Hepatitis C virus clearance and less liver damage in patients with high cholesterol, low-density lipoprotein cholesterol and APOE ε4 allele

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.

Intensive lipid-lowering therapy,time to think beyond low-density lipoprotein cholesterol

Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

The rate of patients at high risk for cardiovascular disease with an optimal low-density cholesterol level: a multicenter study from Thailand

Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investigate the rate of optimal low-density lipoprotein (LDL) cholesterol level in a multicenter registry of patients at high risk for cardiovascular events. Methods A multicenter registry of EAD and MRF patients was conducted. Demographic data,medical history,cardiovascular risk factors,anthropometric data,laboratory data,and medications were recorded and analyzed. We classified patients according to target LDL levels based on recommendation by the European Society of Cardiology (ESC) 2011 into Group 1 which is EAD and diabetes or chronic kidney disease (CKD)–target LDL below 70 mg/dL,and Group 2 which is MRF without diabetes or CKD–target LDL below 100 mg/dL. The rate of optimal LDL level in patients with Group 1 and Group 2 was analyzed and stratified according to the treatment pattern of lipid-lowering medications. Results A total of 3100 patients were included. Of those,51.7% were male. Average age was 65.8 ± 9.7 years. Average LDL level was 96.3 ± 32.6 mg/dL. A vast majority (92.7%) received statin and 9.3% received ezetimibe. Optimal LDL level was achieved in 20.3% of patients in Group 1 (LDL < 70 mg/dL),and in 46.6% in Group 2 (LDL < 100 mg/dL). The overall rate of optimal LDL control was 23% since 89.6% of study population belongs to Group 1. The rate of optimal LDL was not different between high and low potency statin. Factors that were associated with optimal LDL control were older age,the presence of coronary artery disease or peripheral artery disease. Conclusions The rates of optimal LDL level were unacceptably low in this study population. As such,a strategy to improve LDL control in high-risk population should be implemented.

Editorial on hemoglobin A1c, blood pressure, and lowdensity lipoprotein cholesterol goals in diabetics

The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considered in adults with short duration of diabetes, long life expectancy, and no significant cardiovascular disease if this can be achieved without significant hypoglycemia or other adverse effects of treatment. A hemoglobin A1c level less than 8.0% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced macrovascular and microvascular complications, extensive comorbidities, and long-standing diabetes in whom the hemoglobin A1c goal is difficult to attain despite multiple glucoselowering drugs including insulin. The ADA 2013 guidelines recommend that the systolic blood pressure in most diabetics with hypertension should be reduced to less than 140 mmHg. These guidelines also recommend use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the treatment of hypertension in diabetics unless they are pregnant. Diabetics at high risk for cardiovascular events should have theirserum low-density lipoprotein (LDL) cholesterol lowered to less than 70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dL. Combination therapy of a statin with either a fibrate or niacin has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not recommended. Hypertriglyceridemia should be treated with dietary and lifestyle changes. Severe hypertriglyceridemia should be treated with drug therapy to reduce the risk of acute pancreatitis.

Lower Baseline LDL Cholesterol Affects All-cause Mortality in Patients with First Percutaneous Coronary Intervention

Objective Foreign studies have reported that coronary artery disease(CAD) patients with high baseline low-density lipoprotein cholesterol(LDL-C) may have a good prognosis, which is called the “cholesterol paradox”. This study aimed to examine whether the “cholesterol paradox” also exists in the Chinese population.Methods A total of 2,056 patients who underwent the first percutaneous coronary intervention(PCI)between 2014 and 2016 were enrolled in this retrospective cohort study and classified into two groups based on baseline LDL-C = 2.6 mmol/L(100 mg/d L). The outcomes of interest included major adverse cardiovascular events(MACE), all-cause mortality, recurrent nonfatal myocardial infarction, unexpected coronary revascularization, or any nonfatal stroke.Results All-cause mortality occurred in 8 patients(0.7%) from the low-LDL-C group and 12 patients(2.4%) in the high-LDL-C group, with a significant difference between the two groups(adjusted hazard ratio: 4.030, 95% confidence interval: 1.088–14.934;P = 0.037). However, no significant differences existed for the risk of MACE or other secondary endpoints, such as unexpected revascularization, nor any nonfatal stroke in the two groups.Conclusion In this study, a high baseline LDL-C was not associated with a low risk of clinical outcomes in CAD patients undergoing first PCI, which suggested that the “cholesterol paradox” may be inapplicable to Chinese populations.

