Objective PERK/eI F2α/CHOP is a major signaling pathway mediating endoplasmic reticulum(ER) stress related with atherosclerosis.Oxidized LDL(ox-LDL) also induces endothelial apoptosis and plays a vital role in the in...Objective PERK/eI F2α/CHOP is a major signaling pathway mediating endoplasmic reticulum(ER) stress related with atherosclerosis.Oxidized LDL(ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis.The present study was conducted to explore the regulatory effect of ox-LDL on PERK/e IF2α/CHOP signaling pathway in vascular endothelial cells.Methods The effects of ox-LDL on PERK and p-e IF2α protein expression of primary human umbilical vein endothelial cells(HUVECs) were investigated by Western blot analysis.PERK gene silencing and selective eI F2α phosphatase inhibitor,salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis,caspase-3 activity,and CHOP mR NA level.Results Ox-LDL treatment significantly increased the expression of PERK,PERK-mediated inactivation of e IF2α phosphorylation,and the expression of CHOP,as well as the caspase-3 activity and apoptosis.The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral sh RNA or by selective eI F2α phosphatase inhibitor,salubrinal.Conclusion This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eI F2α/CHOP ER-stress pathway.It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis.展开更多
Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive...Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.展开更多
AIM: To investigate whether intravitreal injection of oxidized low-density lipoprotein(OxLDL) can promote laserinduced choroidal neovascularization(CNV) formation in mice and the mechanism involved, thereby to develop...AIM: To investigate whether intravitreal injection of oxidized low-density lipoprotein(OxLDL) can promote laserinduced choroidal neovascularization(CNV) formation in mice and the mechanism involved, thereby to develop a better animal model.METHODS: C57BL6/J mice were randomized into three groups. Immediately after CNV induction with 532 nm laser photocoagulation, 1.0 μL of OxLDL [100 μg/m L in phosphate-buffered saline(PBS)] was intravitreally injected, whereas PBS and the same volume low-density lipoprotein(LDL;100 μg/m L in PBS) were injected into the vitreous as controls. Angiogenic and inflammatory cytokines were measured by quantitative real-time polymerase chain reaction(q RT-PCR) and Western blotting(WB) after 5 d, and CNV severity was analyzed by choroid flat mount and immunofluorescence staining after 1wk. In vitro, retinal pigment epithelial(RPE) cell line(ARPE19) were treated with OxLDL(LDL as control) for 8 h. Angiogenic and inflammatory cytokine levels were measured. A specific inhibitor of lectin-like oxidized low-density lipoprotein receptor 1(LOX1) was used to evaluate the role of LOX1 in this process.RESULTS: At 7 d after intravitreal injection of 1 μL(100 μg/mL) OxLDL, T15-labeled OxLDL was mainly deposited around the CNV area, and the F4/80-labeled macrophages, the CD31-labeled vascular endothelial cells number and CNV area were increased. Meanwhile, WB and qR T-PCR results showed that vascular endothelial growth factor(VEGF), CC chemokine receptor 2(CCR2), interleukin-6(IL-6), IL-1β, and matrix metalloproteinase 9(MMP9) expressions were increased, which was supported by in vitro experiments in RPE cells. LOX1 inhibitors significantly reduced expressions of inflammatory factors IL-1β and VEGF. CONCLUSION: A modified laser-induced CNV animal model is established with intravitreal injection of 1 μL(100 μg/mL) of OxLDL at 7 d, which at least partially through LOX1. This animal model can be used as a simple model for studying the role of OxLDL in age-related macular degeneration.展开更多
BACKGROUND Oxidized low-density lipoprotein(ox-LDL),which is abnormally increased in the serum of colorectal cancer(CRC)patients consuming a high-fat diet(HFD),may be one of the risk factors for the development of CRC...BACKGROUND Oxidized low-density lipoprotein(ox-LDL),which is abnormally increased in the serum of colorectal cancer(CRC)patients consuming a high-fat diet(HFD),may be one of the risk factors for the development of CRC.Ox-LDL exerts a regulatory effect on macrophages and may influence CRC through the tumor microenvironment.The role of ox-LDL in CRC remains unclear.AIM To investigate the role of ox-LDL through macrophages in HFD associated CRC.METHODS The expression of ox-LDL and CD206 was detected in colorectal tissues of CRC patients with hyperlipidemia and HFD-fed mice by immunofluorescence.We stimulated the macrophages with 20μg/mL ox-LDL and assessed the expression levels of CD206 and the cytokines by cell fluorescence and quantitative polymerase chain reaction.We further knocked down LOX-1,the surface receptor of ox-LDL,to confirm the function of ox-LDL in macrophages.Then,LoVo cells were co-cultured with the stimulated macrophages to analyze the CD44 and CD133 expression by western blot.RESULTS The expression of ox-LDL and the CD206 was significantly increased in the stroma of colorectal tissues of CRC patients with hyperlipidemia,and also upregulated in the HFD-fed mice.Moreover,an increased level of CD206 and decreased level of inducible nitric oxide synthase were observed in macrophages after ox-LDL continuous stimulation.Such effects were inhibited when the surface receptor LOX-1 was knocked down in macrophages.Ox-LDL could induce CD206+macrophages,which resulted in high expression of CD44 and CD133 in co-cultured LoVo cells.CONCLUSION Ox-LDL stimulates CD206+macrophages to upregulate CD44 and CD133 expression in HFD related CRC.展开更多
It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein(LDL)cholesterol(LDL-C),but its impact on lipoprotein subfractions and oxidized low-density lipoprotein(oxLDL)has not been det...It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein(LDL)cholesterol(LDL-C),but its impact on lipoprotein subfractions and oxidized low-density lipoprotein(oxLDL)has not been determined.The aim of the present study was to investigate the potential effects of pitavastatin on subfractions of LDL and high-density lipoprotein(HDL)as well as oxLDL in untreated patients with coronary atherosclerosis(AS).Thirty-six subjects were enrolled in this study.O f them,18 patients with AS were administered pitavastatin 2 mg/day for 8 weeks and 18 healthy subjects without therapy served as controls.The plasma lipid profile,lipoprotein subfractions and circulating oxLDL were determined at baseline and 8 weeks respectively.The results showed that pitavastatin treatment indeed not only decreased LDL-C,total cholesterol(TC),triglycerides(TG)and apolipoprotein B(ApoB)levels,and increased HDL cholesterol(HDL-C),but also reduced the cholesterol concentration of all of the LDL subfractions and the percentage of intermediate and small LDL subfractions.Meanwhile,pitavastatin could decrease plasma oxLDL levels.Furthermore,a more close correlation was found between oxLDL and LDL-C as well as LDL subfractions after pitavastatin treatment.We concluded that a moderate dose of pitavastatin therapy not only decreases LDL-C and oxLDL concentrations but also improves LDL subfractions in patients with AS.展开更多
