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The efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has broadened lipid-lowering therapy thus providing decreased risk in atherosclerotic cardiovascular disease. Unfortunately, the widespread use of PCSK9 inhibitors (PCSK9i), ie, monoclonal antibodies, has led to the findings of unusual responsiveness, ie, a phenomenon defined as an LDL-C reduction of30% vs the average LDL-C reduction efficacy of 50-60%. This unusual responsiveness to PCSK9i is attributable to several factors, ie, lack of adherence, impaired absorption, poor distribution or early elimination as well as abnormal effects of PCSK9i in the presence of anti-antibodies or mutations in PCSK9 and LDLR. Unexpectedly increased lipoprotein (Lp)(a) also appear to contribute to the unusual responsiveness scenario. Identification of these responses and mechanisms underlying them are essential for effective management of LDL-C and cardiovascular risk. In this review, we describe plausible reasons underlying this phenomenon supported by findings of clinical trials. We also elaborate on the need for education and regular follow-up to improve adherence. Collectively, the review provides a summary of the past, present, and future of mechanisms and countermeasures revolving around unusual responses to PCSK9i therapy.

Liver X nuclear receptor (LXR) agonists are promising anti-atherosclerotic agents that increase the expression of cholesterol transporters on atheroma macrophages leading to increased efflux of cholesterol to endogenous high-density lipoprotein (HDL) acceptors. HDL subsequently delivers effluxed cholesterol to the liver by the process of reverse cholesterol transport, resulting in reduction of atherosclerotic plaques. However, LXR agonists administration triggers undesirable liver steatosis and hypertriglyceridemia due to increased fatty acid and sterol synthesis. LXR-induced liver toxicity, poor drug aqueous solubility and low levels of endogenous HDL acceptors in target patient populations limit the clinical translation of LXR agonists. Here, we propose a dual-antiatherogenic strategy for administration of the LXR agonist, T0901317 (T1317), by encapsulating in synthetic HDL (sHDL) nanoparticles. sHDL had been clinically proven to serve as cholesterol acceptors, resulting in plaque reduction in atherosclerosis patients. In addition, the hydrophobic core and endogenous atheroma-targeting ability of sHDL allow for encapsulation of water-insoluble drugs and their subsequent delivery to atheroma. Several compositions of sHDL were tested to optimize both T1317 encapsulation efficiency and ability of T1317-sHDL to efflux cholesterol. Optimized T1317-sHDL exhibited more efficient cholesterol efflux from macrophages and enhanced atheroma-targeting relative to free drug. Most importantly, in an apolipoprotein E deficient (ApoE-/-) atherosclerosis progression murine model, T1317-sHDL showed superior inhibition of atherogenesis and reduced hypertriglyceridemia side effects in comparison to the free drug and blank sHDL. The T1317-sHDL pharmacological efficacy was observed at doses lower than those previously described for LXR agents, which may have additional safety benefits. In addition, the established clinical manufacturing, safety and efficacy of blank sHDL nanoparticles used in this study could facilitate future clinical translation of LXR-loaded sHDLs.

Lactic acid bacteria (LAB) can produce extracellular polysaccharides that can be used as thickeners, emulsifiers, and gels in foods. The immobilization technology can effectively simplify and improve the separation and regeneration of extracellular polysaccharides. In this study, six strains of LAB, including the extracellular polysaccharide-producing strain Lactobacillus plantarum, were screened. The different immobilized carriers of sodium alginate, agar, gelatin-glutaraldehyde, and carrageenan were assessed for fermentation by these six LAB. Different diameters of beads were selected, and the optimum culture temperature, carrier concentration, and inoculum volume were evaluated. The results showed that the agar-embedding method was the best immobilization method and the optimum process conditions were as follows: 3% inoculum of L. plantarum, 30 g/L of agar as immobilization carrier with a particle diameter of 1 cm, and fermentation at 37 °C for 24 h. Through orthogonal experiments, the maximum exopolysaccharide (EPS) yield obtained was 1489.9 mg/L.