Lipoprotein(a)and Benefit of PCSK9 Inhibition in Emergency Complex Higher-risk and Indicated Patients

Objective There is a large population of patients classified as complex higher-risk and indicated patients(CHIPs)in China with a poor prognosis.The treatment of these patients is complex and challenging,especially when acute cardiac events occur,such as acute coronary syndrome(ACS)or heart failure.Pharmacotherapy and some mechanical circulatory support(MCS)therapeutic devices can provide stable hemodynamic support for CHIPs-percutaneous coronary intervention(PCI).LDL-C is an important pathogenic factor in atherosclerosis,and the target of blood lipid control.Recent studies have revealed that lipoprotein(a)[Lp(a)],which is formed when a covalent bond between apolipoprotein(a)and apolipoprotein B-100 is made,produces an LDL-like particle.This particle is an independent risk factor for the development of atherosclerosis,and is closely correlated to stent thrombosis and restenosis.Furthermore,this requires active intervention.PCSK9 inhibitors have been used in lipid-lowering treatment,and preventing atherosclerosis.The present study explores the efficacy of PCSK9 inhibitors in CHIPs-ACS,and the association between the change in Lp(a)and survival after 2 years of follow-up.Methods The present real-world,prospective control study enrolled 321 CHIPs-ACS who underwent emergency PCI from August 2019 to November 2020,and these patients were followed up for 2 years.These patients were divided into two groups:PCSK9 group(n=161)given the combined PCSK9 inhibitor(140 mg of evolocumab every 2 weeks)and statins-based therapy,and SOC group(n=160)treated with statin-based lipid-lowering therapy alone.Then,the change in lipid index was measured,and the cardiovascular(CV)event recurrence rate was evaluated after one month and 2 years.Afterwards,the contribution of serum lipid parameters,especially the Lp(a)alteration,in patients with earlier initiation of the PCSK9 inhibitor to the CV outcome was analyzed.Results The LDL-C level was significantly reduced in both groups:52.3%in the PCSK9 group and 32.3%(P<0.001)in the SOC group.It is noteworthy that the Lp(a)level decreased by 13.2%in the PCSK9 group,but increased by 30.3%in the SOC group(P<0.001).Furthermore,the number of CV events was not significantly different between the PCSK9 and SOC groups after the 2-year follow-up period.In the PCSK9 group,the Lp(a)reduction was associated with the baseline Lp(a)levels of the patients(r2=−0.315,P<0.001).Moreover,the decrease in Lp(a)contributed to the decline in CV events in patients who received ACS CHIPs-PCI,and the decrease in Lp(a)level was independent of the LDL-C level reduction.Conclusion The early initiation of PCSK9 inhibitors can significantly reduce the LDL-C and Lp(a)levels in ACS CHIPs-PCI.However,further studies are needed to confirm whether PCSK9 inhibitors can reduce the incidence of CV disease in CHIPs.

Lipoprotein in cholesterol transport: Highlights and recent insights into its structural basis and functional mechanism

Lipoproteins are protein-lipid macromolecular assemblies which are used to transport lipids in circulation and are key targets in cardiovascular disease （CVD）. The highly dynamic lipoprotein molecules are capable of adopting an array of conformations that is crucial to lipid transport along the cholesterol transport pathway, among which high-density lipopro- tein （HDL） and low-density lipoprotein （LDL） are major players in plasma cholesterol metabolism. For a more detailed illustration of cholesterol transport process, as well as the development of therapies to prevent CVD, here we review the functional mechanism and structural basis of lipoproteins in cholesterol transport, as well as their structural dynamics in the plasma lipoprotein （HDL and LDL） elevations, in order to obtain better quantitative understandings on structure-function relationship of lipoproteins. Finally, we also provide an approach for further research on the lipoprotein in cholesterol transport.