Background:Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis.Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promo...Background:Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis.Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promoting oxidative metabolism attenuated atherosclerosis progression.Therefore,this study aimed to investigate whether metformin,which has ameliorated atherosclerosis in animal models and clinical trials,modulated oxidized low-density lipoprotein (Ox-LDL) induced inflammatory status in macrophages by regulating cellular oxidative metabolism.Methods:Murine raw264.7 macrophages were incubated with Ox-LDL (50 μg/mL) in the presence or absence of metformin (15 μmol/L) for 24 h.Real-time polymerase chain reaction was used to quantify the transcription of classically activated (M1) proinflammatory and alternatively activated (M2) anti-inflammatory markers and mitochondrial DNA copy numbers.Cellular reactive oxygen species (ROS) production and mitochondrial membrane potential were detected by immunofluorescence.Cellular adenosine triphosphate (ATP) synthesis,glucose uptake,and lactic acid production were measured by commercial kit and normalized to cellular lysates.Western blotting analysis was performed to detect the expression of mitochondrial fusion/fission related proteins,enzymes mediating lipid metabolism and signaling pathway of glucose transport.Differences between groups were analyzed using one-way analysis of variance.Results:Metformin improved Ox-LDL-impaired anti-inflammatory phenotype in raw264.7 macrophages as shown by up-regulated transcription of anti-inflammatory markers including interleukin 10 (0.76 ± 0.04 vs.0.94 ± 0.01,P =0.003) and Resistin-like molecule alpha (0.67 ± 0.08 vs.1.78 ± 0.34,P =0.030).Conversely,Ox-LDL-diminished phosphorylation of Akt was up regulated by metformin treatment (0.47 ± 0.05 vs.1.02 ± 0.08,P =0.040),associated with an improvement of mitochondrial function,characterized by decreased ROS generation (2.50 ± 0.07 vs.2.15 ± 0.04,P =0.040),increased lipid oxidation,and elevated cellular ATP production (0.026 ± 0.001 vs.0.035 ± 0.003,P =0.020).Moreover,metformin-mediated Akt activation increased Akt substrate of 160 kDa (AS160) phosphorylation (0.51 ± 0.04 vs.1.03 ± 0.03,P =0.0041),promoted membrane translocation of glucose transporter 1,and increased glucose influx into the cells (4.78 ± 0.04 vs.5.47 ± 0.01,P < 0.001).Contusion:This study suggested that targeting macrophage metabolism with new or existing drugs had therapeutic potential for the prevention and treatment of diabetes-accelerated atherosclerosis.展开更多
In this study,we examined the protective effects of Danshen both on endothelial progenitor cells(EPCs) in patients with hypercholesterolemia and on in-vitro EPCs of healthy volunteers.In the clinical study,we randomly...In this study,we examined the protective effects of Danshen both on endothelial progenitor cells(EPCs) in patients with hypercholesterolemia and on in-vitro EPCs of healthy volunteers.In the clinical study,we randomly divided 24 subjects with hypercholesterolemia into two groups(the control group and the Danshen-treated group).At the end of two weeks of treatment,the EPC cellular functions of both groups were tested.The results indicated that,compared to the control group,EPCs in the Danshen-treated group showed significantly better cellular functions,which was manifested in the cloning number,the proliferation capacity,the number of EPC adhesions,and cell migration.In the subsequent in-vitro experiments,EPCs were treated with vehicle,oxidized low-density lipoprotein(Ox-LDL,100 μg/ml),or Ox-LDL(100 μg/ml) plus different concentrations of Danshen(Danshensu 2,10,or 50 μg/ml,respectively) for 24 h.The results showed that Danshen treatments can prevent the detrimental effects of Ox-LDL on EPC cellular functions measured by proliferation capacity(0.24±0.08,0.37±0.11,0.30±0.04 vs.0.13±0.02,P<0.05,P<0.01,and P<0.01,respectively),and adhesion ability(63.00±11.60,70.00±10.80,85.50±11.41 vs.40.50±6.85,all P<0.01).Compared to the group treated with Ox-LDL alone,Danshen treatment significantly decreased the lipid peroxidation end product malondialdehyde(MDA) [(4.34±0.54),(3.98±0.47),(3.46±0.31) vs.(5.57±0.64) nmol/ml,all P<0.01],increased the production of superoxide dismutase(SOD) [(29.74±0.71),(31.09±0.83),(30.41±0.65) vs.(14.76±3.99) U/ml,all P<0.01],and lowered the expression of interleukin-6(IL-6) [(24.62±7.69),(27.04±3.14),(33.38±18.86) vs.(230.67±33.53) pg/ml,all P<0.01] and tumor necrosis factor-α(TNF-α) [(41.72±6.10),(17.02±6.82),(3.73±2.26) vs.(228.71±41.53) pg/ml,all P<0.01] in Ox-LDL treated EPCs.These results suggest that Danshen may exert a protective effect through its antioxidant and anti-inflammatory features.展开更多
Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed(HD) and post-renal transplant(Tx) patients are proatherogenic,but elevated concentrations of plasma high-density lipoprotein(...Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed(HD) and post-renal transplant(Tx) patients are proatherogenic,but elevated concentrations of plasma high-density lipoprotein(HDL) reduce the risk of cardiovascular disease.We investigated the concentrations of lipid,lipoprotein,HDL particle,oxidized low-density lipoprotein(ox-LDL) and anti-ox-LDL,and paraoxonase-1(PON-1) activity in HD(n=33) and Tx(n=71) patients who were non-smokers without active inflammatory disease,liver disease,diabetes,or malignancy.HD patients had moderate hypertriglyceridemia,normocholesterolemia,low HDL-C,apolipoprotein A-I(apoA-I) and HDL particle concentrations as well as PON-1 activity,and increased ox-LDL and anti-ox-LDL levels.Tx patients had hypertriglyceridemia,hypercholesterolemia,moderately decreased HDL-C and HDL particle concentrations and PON-1 activity,and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference,but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients.However,in both patient groups,lipid and lipoprotein ratios(total cholesterol(TC)/HDL-C,LDL-C/HDL-C,triglyceride(TG)/HDL-C,HDL-C/non-HDL-C,apoA-I/apoB,HDL-C/apoA-I,TG/HDL) were atherogenic.The Spearman's rank coefficient test showed that the con-centration of ox-LDL correlated positively with HDL particle level(R=0.363,P=0.004),and negatively with TC(R=?0.306,P=0.012),LDL-C(R=?0.283,P=0.020),and non-HDL-C(R=?0.263,P=0.030) levels in Tx patients.Mul-tiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration,as an independent variable,was associated significantly positively with HDL particle level.The results indicated that ox-LDL and de-creased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs,which are less stable,easily un-dergo metabolic remodeling,generate a greater number of smaller pre-β-HDL particles,and thus accelerate reverse cholesterol transport,which may be beneficial for Tx patients.Further studies are necessary to confirm this.展开更多
