcified plaque'class,which the numbers were less than'no calcified plaque'class in one pullback.Conclusions The obtained results showed that the method is fast and effective to classify calcific plaques with imbalance label distribution in each pullback.The results suggest that the proposed method could be facilitating our understanding of coronary artery calcification in the process of atherosclerosis andhelping guide complex interventional strategies in coronary arteries with superficial calcification.
基金supported in part by NSFC ( 11672001,11802060)Jiangsu NSF ( BK20180352)Jiangsu Province Science and Technology Agency ( BE2016785)
文摘Plaque erosion,together with plaque rupture,is a common cause for acute coronary syndrome(ACS).Plaque erosion alone is responsible for about one third of the patients with ACS.Eroded plaque is defined as thrombosed,endothelium-absent and non-ruptured but often-inflamed plaques based on histological findings.Even though there is efficient imaging technologies to detect the eroded plaque in vivo and tailored treatment strategy has also been developed for ACScaused by erosion in clinics,the pathogenesis mechanisms that cause plaque erosion are not fully understood.It is widely postulated that thrombus formation and endothelial apoptosis(the precursors of plaque erosion)have closed association with biomechanical conditions in the coronary vessel.Revealing of the mechanical conditions in the eroded plaque could advance our knowledge in understanding the formation of plaque erosion.To this end,patient-specific OCT-based fluid-structure interaction(FSI)models were developed to investigate the plaque biomechanical conditions and investigate the impact of erosioninduced inflammation on biomechanical conditions.In vivo OCTand Biplane X-ray angiographic data of eroded coronary plaque were acquired from one male patient(age:64). OCT images were segmented manually with external elastic membrane contour and the trailing edge of the lipid-rich necrotic core(lipid)assumed to have positive remodeling ratio 1.1.Locations with luminal surface having direct contact with intraluminal thrombus on OCT images were identified erosion sites.Fusion of OCT and biplane X-ray angiographic data were performed to obtain the 3D coronary geometry.OCT-based FSI models with pre-shrink-stretch process and anisotropic material properties were constructed following previously established procedures.To reflect tissue weakening caused by erosion-induced inflammation,the material stiffness of plaque intima at the erosion site was adjust to one tenth of un-eroded fibrous plaque tissue.Three FSI models were constructed to investigate the impacts of inflammation and lipid component on plaque biomechanics:M1,without erosion(this means plaque intima at the erosion sites were not softened)and without inclusion of lipid component;M2,with erosion but no lipid;M3,with erosion and inclusion of lipid.FSI models were solved by ADINA to obtain the biomechanical conditions at peak blood pressure including plaque wall stress/strain(PWS/PWSn)and flow wall shear stress(WSS).The average values of three biomechanical conditions at the erosion sites and at the fibrous cap overlaying lipid component were calculated from three models for analysis.The results of M1 and M2 were compared to investigate the impact of erosion-induced inflammation on plaque biomechanics.Mean PWS value decreases from 49.98 kPa to 18.83 kPa(62.32%decrease)while Mean PWSn value increases from 0.123 1 to 0.138 4(12%increase)as the material stiffness becomes 10times soft.Comparing M2 and M3 at the cap sites,M3(with inclusion of lipid)will elevates mean PWS and PWSn values by48.59%and 16.09%,respectively.The impacts of erosion and lipid on flow shear stress were limited(<2%).To conclude,erosion-induced inflammation would lead to lower stress distribution but larger strain distribution,while lipid would elevate both stress and strain conditions.This shows the influence of erosion and lipid component has impacts on stress/strain cal-culations which are closely related to plaque assessment.