Situational Analysis of Low-density Lipoprotein Cholesterol Control and the Use of Statin Therapy in Diabetes Patients Treated in Community Hospitals in Nanjing, China

Background：Comprehensive management of diabetes should include management of its comorbid conditions,especially cardiovascular complications,which are the leading cause of morbidity and mortality among patients with diabetes.Dyslipidemia is a comorbid condition of diabetes and a risk factor for cardiovascular complications.Therefore,lipid level management is a key of managing patients with diabetes successfully.However,it is not clear that how well dyslipidemia is managed in patients with diabetes in local Chinese health-care communities.This study aimed to assess how well low-density lipoprotein cholesterol （LDL-C） was managed in Nanjing community hospitals,China.Methods：We reviewed clinical records of 7364 diabetic patients who were treated in eleven community hospitals in Nanjing from October 2005 to October 2014.Information regarding LDL-C level,cardiovascular risk factors,and use of lipid-lowering agents were collected.Results：In patients without history of cardiovascular disease （CVD）,92.1% had one or more CVD risk factors,and the most common CVD risk factor was dyslipidemia.The overall average LDL-C level was 2.80 ± 0.88 mmol/L,which was 2.62 ± 0.90 mmol/L and 2.82 ± 0.87 mmol/L in patients with and without CVD history respectively.Only 38% of all patients met the target goal and 37.3% of patients who took lipid-lowering agents met target goal.Overall,24.5% of all patients were on lipid-lowering medication,and 36.3% of patients with a CVD history and 20.9% of patients without CVD history took statins for LDL-C management.The mean statin dosage was 13.9 ± 8.9 mg.Conclusions：Only a small portion of patients achieved target LDL-C level,and the rate of using statins to control LDL-C was low.Managing LDL-C with statins in patients with diabetes should be promoted,especially in patients without a CVD history and with one or more CVD risk factors.

Linkage of the cholesterol 7α-hydroxylase gene and low-density lipoprotein cholesterol conditional on apolipoprotein E association: the National Heart, Lung, and Blood Institute Family Heart Study

Background Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7α-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. Methods Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. Results The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly.Conclusion Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases.

Lowering low-density lipoprotein cholesterol: from mechanisms to therapies

Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD).LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD.Statins,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy.Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments.Here,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C levels.The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD.Special treatments for those with little or no LDL receptor function then follow.The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein,which are recently approved and still under investigation for LDL-C lowering,respectively,are also included.Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.

Mechanisms of dysregulation of low-density lipoprotein receptor expression in HepG2 cells induced by inflammatory cytokines

Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated LDL receptor feedback regulation causing intracellular accumulation of unmodified LDL in peripheral cells. Liver is the central organ for lipid homeostasis. The aim of this study was to investigate the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms in human hepatic cell line （HepG2） cells under physiological and inflammatory conditions. Methods Intracellular total cholesterol （TC）, free cholesterol （FC） and cholesterol ester （CE） were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein （SREBP）-2 and SREBP cleavage-activating protein （SCAP） mRNA levels using real-time quantitative PCR. LDL receptor and SREBP-2 protein expression were examined by Western blotting. Confocal microscopy was used to investigate the translocation of SCAP-SREBP complex from the endoplasmic reticulum （ER） to the Golgi by dual staining with anti-human SCAP and anti-Golgin antibodies. Results LDL loading increased intracellular cholesterol level, thereby reduced LDL receptor mRNA and protein expression in HepG2 cells under physiological conditions. However, interleukin 1β （IL-1β） further increased intracellular cholesterol level in the presence of LDL by increasing both LDL receptor mRNA and protein expression in HepG2. LDL also reduced the SREBP and SCAP mRNA level under physiological conditions. Exposure to IL-1β caused over-expression of SREBP-2 and also disrupted normal distribution of SCAP-SREBP complex in HepG2 by enhancing translocation of SCAP-SREBP from the ER to the Golgi despite a high concentration of LDL in the culture medium. Conclusions IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi, thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL. This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.