Objective:To investigate the role of aqueous extracts of Tribulus terrestris(TT) against oxidized low-density lipoprotein(ox-LDL)-induced human umbilical vein endothelial cells(HUVECs) dysfunction in vitro.Methods:HUV...Objective:To investigate the role of aqueous extracts of Tribulus terrestris(TT) against oxidized low-density lipoprotein(ox-LDL)-induced human umbilical vein endothelial cells(HUVECs) dysfunction in vitro.Methods:HUVECs were pre-incubated for 60 min with TT(30 and 3 μg/mL respectively) or 10^(-5) mol/L valsartan(as positive controls) and then the injured endothelium model was established by applying 100 μg/mL ox-LDL for 24 h.Cell viability of HUVECs was observed by real-time cell electronic sensing assay and apoptosis rate by Annexin V/PI staining.The cell migration assay was performed with a transwell insert system.Cytoskeleton remodeling was observed by immunofluorescence assay.The content of endothelial nitric oxide synthase(eNOS) was measured by enzyme-linked immunosorbent assay.Intracellular reactive oxygen species(ROS) generation was assessed by immunofluorescence and flow cytometer.Key genes associated with the metabolism of ox-LDL were chosen for quantitative real-time polymerase chain reaction to explore the possible mechanism of TT against oxidized LDL-induced endothelial dysfunction.Results:TT suppressed ox-LDL-induced HUVEC proliferation and apoptosis rates significantly(41.1%and 43.5%after treatment for 3 and 38 h,respectively;P<0.05).It also prolonged the HUVEC survival time and postponed the cell's decaying stage(from the 69 th h to over 100 h).According to the immunofluorescence and transwell insert system assay,TT improved the endothelial cytoskeletal network,and vinculin expression and increased cell migration.Additionally,TT regulated of the synthesis of endothelial nitric oxide synthase and generation of intracellular reactive oxygen species(P<0.05).Both 30 and 3 μg/mL TT demonstrated similar efficacy to valsartan.TT normalized the increased mRNA expression of PI3Kα and Socs3.It also decreased mRNA expression of Akt1,AMPKα1,JAK2,LepR and STAT3 induced by ox-LDL.The most notable changes were JAK2,LepR,PI3 K α,Socs3 and STAT3.Conclusions:TT demonstrated potential lowering lipid benefits,anti-hypertension and endothelial protective effects.It also suggested that the JAK2/STAT3 and/or PI3K/AKT pathway might be a very important pathway which was involved in the pharmacological mechanism of TT as the vascular protective agent.展开更多
Objective:To evaluate the protective effect of propyl gallate(PG),an alkyl ester of gallic acid which is an active ingredient of Radix Paeoniae,against oxidized low-density lipoprotein(ox-LDL)-induced apoptosis and de...Objective:To evaluate the protective effect of propyl gallate(PG),an alkyl ester of gallic acid which is an active ingredient of Radix Paeoniae,against oxidized low-density lipoprotein(ox-LDL)-induced apoptosis and death in endothelial cells(ECs) and to find out its preliminary mechanism.Methods:The cultured endothelial cells were divided into normal,model(ox-LDL),control(fetal bovine serum),PG high dose(20 μg/mL),PG middle dose(10 μg/mL),and PG low dose(5 μg/mL) groups,each derived from three different pools of umbilical cords.The model of injured human umbilical vein endothelial cells(HUVECs)was induced by ox-LDL.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide(MTT) assay,Hoechst 33258 staining,flow cytometry and measurement of nitrogen monoxidum(NO) release were used to evaluate the protective effect of PG against ox-LDL-induced apoptosis and death in HUVECs.To find out the mechanism of this protective effect,the expression of endothelial nitric oxide synthase(eNOS) mRNA,eNOS protein expression,immunofluorescence of intracellular reactive oxygen species(ROS) and activities of malondialdehyde(MDA),superoxidedismutase(SOD) and glutathione peroxidase(GPx) were observed.Results:PG significantly reduced ox-LDL-induced apoptosis and cell death.The percentage of cells death and apoptosis was significantly higher in the ox-LDL group than that in the control group(P<0.05).Compared with the control group,the cells death and apoptosis of PG group was no different(P>0.05).As compared with the ox-LDL group,results of the PG high dose group showed that cell viability was significantly increased(P<0.05),the level of NO release,expression of eNOS mRNA,densitometric value of eNOS protein expression,as well as the activities of SOD and GPx were all significantly higher(all P<0.05).Conclusion:PG could potentially serve as a novel endothelial protective agent against ox-LDL-induced injury of endothelial cell.展开更多
Objective Increased transcytosis of low-density lipoprotein (LDL)across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein...Objective Increased transcytosis of low-density lipoprotein (LDL)across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined.展开更多