Introduction: Apolipoprotein O (APOO), also known as MIC26, was first discovered through a functional genomics study aimed at identifying genes differentially regulated in the heart by obesity. While its physiologic role is incompletely understood, recent studies implicate a critical intracellular role for APOO in regulating lipid metabolism. The overall objective of the present study was to determine whether genetic deletion of APOO in mice would affect cholesterol metabolism and accelerate atherosclerosis. Methods and Results: Hepatic Apoo expression was induced in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout ( Apoo -/- ) model and liver-specific APOO knockout ( Alb Cre Apoo fl/f l ) model, we report here that APOO deletion elevates hepatic and plasma cholesterol levels. Then, we bred Apoo -/- mouse onto both the Ldlr and Apoe KO hyperlipidemic mouse models. Female Apoo -/- Apoe -/- mice and Apoo -/- Ldlr -/- mice in both sexes displayed markedly elevated plasma cholesterol levels and more severe atherosclerotic lesions as compared to their littermate controls, implying the effect of APOO on cholesterol metabolism independent of LDLR and APOE. We demonstrate that APOO reduces cholesterol excretion through bile and feces. In addition, APOO deficiency led to hepatic triglycerides accumulation and decreased phospholipid unsaturation by inhibiting the expression of CYB5R3, which is responsible for hepatic fatty acid desaturation and elongation. Conclusions: These data represent the first in vivo experimental validation of the association of APOO with plasma cholesterol metabolism independent of LDLR. These results demonstrate that APOO deficiency led to the decreased CRB5R3 expression and fatty acid unsaturation, which responsible for the decrease of cholesterol excretion and elevated plasma cholesterol levels.

Obesity is the most common nutritional disorder worldwide and is associated with dyslipidemia and atherosclerotic cardiovascular disease. The hallmark of dyslipidemia in obesity is low high density lipoprotein (HDL) cholesterol (HDL-C) levels. Moreover, the quality of HDL is also changed in the obese setting. However, there are still some disputes on the explanations for this phenomenon. There is increasing evidence that adipose tissue, as an energy storage tissue, participates in several metabolism activities, such as hormone secretion and cholesterol efflux. It can influence overall reverse cholesterol transport and plasma HDL-C level. In obesity individuals, the changes in morphology and function of adipose tissue affect plasma HDL-C levels and HDL function, thus, adipose tissue should be the main target for the treatment of HDL metabolism in obesity. In this review, we will summarize the cross-talk between adipocytes and HDL related to cardiovascular disease and focus on the new insights of the potential mechanism underlying obesity and HDL dysfunction.

Objective: Metformin, a first-line drug for treating individuals with type 2 diabetes, exerts beneficial effects on cholesterol-lowering, yet its precise mechanism has not been established. Approach and Results: In 2 dyslipidemia mouse models, administration of metformin significantly decreased serum cholesterol and PCSK9 (proprotein convertase subtilisin/kexin type 9) levels, accompanied by decreased expression of PCSK9 in both mRNA and protein levels resulting in a 3-fold increase of LDLR (low-density lipoprotein receptor) in the liver. In human hepatocytes, metformin treatment suppressed the PCSK9 transcription. Depressed transcription was driven by a glucose sensor, the ChREBP (carbohydrate-responsive element-binding protein) but not by the intracellular cholesterol sensor, the SREBP2 (sterol regulatory element-binding protein 2). We further identified PCSK9 as a novel target gene of ChREBP. Metformin decreased the expression of ChREBP and inhibited its transcriptional activity by blocking its nuclear translocation attributed to the decreased intracellular glucose and glucose metabolites levels. Moreover, metformin treatment significantly decreased serum low-density lipoprotein cholesterol and PCSK9 levels in nondiabetic individuals. Conclusions: Collectively, we revealed a new mechanism of action of metformin in cholesterol-lowering and identified a novel crosstalk signal between glucose and cholesterol homeostasis via ChREBP-mediated PCSK9 regulation.

Abdominal aortic aneurysm (AAA) is defined as a progressive segmental dilation of the abdominal aorta and is associated with high mortality. The characterized features of AAA indicate several underlying mechanisms of AAA formation and progression, including reactive oxygen species production, inflammation, and atherosclerosis. Mitochondrial functions are critical for determining cell fate, and mitochondrial dynamics, especially selective mitochondrial autophagy, which is termed as mitophagy, has emerged as an important player in the pathogenesis of several cardiovascular diseases. The PARKIN/PARIS/PGC1α pathway is associated with AAA formation and has been proposed to play a role in mitochondrial dynamics mediated by the PINK/PARKIN pathway in the pathogenesis underlying AAA. This review is aimed at deepening our understanding of AAA formation and progression, which is vital for the development of potential medical therapies for AAA.