PCSK9结构与功能

前蛋白转化酶枯草溶菌素9(PCSK9)基因属于前蛋白转化酶(PC)家族,由信号肽、前结构域、催化结构域和羧基末端结构域组成.大量研究发现,PCSK9能介导低密度脂蛋白受体(LDLR)降解,调节血浆LDL胆固醇(LDL-C)水平;而PCSK9的两类主要突变,功能获得型、功能缺失型可分别导致高胆固醇血症和低胆固醇血症.因而研究PCSK9对相关心血管疾病的防治有重要意义.PCSK9结构特性与其生化功能密切相关,突变致使其调节胆固醇代谢的机制更为复杂.本文旨在总结PCSK9结构与功能的分子生物学特性,并指出目前研究中存在的问题,以利对PCSK9的进一步探索.

低密度脂蛋白受体基因表达调控研究

低密度脂蛋白受体(LDLR)调节体内胆固醇的平衡是通过其启动区的固醇调节元件(SRE)感受体内胆固醇的变化,从而调控LDLR基因的表达来实现的。胆固醇调节元件结合蛋白(SREBP)、SREBP裂解蛋白(SCAP)参与这一调节。LDLR基因的表达还受到HMG-CoA还原酶抑制剂、激素、细胞生长因子等因素的影响。

Influences of blood lipids on the occurrence and prognosis of hemorrhagic transformation after acute cerebral infarction: a case-control study of 732 patients

Background: To study the influence of blood lipid levels on hemorrhagic transformation(HT) and prognosis after acute cerebral infarction(ACI).Methods: Patients with ACI within 72 h of symptoms onset between January 1 st, 2015, and December 31 st, 2016, were retrospectively analyzed. Patients were divided into group A(without HT) and group B(HT). The outcomes were assessed after 3 months of disease onset using the modified Rankin Scale(m RS). An m RS score of 0–2 points indicated excellent prognosis, and an m RS score of 3–6 points indicated poor prognosis.Results: A total of 732 patients conformed to the inclusion criteria, including 628 in group A and 104 in group B. The incidence of HT was 14.2%, and the median onset time was 2 d(interquartile range, 1–7 d). The percentages of patients with large infarct size and cortex involvement in group B were 80.8% and 79.8%, respectively, which were both significantly higher than those in group A(28.7 and 33.4%, respectively). The incidence rate of atrial fibrillation(AF) in group B was significantly higher than that in group A(39.4% vs. 13.9%, P<0.001). The adjusted multivariate analysis results showed that large infarct size, cortex involvement and AF were independent risk factors of HT, while total cholesterol(TC) was a protective factor of HT(OR=0.359, 95% CI 0.136–0.944, P=0.038). With every 1 mmol/L reduction in normal TC levels, the risk of HT increased by 64.1%. The mortality and morbidity at 3 months in group B(21.2% and 76.7%, respectively) were both significantly higher than those in group A(8.0% and 42.8%, respectively). The adjusted multivariate analysis results showed that large infarct size(OR=12.178, 95% CI 5.390–27.516, P<0.001) was an independent risk factor of long-term unfavorable outcomes, whereas low-density lipoprotein cholesterol(LDL-C) was a protective factor(OR=0.538, 95% CI 0.300–0.964, P=0.037). With every 1 mmol/L reduction in normal LDL-C levels, the risk of an unfavorable outcome increased by 46.2%. Major therapies, including intravenous recombinant human tissue plasminogen activator(r TPA), intensive lipid-lowering statins and anti-platelets, were not significantly related to either HT or long-term, post-ACI poor prognosis.Conclusions: For patients with large infarct sizes, especially those with cortex involvement, AF, or lower levels of TC, the risk of HT might increase after ACI. The risk of a long-term unfavorable outcome in these patients might increase with a reduction in LDL-C.