AIM: To investigate how hepatitis C virus(HCV) G1 b infection influences the particle number of lipoproteins.METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV...AIM: To investigate how hepatitis C virus(HCV) G1 b infection influences the particle number of lipoproteins.METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1 b infection(active HCV group) and 91 with cleared HCV infection(SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using Lipo SEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1 b infection and the lipoprotein particle number was determined by multiple linear regression analysis.RESULTS: The median number of low-density lipoprotein(LDL) particles was significantly lower in the active HCV group [1182 nmol/L, interquartile range(IQR): 444 nmol/L] than in the SVR group(1363 nmol/L, IQR: 472 nmol/L, P < 0.001), as was that of highdensity lipoprotein(HDL) particles(14168 nmol/L vs 15054 nmol/L, IQR: 4114 nmol/L vs 3385 nmol/L, P = 0.042). The number of very low-density lipoprotein(VLDL) particles was similar between the two groups. Among the four LDL sub-fractions, the number of large LDL particles was similar between the two groups. However, the numbers of medium(median: 533.0 nmol/L, IQR: 214.7 nmol/L vs median: 633.5 nmol/L, IQR: 229.6 nmol/L, P < 0.001), small(median: 190.9 nmol/L, IQR: 152.4 nmol/L vs median: 263.2 nmol/L, IQR: 159.9 nmol/L; P < 0.001), and very small LDL particles(median: 103.5 nmol/L, IQR: 66.8 nmol/L vs median: 139.3 nmol/L, IQR: 67.3 nmol/L, P < 0.001) were significantly lower in the active HCV group than in the SVR group, respectively. Multiple linear regression analysis indicated an association between HCV G1 b infection and the decreased numbers of medium, small, and very small LDL particles. However, active HCV infection did not affect the number of large LDL particles or any sub-fractions of VLDL and HDL particles.CONCLUSION: HCV G1 b infection decreases the numbers of medium, small, and very small LDL particles.展开更多
Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capac...Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capacity of human peripheral blood monocytes to express MCP-1 and effects of native very low density lipoprotein (VLDL) and oxidized VLDL(OX-VLDL) on the expression. The total RNA was extracted from cultured monocytes, which were exposed to VLDL and OX-VLDL, and the media conditioned by monocytes were collected. MCP-1 mRNA expression was examined by Northern blot analysis. MCP-1 protein in conditioned media was determined by using sandwich ELISA. The results showed that monocytes can express MCP-1 after a 24 h incubation at 37℃，and the expression was markedly increased by a exposure to OX-VLDL, whereas the expression was slightly increased when exposed to VLDL. It suggests that the capacity of monocytes to produce MCP-1 that recruits and activates circulating monocytes may be of considerable importance in atherogenesis, and oxidation of VLDL enhances its potential to promote atherogenesis.展开更多
BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modif...BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.展开更多
Lipoprotein(a) [Lp(a)] is composed of a low density lipoprotein(LDL)-like particle to which apolipoprotein(a)[apo(a)] is linked by a single disulfide bridge. Lp(a) is considered a causal risk factor for ischemic cardi...Lipoprotein(a) [Lp(a)] is composed of a low density lipoprotein(LDL)-like particle to which apolipoprotein(a)[apo(a)] is linked by a single disulfide bridge. Lp(a) is considered a causal risk factor for ischemic cardiovascular disease(CVD) and calcific aortic valve stenosis(CAVS). The evidence for a causal role of Lp(a) in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp(a) as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp(a) functionality may be played by its oxidized phospholipids(OxPL) content. Importantly, most of circulating OxPL are associated with Lp(a); however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp(a) over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp(a) is primarily driven by its OxPL content.An important role in Lp(a) functionality may be played by the lipoprotein-associated phospholipase A_2(Lp-PLA_2),an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp(a). The present review article discusses new data on the pathophysiological role of Lp(a) and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp(a).展开更多
Aim:The oxidized low-density lipoprotein(OxLDL) plays an important role in atherosclerosis yet it remains unclear if it damages circulating erythrocytes. Method: In this study。
The effects of oxidized low density lipoprotein (ox-LDL) on the proliferation of cultured human vascular smooth muscle cells (vSMC) were investigated in vitro. By using NaBr density gra-dient centrifugation, LDL was i...The effects of oxidized low density lipoprotein (ox-LDL) on the proliferation of cultured human vascular smooth muscle cells (vSMC) were investigated in vitro. By using NaBr density gra-dient centrifugation, LDL was isolated and purified from human plasma. Ox-LDL was produced from LDL by being incubated with CuSO4. ox-LDL was then added to the culture medium at different concentrations (35, 60, 85, 110, 135 and 160 μg/mL) for 7 days. The influence of ox-LDL on vSMC proliferation was observed in growth curve, mitosis index, and in situ determination of apoptosis. The data were analyzed with SPSS 10.0 software. The results showed that the ox-LDL produced in vitro had a good purity and optimal oxidative degree, which was similar to the intrinsic ox-LDL in athero-sclerotic plaque. ox-LDL at a concentration of 35 μg/mL demonstrated the strongest proliferation in-ducement, and at a concentration of 135 μg/mL, ox-LDL could inhibit the growth of vSMC. ox-LDL at concentrations of 35 and 50 μg/mL presented powerful mitotic trigger, and with the increase of ox-LDL concentration, the mitotic index of vSMC was decreased gradually. ox-LDL at higher con-centrations promoted more apoptotic vSMCs. ox-LDL at lower concentrations triggered proliferation of vSMCs, and at higher concentrations induced apoptosis in vSMCs. ox-LDL played a promotional role in the pathogenesis and development of atherosclerosis by affecting vSMC proliferation and apoptosis.展开更多
基金State Key Clinical Specialty Construction Project,China
文摘Objective PERK/eI F2α/CHOP is a major signaling pathway mediating endoplasmic reticulum(ER) stress related with atherosclerosis.Oxidized LDL(ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis.The present study was conducted to explore the regulatory effect of ox-LDL on PERK/e IF2α/CHOP signaling pathway in vascular endothelial cells.Methods The effects of ox-LDL on PERK and p-e IF2α protein expression of primary human umbilical vein endothelial cells(HUVECs) were investigated by Western blot analysis.PERK gene silencing and selective eI F2α phosphatase inhibitor,salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis,caspase-3 activity,and CHOP mR NA level.Results Ox-LDL treatment significantly increased the expression of PERK,PERK-mediated inactivation of e IF2α phosphorylation,and the expression of CHOP,as well as the caspase-3 activity and apoptosis.The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral sh RNA or by selective eI F2α phosphatase inhibitor,salubrinal.Conclusion This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eI F2α/CHOP ER-stress pathway.It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis.