文摘Aim Salidroside （SAL） is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor - deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Method Six-week old apoE-/- male mice were fed a high-fat diet for 8 weeks and then were ad- ministered with SAL for another 8 weeks. Atherosclerotic lesion and vascular function were analyzed. Primary cul- tured human umbilical vein endothelial cells （HUVECs） were prepared. Superoxide anion （O2^-）, NO produc- tion, mitochondrial membrane potential （△ψm） and intracellular ATP and AMP levels were measured. Expression of eNOS and AMPK were analyzed by Western blot. Result SAL significantly improved endothelial function asso- ciated with increasing eNOS activation thus reduced the atherosclerotic lesion area. SAL increased eNOS-Serl177 phosphorylation and decreased eNOS-Thr495 phosphorylation. SAL significantly activated AMP-activated protein ki- nase （AMPK）. Both AMPK inhibitor and AMPK small interfering RNA （siRNA） abolished SAL-induced Akt- Ser473 and eNOS-Serl177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. SAL decreased cellular ATP content and increased the cel- lular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease A^m, which is likely consequence of reduced ATP production. Conclusion The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide （NO） production, which was associated with mitochondria depolarization and subsequent activation of the AMPK/PI3 IC/ Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.
基金supported in part by NIH grant ( R01 EB004759)Jiangsu Province Science and Technology Agency grant ( BE2016785)
文摘China Cardiovascular Disease Report 2017(Summary)pointed out that at present,cardiovascular diseases(CVD)account for the highest number of deaths among urban and rural residents.In the middle or later stages of atherosclerosis,the plaques become increasingly unstable with high chance to rupture,which may lead acute death from coronary heart diseases.Medical imaging and image-based computational modeling have been used in recent years to quantify ather-osclerotic plaque morphological and biomechanical characteristics and predict the coronary plaque growth and rupture processes.Analyzing the vulnerability of plaques effectively could lead to better patient screening strategies and enable physicians to adopt timely and necessary intervention or conservative treatment.Earlier investigations of vulnerable plaques were mostly based on histopathological data.With the accumulation of experience in pathology and the gradual enrichment of autopsy materials,the criteria for the diagnosis of vulnerable plaques appeared in 2001,mainly manifested as the necrotic lipid nuclei,fibrous caps that are infiltrated by a large number of macrophages,and fibrous cap thickness less than 65μm.Because of the obvious importance of the thin fibrous cap in the study of plaque vulnerability,it has been a focus of attention by many investigations.Watson,M.G.et al.are concerned about the formation of early fibrous caps in recent years.The presentation of local maximum stress on plaque further confirmed the importance of thin fibrous cap.The development of medical images has greatly promoted the study of coronary atherosclerosis.Compared with autopsy ex vivo,medical image could provide plaque data under in vivo conditions and greatly promote the study of coronary atherosclerosis.Huang XY et al.used ex vivo magnetic resonance imaging(MRI)to study the relationship between plaque wall stress(PWS)and death caused by coronary artery disease.Due to technical limitations and the accessibility of the coronary artery in the body,MRI is not widely used for in vivo coronary studies.Interventional intravascular ultrasound(IVUS),with an image resolution of 150-200μm,has been used in research and clinical practice to identify plaques,quantify plaque morphology,and characterize plaque components.More recently,optical coherence tomography(OCT),with its resolution of 5-10μm,has emerged as an imaging modality which can be used to detect thin fibrous caps and improve diagnostic accuracy.It is commonly believed that mechanical forces play an important role in plaque progression and rupture.Image-based biomechanical plaque models have been developed and used to quantify plaque mechanical conditions and seek their linkage to plaque progression and vulnerability development activities.Based on recent advances in imaging and modeling,this paper attempts to provide a brief review on plaque research,including histological classification,image preparation,biomechanical modeling and analysis methods including medical imaging techniques represented by intravascular ultrasound(IVUS)and optical coherence tomography(OCT),computational modeling and their applications in plaque progression and vulnerability analyses and predictions.The clinical application and future development direction are also briefly described.We focus more on human coronary plaque modeling and mainly included results from our group for illustration purpose.We apologize in advance for our limitations.