姜黄素下调IDOL水平促进肝细胞摄取血浆LDLC

目的明确姜黄素可通过下调低密度脂蛋白受体诱导降解蛋白(IDOL)来升高低密度脂蛋白受体(LDLR)的表达水平,从而促进肝细胞摄取低密度脂蛋白胆固醇(LDLC)。方法利用过表达IDOL和干扰IDOL慢病毒(OE/RNAi-IDOL)感染HepG2和LO2两种体外培养的肝细胞,倒置荧光显微镜观察病毒感染情况;Western blot检测IDOL及LDLR蛋白表达;油红O染色观察细胞中脂质情况;酶法检测细胞内胆固醇含量;DiI-LDL摄取实验检测肝细胞对LDLC的摄取能力;流式细胞术检测肝细胞膜LDLR分布丰度。结果与明场比较,暗场下可见胞内呈绿色荧光;与对照组比较,三种不同干扰IDOL慢病毒感染的HepG2和LO2细胞中,仅RNAi-IDOL-2的IDOL蛋白表达显著降低,且相应组的LDLR蛋白表达显著增强(P<0.01),选择为后续RNAi-IDOL组所用;相反,OE-IDOL慢病毒感染的HepG2和LO2细胞中,IDOL表达显著增高,相应组内LDLR表达减弱;以上结果表明已获得RNAi-IDOL-2及OE-IDOL慢病毒感染的HepG2和LO2细胞模型。与无药物处理的Control组相比,RNAi-IDOL-2及OEIDOL慢病毒感染的肝细胞内经25μmol/L姜黄素处理24 h后,油红O染色及胆固醇含量测定结果显示:细胞内脂滴含量和相对胆固醇含量均显著增加(P<0.01);且DiI-LDL摄取及免疫流式细胞结果显示:肝细胞摄取LDLC的能力增强(P<0.01);肝细胞膜表面LDLR分布丰度增多(P<0.01);以上结果与阳性药物对照组的结果趋势一致。结论姜黄素可以下调肝细胞内IDOL水平,提高细胞膜LDLR分布丰度,从而促进肝细胞摄取LDLC。

Effect of Gengnianchun Recipe (更年春方) on Bone Mineral Density, Bone Biomechanical Parameters and Serum Lipid Level in Ovariectomized Rats

Objective： To observe the effect of Gengnianchun Recipe （更年春方, GNC） on bone mineral density （BMD）, bone biomechanical parameters and serum lipid level in the bilaterally ovariectomized （OVX） rats and to explore the prophylactic and therapeutic action of GNC on ovariectomy induced osteoporosis and hyperlipidemia. Methods： OVX SD rats, 10- 12 months old, were divided into different groups and fed with GNC 2 g/d, GNC 1 g/d and Nilestriol 0. 125 mg/week, respectively for 4 months to observe the change of BMD and bone biomechanical parameters of the lumbar vertebrae, and the serum levels of total cholesterol （TO）, triglyceride（TG）, high-density lipoprotein cholesterol （HDL-C） and low-density lipoprotein cholesterol （LDL-C）, and to compare the effect of the two drugs on the morphology of the uterus. Results： There was marked reduction in BMD and biomechanical parameters in lumbar vertebrae （ P〈0. 01 ） and increase of serum TO and LDL-C levels （ P〈0. 01 ） in rats after OVX. GNC or Nilestriol significantly improved the decreased BMD and biomechanical parameters of the lumbar vertebrae （ P〈0.05 or P〈0. 01 ）, and reduced the serum TO and LDL-C levels （ P〈0. 01 ）. In the Nilestriol group, the wet weight of uterus got increased obviously （ P〈0.01 ）, the number of uterine glands increased, uterine columnar epithelium thickened, and the mitotic figures in the epithelial stroma and myointimal cells augmented. But no such effect in wet weight and morphology of uterus was found in the GNC group. Conclusion： GNC could increase the BMD and biomechanical parameters of the lumbar vertebrae, reduce the serum TO and LDL-C levels, yet produce no adverse reaction in stimulating proliferation and hypertrophy of uterus.