基金supported by the National Natural Science Foundation of China,No.81971125(to ZYH).
文摘Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.
基金Supported by the National Natural Science Foundation of China (No.81470654)Science and Technology Plan of Natural Science Foundation of Shaanxi Province (No.2019SF-047)。
文摘AIM: To investigate whether intravitreal injection of oxidized low-density lipoprotein(OxLDL) can promote laserinduced choroidal neovascularization(CNV) formation in mice and the mechanism involved, thereby to develop a better animal model.METHODS: C57BL6/J mice were randomized into three groups. Immediately after CNV induction with 532 nm laser photocoagulation, 1.0 μL of OxLDL [100 μg/m L in phosphate-buffered saline(PBS)] was intravitreally injected, whereas PBS and the same volume low-density lipoprotein(LDL;100 μg/m L in PBS) were injected into the vitreous as controls. Angiogenic and inflammatory cytokines were measured by quantitative real-time polymerase chain reaction(q RT-PCR) and Western blotting(WB) after 5 d, and CNV severity was analyzed by choroid flat mount and immunofluorescence staining after 1wk. In vitro, retinal pigment epithelial(RPE) cell line(ARPE19) were treated with OxLDL(LDL as control) for 8 h. Angiogenic and inflammatory cytokine levels were measured. A specific inhibitor of lectin-like oxidized low-density lipoprotein receptor 1(LOX1) was used to evaluate the role of LOX1 in this process.RESULTS: At 7 d after intravitreal injection of 1 μL(100 μg/mL) OxLDL, T15-labeled OxLDL was mainly deposited around the CNV area, and the F4/80-labeled macrophages, the CD31-labeled vascular endothelial cells number and CNV area were increased. Meanwhile, WB and qR T-PCR results showed that vascular endothelial growth factor(VEGF), CC chemokine receptor 2(CCR2), interleukin-6(IL-6), IL-1β, and matrix metalloproteinase 9(MMP9) expressions were increased, which was supported by in vitro experiments in RPE cells. LOX1 inhibitors significantly reduced expressions of inflammatory factors IL-1β and VEGF. CONCLUSION: A modified laser-induced CNV animal model is established with intravitreal injection of 1 μL(100 μg/mL) of OxLDL at 7 d, which at least partially through LOX1. This animal model can be used as a simple model for studying the role of OxLDL in age-related macular degeneration.
文摘BACKGROUND Oxidized low-density lipoprotein(ox-LDL),which is abnormally increased in the serum of colorectal cancer(CRC)patients consuming a high-fat diet(HFD),may be one of the risk factors for the development of CRC.Ox-LDL exerts a regulatory effect on macrophages and may influence CRC through the tumor microenvironment.The role of ox-LDL in CRC remains unclear.AIM To investigate the role of ox-LDL through macrophages in HFD associated CRC.METHODS The expression of ox-LDL and CD206 was detected in colorectal tissues of CRC patients with hyperlipidemia and HFD-fed mice by immunofluorescence.We stimulated the macrophages with 20μg/mL ox-LDL and assessed the expression levels of CD206 and the cytokines by cell fluorescence and quantitative polymerase chain reaction.We further knocked down LOX-1,the surface receptor of ox-LDL,to confirm the function of ox-LDL in macrophages.Then,LoVo cells were co-cultured with the stimulated macrophages to analyze the CD44 and CD133 expression by western blot.RESULTS The expression of ox-LDL and the CD206 was significantly increased in the stroma of colorectal tissues of CRC patients with hyperlipidemia,and also upregulated in the HFD-fed mice.Moreover,an increased level of CD206 and decreased level of inducible nitric oxide synthase were observed in macrophages after ox-LDL continuous stimulation.Such effects were inhibited when the surface receptor LOX-1 was knocked down in macrophages.Ox-LDL could induce CD206+macrophages,which resulted in high expression of CD44 and CD133 in co-cultured LoVo cells.CONCLUSION Ox-LDL stimulates CD206+macrophages to upregulate CD44 and CD133 expression in HFD related CRC.
基金This work was supported,in part,by Capital Special Foundation of Clinical Application Research(No.Z121107001012015)Capital Health Development Fund(No.201614035)+1 种基金CAMS Major Collaborative Innovation Project(No.2016-I2M-1-011)PUMC Youth Fund(No.3332018200).