基金supported in part by a Jiangsu Province Science and Technology Agency grant ( BE2016785)
文摘Background Current bottleneck of patient-specific coronary plaque model construction is the resolution of in vivo medical imaging.The threshold of cap thickness of vulnerable coronary plaques is 65 microns,while the resolution of in vivo coronary intravascular ultrasound(IVUS)images is 150-200 microns,which is not enough to identify vulnerable plaques with thin caps and construct accurate biomechanical plaque models.Optical coherence tomography(OCT)with a 15-20μm resolution has the capacity to identify thin fibrous cap.IVUS and OCT images could complement each other and provide for more accurate plaque morphology,especially,fibrous cap thickness measurements.A modeling approach combining IVUS and OCT was introduced in our previous publication for cap thickness quantification and more accurate cap stress/strain calculations.In this paper,patient baseline and follow-up IVUS and OCT data were acquired and multimodality image-based Fluidstructure interaction(FSI)models combining 3D IVUS,OCT,angiography were constructed to better quantify human coronary atherosclerotic plaque morphology and plaque stress/strain conditions and investigate the relationship of plaque vulnerability and morphological and mechanical factors.Methods Baseline and 10-Month follow-up in vivo IVUS and OCT coronary plaque data were acquired from one patient with informed consent obtained.Co-registration and segmentation of baseline and follow-up IVUS and OCT images were performed for modeling use.Baseline and follow-up 3D FSI models based on IVUS and OCT were constructed to simulate the mechanical factors which integrating plaque morphology were employed to predict plaque vulnerability.These 3D models were solved by ADINA(ADINA R&D,Watertown,MA,USA).The quantitative indices of cap thickness,lipid percentage were classified according to histological literatures and denoted as Cap Index and Lipid Index.Cap Index,Lipid Index and Morphological Plaque Vulnerability Index(MPVI)were chosen to quantify plaque vulnerability,respectively.Random forest(RF)which was based 13 extracted features including morphological and mechanical factors was used for plaque vulnerability classification and prediction.Over sampling scheme and a 5-fold crossvalidation procedure was employed in all 45 slices for training and testing sets.Single and all different combinations of morphological and mechanical risk factors were used for plaque progression prediction.Results When Cap Index was used as the measurement,minimum cap thickness(MCT)was the best single predictor which area under curve(AUC)is 0.782 0;the combination of MCT,critical plaque wall strain(CPWSn),critical wall shear stress(CWSS)and cap wall shear stress(CapWSS)was the best predictor with ACU=0.868 6.When Lipid Index was used as the measurement,the lipid percentage(LP)was the best single predictor which AUC value is 0.857 8;the combination of Mean cap thickness(MeanCT),LP,CWSS and cap plaque wall stress(CapPWS)and was the best predictor with ACU=0.9821.When MPVI was used as the measurement,MCT was the best single predictor which AUC value is 0.782 9;the combination of MCT,LP,plaque area(PA),CPWSn and CapWSS was the best predictor with ACU=0.872 9.Conclusions Combinations of morphological and mechanical risk factors had higher prediction accuracy,compared to the prediction of single factors and other combination of morphological factors.
基金partially supported by the National 973 Basic Research Program of China (No.2013CB733803)the National Natural Science Foundation of China(NSFC)(No.11272091)
文摘Introduction Stroke or heart attack,the leading cause of death and disability worldwide,is usually caused by rupture of atheromatous plaque.Therefore,the identification of vulnerable atheroma pre rupture has become extremely important for patient risk stratification.Previous studies have shown that the vulnerable plaque,i.e.one that is prone to rupture with thromboembolic complications,is often associated with a thin fibrous cap,a large lipid core and a high inflammatory burden.The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap by enzymes secreted by activa-
文摘Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of α3- nAChR in the inflammatory responses of atherosclerosis. Methods The inflammatory indicators were detected in mouse macrophage, adipocytes and mouse aortic endothelial cells （MAECs） after the α3-nAChR was antagonized or after the α3-nAChR gene was silenced. Meanwhile, atherogenesis was induced in the apolipoprotein E knock-out （ ApoE^ -/- ） mice after fed with an atherogenic high-fat diet for 7 weeks. Results In MAECs, the lipopolysaccha- ride （LPS）-stimulated secretions of the adhesion molecules and inflammatory cytokines were significantly enhanced （30%± 80% ） after pretreatment with α-Conotoxin MII （an antagonist for α3-nAChR） or after knock-down with α3-nAChR gene. In adipocytes, the knock-down of α3 gene promoted the generations of the proin？ ammatory adi- pokines or cytokines but decreased the production of adiponectin, an anti-inflammatory adipokine, by 29.29 ± 9.43%. In macrophage silenced with α3-nAChR gene, the M1 （classical） activation was predominantly stimula- ted, whereas the M2 （alternative） activation was suppressed. In addition, the amount of the atherosclerotic lesions and the infiltration of the M1 type activated macrophages into the arterial wall were markedly elevated in the α- Conotoxin MII-treated ApoE -/- mice. Conclusion The α3-nAChR may play a pivotal role in regulating the atherogenesis through influencing the inflammatory responses of ECs, macrophages and adipocytes. The mecha- nisms involve the regulations of multiple cell signaling pathways.