Elevated Levels of Very Low？density Lipoprotein Cholesterol Independently Associated with In？stent Restenosis in Diabetic Patients after Drug？eluting Stent Implantation

Background： High rate of in-stent restenosis （ISR） remained an unsolved clinical problem in clinical practice, especially among patients with diabetes mellitus （DM）. Diabetic patients often had hypertriglyceridemia with elevated levels of very low-density lipoprotein cholesterol （VLDL-C）. Increasing evidence suggested that VLDL-C was known as a significant risk factor for atherosclerosis and had been recommended as a treatment target by current dyslipidemia guidelines. However, the role of VLDL-C in the occurrence and development of ISR in coronary artery disease （CAD） patients with DM had not been studied. The aim of this study was to evaluate the association between the elevated levels of VLDL-C and the risk of ISR in CAD patients with DM. Methods： A total of 1390 diabetic patients, who underwent coronary drug-eluting stent （DES） implantation at Beijing Anzhen Hospital and followed up by angiography within 6–24 months, were consecutively enrolled. Patients＇ demographic and clinical characteristics, including age, gender, CAD risk factors, family history, life style, medical history, and coronary angiographic information, were collected carefully at baseline percutaneous coronary intervention and follow-up angiography. Multivariate Cox＆#39;s proportional hazards regression modeling using the step-wise method （entry, 0.05; removal, 0.05） was used to determine the independent risk associated with ISR in diabetic patients. Results： Finally, 1206 of patients were included in this study. ISR occurred in 132/1206 diabetic patients （10.9%） by follow-up angiography. Patients with ISR had elevated median serum VLDL-C levels compared with those without ISR （0.65 mmol/L vs. 0.52 mmol/L, P = 0.030）. The multivariate regression analysis showed that VLDL-C was significantly associated with the risk of ISR in diabetic CAD patients （hazard ratio [HR] = 1.15, 95% confidence interval [CI]： 1.03–1.29, P = 0.017）. The HR for the risk of ISR associated with VLDL-C level ≥0.52 mmol/L was 3.01 （95% CI： 1.24–7.34, P = 0.015）. Conclusion： The elevated level of serum VLDL-C was a significant and independent risk factor for ISR in diabetic CAD patients after coronary DES implantation.

胆囊胆固醇结石患者肝脏诱导低密度脂蛋白受体降解物的表达水平

目的研究诱导低密度脂蛋白受体(low density lipoprotein receptor,LDLR)降解物(inducible degrader of the LDLR,IDOL)在胆囊胆固醇结石患者肝脏中的表达水平,探讨其与胆囊胆固醇结石间的相关性。方法选取复旦大学附属华山医院2015年6月至12月收治的腹部手术患者35例,其中胆囊胆固醇结石患者(cholesterol gallstone patients,GS)21例,非胆囊胆固醇结石患者(gallstone-free patients,GSF)14例。采用实时定量PCR分别测定血清三酰甘油和总胆固醇水平,胆汁中胆固醇、胆汁酸和磷脂含量及胆固醇饱和指数(cholesterol saturation index,CSI)。采用半定量免疫组化分析检测肝脏IDOL及其他胆固醇代谢相关基因表达的mRNA和蛋白质水平;最后对GS组肝脏基因表达的mRNA和蛋白质水平与胆汁生化指标相关性分析。结果两组患者血清三酰甘油和总胆固醇水平及胆汁中胆汁酸和磷脂含量相比,差异均无统计学意义。GS组胆汁胆固醇浓度和CSI明显高于GSF组(P均<0.01)。GS组肝脏IDOL mRNA和蛋白质水平低于GSF组(P<0.05)。GS组肝脏LDLR表达水平高于GSF组(P<0.05)。相关性分析表明,GS肝脏IDOL蛋白质水平与胆汁胆固醇摩尔百分比及CSI呈明显负相关(P均<0.01)。结论肝脏IDOL基因表达水平下降与胆囊胆固醇结石的形成相关。

EXPERIMENTAL STUDY ON THE PREVENTION AND TREATMENT EFFECT OF WARMING-REINFORCING METHOD ON RABBIT'S HYPERLIPEMIA

In this experiment, the contents of serum total cholesterol (TC), triglyceride(TG),low-density lipoprotein(LDL), high-density lipoprotein(HDL) were used as indexes to observe the effects of warming-reinforcing method on rabbit’s lipide, liopoprotein. The results indicated that in the warming-reinforcing group, TC decreased markedly and HDL increased obviously with significant difference as compared with the twirling-reinforcing group:TC and LDL also decreased, but no significant differencte as compared with the twirling-reinforcing group. Warming-reinforcing method can decrease lipids more effectively than twirling-reinforcing method.