文摘It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein(LDL)cholesterol(LDL-C),but its impact on lipoprotein subfractions and oxidized low-density lipoprotein(oxLDL)has not been determined.The aim of the present study was to investigate the potential effects of pitavastatin on subfractions of LDL and high-density lipoprotein(HDL)as well as oxLDL in untreated patients with coronary atherosclerosis(AS).Thirty-six subjects were enrolled in this study.O f them,18 patients with AS were administered pitavastatin 2 mg/day for 8 weeks and 18 healthy subjects without therapy served as controls.The plasma lipid profile,lipoprotein subfractions and circulating oxLDL were determined at baseline and 8 weeks respectively.The results showed that pitavastatin treatment indeed not only decreased LDL-C,total cholesterol(TC),triglycerides(TG)and apolipoprotein B(ApoB)levels,and increased HDL cholesterol(HDL-C),but also reduced the cholesterol concentration of all of the LDL subfractions and the percentage of intermediate and small LDL subfractions.Meanwhile,pitavastatin could decrease plasma oxLDL levels.Furthermore,a more close correlation was found between oxLDL and LDL-C as well as LDL subfractions after pitavastatin treatment.We concluded that a moderate dose of pitavastatin therapy not only decreases LDL-C and oxLDL concentrations but also improves LDL subfractions in patients with AS.
文摘Background:Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis.Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promoting oxidative metabolism attenuated atherosclerosis progression.Therefore,this study aimed to investigate whether metformin,which has ameliorated atherosclerosis in animal models and clinical trials,modulated oxidized low-density lipoprotein (Ox-LDL) induced inflammatory status in macrophages by regulating cellular oxidative metabolism.Methods:Murine raw264.7 macrophages were incubated with Ox-LDL (50 μg/mL) in the presence or absence of metformin (15 μmol/L) for 24 h.Real-time polymerase chain reaction was used to quantify the transcription of classically activated (M1) proinflammatory and alternatively activated (M2) anti-inflammatory markers and mitochondrial DNA copy numbers.Cellular reactive oxygen species (ROS) production and mitochondrial membrane potential were detected by immunofluorescence.Cellular adenosine triphosphate (ATP) synthesis,glucose uptake,and lactic acid production were measured by commercial kit and normalized to cellular lysates.Western blotting analysis was performed to detect the expression of mitochondrial fusion/fission related proteins,enzymes mediating lipid metabolism and signaling pathway of glucose transport.Differences between groups were analyzed using one-way analysis of variance.Results:Metformin improved Ox-LDL-impaired anti-inflammatory phenotype in raw264.7 macrophages as shown by up-regulated transcription of anti-inflammatory markers including interleukin 10 (0.76 ± 0.04 vs.0.94 ± 0.01,P =0.003) and Resistin-like molecule alpha (0.67 ± 0.08 vs.1.78 ± 0.34,P =0.030).Conversely,Ox-LDL-diminished phosphorylation of Akt was up regulated by metformin treatment (0.47 ± 0.05 vs.1.02 ± 0.08,P =0.040),associated with an improvement of mitochondrial function,characterized by decreased ROS generation (2.50 ± 0.07 vs.2.15 ± 0.04,P =0.040),increased lipid oxidation,and elevated cellular ATP production (0.026 ± 0.001 vs.0.035 ± 0.003,P =0.020).Moreover,metformin-mediated Akt activation increased Akt substrate of 160 kDa (AS160) phosphorylation (0.51 ± 0.04 vs.1.03 ± 0.03,P =0.0041),promoted membrane translocation of glucose transporter 1,and increased glucose influx into the cells (4.78 ± 0.04 vs.5.47 ± 0.01,P < 0.001).Contusion:This study suggested that targeting macrophage metabolism with new or existing drugs had therapeutic potential for the prevention and treatment of diabetes-accelerated atherosclerosis.
基金Project (No.2007A142) supported by the Health Department of Zhejiang Province,China
文摘In this study,we examined the protective effects of Danshen both on endothelial progenitor cells(EPCs) in patients with hypercholesterolemia and on in-vitro EPCs of healthy volunteers.In the clinical study,we randomly divided 24 subjects with hypercholesterolemia into two groups(the control group and the Danshen-treated group).At the end of two weeks of treatment,the EPC cellular functions of both groups were tested.The results indicated that,compared to the control group,EPCs in the Danshen-treated group showed significantly better cellular functions,which was manifested in the cloning number,the proliferation capacity,the number of EPC adhesions,and cell migration.In the subsequent in-vitro experiments,EPCs were treated with vehicle,oxidized low-density lipoprotein(Ox-LDL,100 μg/ml),or Ox-LDL(100 μg/ml) plus different concentrations of Danshen(Danshensu 2,10,or 50 μg/ml,respectively) for 24 h.The results showed that Danshen treatments can prevent the detrimental effects of Ox-LDL on EPC cellular functions measured by proliferation capacity(0.24±0.08,0.37±0.11,0.30±0.04 vs.0.13±0.02,P<0.05,P<0.01,and P<0.01,respectively),and adhesion ability(63.00±11.60,70.00±10.80,85.50±11.41 vs.40.50±6.85,all P<0.01).Compared to the group treated with Ox-LDL alone,Danshen treatment significantly decreased the lipid peroxidation end product malondialdehyde(MDA) [(4.34±0.54),(3.98±0.47),(3.46±0.31) vs.(5.57±0.64) nmol/ml,all P<0.01],increased the production of superoxide dismutase(SOD) [(29.74±0.71),(31.09±0.83),(30.41±0.65) vs.(14.76±3.99) U/ml,all P<0.01],and lowered the expression of interleukin-6(IL-6) [(24.62±7.69),(27.04±3.14),(33.38±18.86) vs.(230.67±33.53) pg/ml,all P<0.01] and tumor necrosis factor-α(TNF-α) [(41.72±6.10),(17.02±6.82),(3.73±2.26) vs.(228.71±41.53) pg/ml,all P<0.01] in Ox-LDL treated EPCs.These results suggest that Danshen may exert a protective effect through its antioxidant and anti-inflammatory features.