文摘Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. The aim of this study was to investigate the effects of a novel compound ZBM30 on atherosclerosis in ApoE- deficient mice and its associated mechanism. ApoE-deficient mice （6 weeks old）, fed an atherogenic high-fat and high cholesterol diet for 8 weeks, were divided into three groups. Two groups were orally administrated ZBM30 （10, 30 nag ~ kg-1） daily for 12 weeks, while the control group was administered saline. Atherosclerotic lesions with en face aortas were evaluated by Sudan IV staining, and lesion areas in aortic sinuses were evaluated by oil red O staining. Necrotic core areas and fibrous cap areas in the lesion were evaluated by henaatoxylin and eosin （HE） staining and Masson＇ s trichronae staining in the aorta sinuses. The effects of ZBM30 on cholesterol accumulation in naacrophages and cholesterol transporters： ATP binding cassette A1 （ABCA1） and ATP binding cassette G1 （AB- CG1） were evaluated by oil red O assay, 3H-cholesterol efflux assay, Western blot, and real-time PCR on macro- phage cell lines： Raw 264.7 and THP-1. Inanauno-fluoresces was used to determine the ABCA1 expression in naac- rophage in aorta sinuses. Luciferase reporters of wild type and mutant types of ABCA1 promoter were constructed to determine the regulatory domain of ZBM30 on ABCA1 promoter. Results showed that, compared with the control group, en face lesions in ZBM30 group （ 10, 30 mg · kg^-1 ） were reduced 54.96 ± 10.06% and 71.50 ± 15.37% respectively, and aorta sinus lesions were reduced 41.85 ± 11.21% and 82.23 ± 8.25% respectively. Necrotic core areas in the ZBM30 group were markedly reduced and fibrous cap areas were not changed. Oil red O staining and 3 H-cholesterol efflux assays on Raw 264.7 cell line revealed that ZBM30 significantly attenuated the cholesterol accumulation in naacrophages by enhancing apolipoprotein AI and HDL mediated cholesterol efflux. Furthermore, ZBM30 induced the protein and naRNA expression of cholesterol transporters such as ABCA1 and ABCG1. Inanauno- fluoresces experiment revealed that ZBM30 induced the ABCA1 expression in naacrophage in the lesion, which is consistent with the results in vitro. Luciferase reporter assay revealed that ZBM30 exerted its effect on ABCA1 via liver X receptor （LXR） binding domain. In conclusion, ZBM30 suppresses atherosclerosis through up-regulating cholesterol efflux via ABCA1 and ABCG1 transporters in ApoE-deficient mice.