基金Project(Nos.PW 55/09 and DS 41/10) supported by the Department of Laboratory Diagnostics,Medical University of Lublin,Poland
文摘Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed(HD) and post-renal transplant(Tx) patients are proatherogenic,but elevated concentrations of plasma high-density lipoprotein(HDL) reduce the risk of cardiovascular disease.We investigated the concentrations of lipid,lipoprotein,HDL particle,oxidized low-density lipoprotein(ox-LDL) and anti-ox-LDL,and paraoxonase-1(PON-1) activity in HD(n=33) and Tx(n=71) patients who were non-smokers without active inflammatory disease,liver disease,diabetes,or malignancy.HD patients had moderate hypertriglyceridemia,normocholesterolemia,low HDL-C,apolipoprotein A-I(apoA-I) and HDL particle concentrations as well as PON-1 activity,and increased ox-LDL and anti-ox-LDL levels.Tx patients had hypertriglyceridemia,hypercholesterolemia,moderately decreased HDL-C and HDL particle concentrations and PON-1 activity,and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference,but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients.However,in both patient groups,lipid and lipoprotein ratios(total cholesterol(TC)/HDL-C,LDL-C/HDL-C,triglyceride(TG)/HDL-C,HDL-C/non-HDL-C,apoA-I/apoB,HDL-C/apoA-I,TG/HDL) were atherogenic.The Spearman's rank coefficient test showed that the con-centration of ox-LDL correlated positively with HDL particle level(R=0.363,P=0.004),and negatively with TC(R=?0.306,P=0.012),LDL-C(R=?0.283,P=0.020),and non-HDL-C(R=?0.263,P=0.030) levels in Tx patients.Mul-tiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration,as an independent variable,was associated significantly positively with HDL particle level.The results indicated that ox-LDL and de-creased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs,which are less stable,easily un-dergo metabolic remodeling,generate a greater number of smaller pre-β-HDL particles,and thus accelerate reverse cholesterol transport,which may be beneficial for Tx patients.Further studies are necessary to confirm this.
基金Supported by the Development Plan Project of Science and Technology of Shandong Province(No.2014GSF119011)Shandong Province'Taishan Scholar'Construction Project(No.2012-55)
文摘Objective:To investigate the role of aqueous extracts of Tribulus terrestris(TT) against oxidized low-density lipoprotein(ox-LDL)-induced human umbilical vein endothelial cells(HUVECs) dysfunction in vitro.Methods:HUVECs were pre-incubated for 60 min with TT(30 and 3 μg/mL respectively) or 10^(-5) mol/L valsartan(as positive controls) and then the injured endothelium model was established by applying 100 μg/mL ox-LDL for 24 h.Cell viability of HUVECs was observed by real-time cell electronic sensing assay and apoptosis rate by Annexin V/PI staining.The cell migration assay was performed with a transwell insert system.Cytoskeleton remodeling was observed by immunofluorescence assay.The content of endothelial nitric oxide synthase(eNOS) was measured by enzyme-linked immunosorbent assay.Intracellular reactive oxygen species(ROS) generation was assessed by immunofluorescence and flow cytometer.Key genes associated with the metabolism of ox-LDL were chosen for quantitative real-time polymerase chain reaction to explore the possible mechanism of TT against oxidized LDL-induced endothelial dysfunction.Results:TT suppressed ox-LDL-induced HUVEC proliferation and apoptosis rates significantly(41.1%and 43.5%after treatment for 3 and 38 h,respectively;P<0.05).It also prolonged the HUVEC survival time and postponed the cell's decaying stage(from the 69 th h to over 100 h).According to the immunofluorescence and transwell insert system assay,TT improved the endothelial cytoskeletal network,and vinculin expression and increased cell migration.Additionally,TT regulated of the synthesis of endothelial nitric oxide synthase and generation of intracellular reactive oxygen species(P<0.05).Both 30 and 3 μg/mL TT demonstrated similar efficacy to valsartan.TT normalized the increased mRNA expression of PI3Kα and Socs3.It also decreased mRNA expression of Akt1,AMPKα1,JAK2,LepR and STAT3 induced by ox-LDL.The most notable changes were JAK2,LepR,PI3 K α,Socs3 and STAT3.Conclusions:TT demonstrated potential lowering lipid benefits,anti-hypertension and endothelial protective effects.It also suggested that the JAK2/STAT3 and/or PI3K/AKT pathway might be a very important pathway which was involved in the pharmacological mechanism of TT as the vascular protective agent.
文摘Objective:To evaluate the protective effect of propyl gallate(PG),an alkyl ester of gallic acid which is an active ingredient of Radix Paeoniae,against oxidized low-density lipoprotein(ox-LDL)-induced apoptosis and death in endothelial cells(ECs) and to find out its preliminary mechanism.Methods:The cultured endothelial cells were divided into normal,model(ox-LDL),control(fetal bovine serum),PG high dose(20 μg/mL),PG middle dose(10 μg/mL),and PG low dose(5 μg/mL) groups,each derived from three different pools of umbilical cords.The model of injured human umbilical vein endothelial cells(HUVECs)was induced by ox-LDL.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide(MTT) assay,Hoechst 33258 staining,flow cytometry and measurement of nitrogen monoxidum(NO) release were used to evaluate the protective effect of PG against ox-LDL-induced apoptosis and death in HUVECs.To find out the mechanism of this protective effect,the expression of endothelial nitric oxide synthase(eNOS) mRNA,eNOS protein expression,immunofluorescence of intracellular reactive oxygen species(ROS) and activities of malondialdehyde(MDA),superoxidedismutase(SOD) and glutathione peroxidase(GPx) were observed.Results:PG significantly reduced ox-LDL-induced apoptosis and cell death.The percentage of cells death and apoptosis was significantly higher in the ox-LDL group than that in the control group(P<0.05).Compared with the control group,the cells death and apoptosis of PG group was no different(P>0.05).As compared with the ox-LDL group,results of the PG high dose group showed that cell viability was significantly increased(P<0.05),the level of NO release,expression of eNOS mRNA,densitometric value of eNOS protein expression,as well as the activities of SOD and GPx were all significantly higher(all P<0.05).Conclusion:PG could potentially serve as a novel endothelial protective agent against ox-LDL-induced injury of endothelial cell.