基金supported by National Natural Science Foundation of China(81660696) Research and development of new drugs Foundation of Xinjiang administration of traditional Chinese medicine(2017-02-05)
文摘OBJECTIVE ~1H-NMR-based metabolomics approach was conducted to holistically explore the effect and mechanisms of Cydonia oblanga Mill flavonoids(COMF) on high-fat diet induced Atherosclerosis(AS) apoE-/-mice.METHODS AS model was established on the apolipoprotein e knockout mice by high-fat diet.The ApoE-/-mice were split into 6 groups including control group,AS model group,COMF High dose(COMF-H) group,COMF medium dose(COMF-M) group,COMF Low dose(COMF-L) group and Simvastatin group as the positive control group.Serum samples from all groups were analyzed by ~1H-NMR technology and the OPLS-DA was conducted to distinguish the metabolic phenotypes.RESULTS Compared to the control group,serum levels of cholesterol,VLDL,leucine,isoleucine,valine,blood lipid,citrulline,methylamine,glucose,glycine,glycerol,myo-inositol,fructose,phenylalanine,unsaturated lipid,urea and other metabolites content significantly increased,while HDL,lactate,alanine,glutamate,glutamine,pyruvate,carnitine,citrate,choline content signifi.cantly decreased and the difference was statistically significant(P<0.05).The trend of metabolites in serum samples of COMF low,medium and high group was opposite to that of atherosclerosis model group and the difference was statistically significant(P<0.05).CONCLUSION Through functional analysis of these biomakers,amino acid metabolism,lipid metabolism,cholesterol metabolism,energy metabolism and inflammation reaction were considered as the most relevant pathological biomakers in the serum of AS mice.This study also demonstrates that COMF had the therapeutic effectiveness on AS through partly reversing the lipid,cholesterol,amino acid,energy metabolism and Inflammation reaction.
基金supported by National Natural Science Foundation of China(8170382381560744) Science and Technology Research Project of Jiangxi Provincial Education Department(GJJ170753)
文摘OBJECTIVE To explore the biomarkers and molecular mechanism of Huanglianjiedu decoction(HJD) on high fat diet-induced experimental atherosclerosis in rats.METHODS SD male rats were randomly dividedinto five groups(n=8):normal control group,model group,and three dosage groups(1.5,3 and 6 g crude drug per kilogram of body weight).Atherosclerosis was induced by the combination of regular intraperitoneal injection of vitamin D3 and high fat diet for 8 weeks.HJD was administered by oral gavage from the third week once per day and until the end of the study.After the final administration,the blood samples were collected for biochemical analyses [total cholesterol(TC),triglycerides(TG),highdensity lipoprotein(HDL-C),low-density cholesterol(LDL-C)] and blood gas analyses(PaO_2,PaCO_2,pH,ctHb,etc);the abdominal aorta sections were stained with hematoxylin and eosin for histopathology;the liver homogenate were determined for MDA,SOD,OX-LDL,MCP-1 and VCAM-1.The plasma samples were detected using ultraper formance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS).The data of endogenous compounds were preliminarily preprocessed by software Progenesis QI and then analyzed by multivari.ate statistical analysis software EZinfo 2.0 to screen the distinguished biomarkers and the metabolic pathways were analyzed through website http://www.metaboanalyst.ca/.RESULTS Compared with the normal control group,the content of TC,TG,LDL-C,PaCO_2,MDA,Ox-LDL,MCP-1 and VCAM-1 were significantly increased and HDL-C,PaO_2,ctHb and SOD decreased in the atherosclerosis rats.HJD could significantly attenuated the high fat-induced atherosclerosis pathological injury and the abovementioned indexes(P<0.05).The five groups could be clearly distinguished using the metabolomics method.The administration groups profile exhibited an apparent returning trend from that of the model group and that of the normal control group.Twenty-one endogenous metabolites has been significantly changed in atherosclerosis rats.HJD could remarkably up-regulate 5-L-glutamyl-taurine,L-beta-aspartylL-glutamic acid,histidinyl-hydroxyproline,tryptophyl-alanine,4′-O-methyl-(-)-epicatechin,and downregulate protoporphyrin IX,azelaic acid,lacto-N-triaose,cinnamoylglycine and 9′-carboxy-alpha-tocotri.enol.CONCLUSION The beneficial effect of HJD in high fat-induced atherosclerosis rats may be due to anti-oxidant and anti-inflammatory.And it is suggested that HJD may affect the model rats through tryptophan metabolism,taurine and hypotaurine metabolism,histidine metabolism,lysine degradation and porphyrin and chlorophyll metabolism pathway.