文摘Objective Increased transcytosis of low-density lipoprotein (LDL)across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined.
文摘AIM: To investigate how hepatitis C virus(HCV) G1 b infection influences the particle number of lipoproteins.METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1 b infection(active HCV group) and 91 with cleared HCV infection(SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using Lipo SEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1 b infection and the lipoprotein particle number was determined by multiple linear regression analysis.RESULTS: The median number of low-density lipoprotein(LDL) particles was significantly lower in the active HCV group [1182 nmol/L, interquartile range(IQR): 444 nmol/L] than in the SVR group(1363 nmol/L, IQR: 472 nmol/L, P < 0.001), as was that of highdensity lipoprotein(HDL) particles(14168 nmol/L vs 15054 nmol/L, IQR: 4114 nmol/L vs 3385 nmol/L, P = 0.042). The number of very low-density lipoprotein(VLDL) particles was similar between the two groups. Among the four LDL sub-fractions, the number of large LDL particles was similar between the two groups. However, the numbers of medium(median: 533.0 nmol/L, IQR: 214.7 nmol/L vs median: 633.5 nmol/L, IQR: 229.6 nmol/L, P < 0.001), small(median: 190.9 nmol/L, IQR: 152.4 nmol/L vs median: 263.2 nmol/L, IQR: 159.9 nmol/L; P < 0.001), and very small LDL particles(median: 103.5 nmol/L, IQR: 66.8 nmol/L vs median: 139.3 nmol/L, IQR: 67.3 nmol/L, P < 0.001) were significantly lower in the active HCV group than in the SVR group, respectively. Multiple linear regression analysis indicated an association between HCV G1 b infection and the decreased numbers of medium, small, and very small LDL particles. However, active HCV infection did not affect the number of large LDL particles or any sub-fractions of VLDL and HDL particles.CONCLUSION: HCV G1 b infection decreases the numbers of medium, small, and very small LDL particles.
文摘Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capacity of human peripheral blood monocytes to express MCP-1 and effects of native very low density lipoprotein (VLDL) and oxidized VLDL(OX-VLDL) on the expression. The total RNA was extracted from cultured monocytes, which were exposed to VLDL and OX-VLDL, and the media conditioned by monocytes were collected. MCP-1 mRNA expression was examined by Northern blot analysis. MCP-1 protein in conditioned media was determined by using sandwich ELISA. The results showed that monocytes can express MCP-1 after a 24 h incubation at 37℃，and the expression was markedly increased by a exposure to OX-VLDL, whereas the expression was slightly increased when exposed to VLDL. It suggests that the capacity of monocytes to produce MCP-1 that recruits and activates circulating monocytes may be of considerable importance in atherogenesis, and oxidation of VLDL enhances its potential to promote atherogenesis.
基金Supported by Programa para el Desarrollo Profesional Docente(PRODEP)to Gonzalez-Aldaco K,No.UDG-PTC-1422Consejo Nacional de Ciencia y Tecnología(CONACYT)to Panduro A,No.2017-01-5254
文摘BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.
文摘Lipoprotein(a) [Lp(a)] is composed of a low density lipoprotein(LDL)-like particle to which apolipoprotein(a)[apo(a)] is linked by a single disulfide bridge. Lp(a) is considered a causal risk factor for ischemic cardiovascular disease(CVD) and calcific aortic valve stenosis(CAVS). The evidence for a causal role of Lp(a) in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp(a) as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp(a) functionality may be played by its oxidized phospholipids(OxPL) content. Importantly, most of circulating OxPL are associated with Lp(a); however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp(a) over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp(a) is primarily driven by its OxPL content.An important role in Lp(a) functionality may be played by the lipoprotein-associated phospholipase A_2(Lp-PLA_2),an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp(a). The present review article discusses new data on the pathophysiological role of Lp(a) and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp(a).
基金supported by National Natural Science Foundation of China(NSFC10572159)supported by "111 Project" entitled "Biomechanics&Tissue Repair Engineering"(No.:B06023)Chongqing Science&Technology Council(CSTC 2006ba5010)
文摘Aim:The oxidized low-density lipoprotein(OxLDL) plays an important role in atherosclerosis yet it remains unclear if it damages circulating erythrocytes. Method: In this study。
基金This project was supported by a grant from Provincial Outstanding Youth Program for Henan Province Committee of Sciences and Technology (No. 19972002).
文摘The effects of oxidized low density lipoprotein (ox-LDL) on the proliferation of cultured human vascular smooth muscle cells (vSMC) were investigated in vitro. By using NaBr density gra-dient centrifugation, LDL was isolated and purified from human plasma. Ox-LDL was produced from LDL by being incubated with CuSO4. ox-LDL was then added to the culture medium at different concentrations (35, 60, 85, 110, 135 and 160 μg/mL) for 7 days. The influence of ox-LDL on vSMC proliferation was observed in growth curve, mitosis index, and in situ determination of apoptosis. The data were analyzed with SPSS 10.0 software. The results showed that the ox-LDL produced in vitro had a good purity and optimal oxidative degree, which was similar to the intrinsic ox-LDL in athero-sclerotic plaque. ox-LDL at a concentration of 35 μg/mL demonstrated the strongest proliferation in-ducement, and at a concentration of 135 μg/mL, ox-LDL could inhibit the growth of vSMC. ox-LDL at concentrations of 35 and 50 μg/mL presented powerful mitotic trigger, and with the increase of ox-LDL concentration, the mitotic index of vSMC was decreased gradually. ox-LDL at higher con-centrations promoted more apoptotic vSMCs. ox-LDL at lower concentrations triggered proliferation of vSMCs, and at higher concentrations induced apoptosis in vSMCs. ox-LDL played a promotional role in the pathogenesis and development of atherosclerosis by affecting vSMC proliferation and apoptosis.