Serum concentration of low-density lipoprotein cholesterol (LDL-C) is markedly reduced after a meal. Does postprandial cholesterol in LDL truly decline via clearance of LDL particles or is there simply a redistribution of cholesterol in LDL subclasses? Thus, we sought to evaluate whether postprandial decline of LDL-C reflects a reduction of LDL particle and to assess the correlation between proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration and postprandial atherogenic lipoproteins profile.Eighty-seven persons were enrolled in this study. We measured lipid profiles by enzymatic and nuclear magnetic resonance (NMR)-based methods and serum PCSK9 concentration by enzyme-linked immunosorbent assays before and after a meal. Plasma samples were collected after a 10-h fasting and 2 and 4 h post-meal.Compared to the fasting status, there was significant postprandial decline of LDL-C measured enzymatically (LDL-Ce) at 2nd and 4th h [99.38 (80.43, 120.65) vs 95.51 (74.25, 117.17) vs 87.01 (69.99, 108.28) mg/dl, p 0.000]. But there was no significant reduction in LDL particle and its cholesterol content (LDL-Cn) determined by NMR. Just the postprandial large LDL particle [186.45 (151.36, 229.42) vs 176.92 (147.43, 220.91) vs 181.77 (149.05, 224.17), p 0.000] and its cholesterol content [19.10 (15.09, 22.37) vs 18.28 (14.59, 21.84) vs 17.79 (14.62, 22.14), p 0.000] were greatly decreased at 2nd and 4th h compared to the fasting one. Interestingly, postprandial serum PCSK9 was decreased at 2nd and 4th h compared with fasting concentration [298.75 (233.25, 396.92) vs 257.34 (207.52, 342.36) vs 250.57 (215.02, 339.66) ng/ml, p 0.000]. The postprandial percent decrease in serum PCSK9 at 4th h was positively correlated to the percent decline in postprandial LDL-Ce (r = 0.252, p = 0.019) but was independently associated with the percent increase in remnant cholesterol (r = 0.262, p = 0.016).Postprandial decline of LDL-C determined enzymatically was not confirmed by NMR-based methods. Indeed, there exists cholesterol redistribution in LDL subclasses following a meal. The decrease of postprandial PCSK9 may be secondary to the increase in intrahepatic lipids following food intake.

Background: Cholesterol efflux capacity (CEC), a crucial atheroprotective function of high-density lipoprotein (HDL), has proven to be a reliable predictor of cardiovascular risk. Inflammation can damage CEC, but few studies have focused on the relationship between the systemic inflammation marker high-sensitivity C-reactive protein (hsCRP) and CEC in patients with coronary artery disease (CAD). Methods: Thirty-six CAD patients and sixty-one non-CAD controls were enrolled in this observational, cross-sectional study. CEC was measured using a [3H] cholesterol loading Raw 264.7 cell model with apolipoprotein B-depleted plasma (a surrogate for HDL). Proton nuclear magnetic resonance (NMR) spectroscopy was used to assess HDL components and subclass distribution. hsCRP was measured with a latex particle, enhanced immunoturbidimetric assay.Results: CEC was impaired in CAD patients compared to controls (11.9±2.3% vs. 13.0±2.2%, p=0.022). In the control group, CEC was positively correlated with enzymatically measured HDL cholesterol (HDL-C) levels (r=0.358, p=0.006) or NMR-determined HDL-C levels (r=0.416, p=0.001). However, in the CAD group, the significance of correlation disappeared (enzymatic method: r=0.216, p=0.206; NMR spectroscopy: r=0.065, p=0.708). Instead, we found that the level of hsCRP was negatively correlated with CEC (r=-0.351, p=0.036), and this relationship was not modified by CAD risk factors, HDL-C, and HDL subclasses. NMR showed that HDL particles shifted to larger ones in patients with high hsCRP levels, and this phenomenon was accompanied by decreased CEC. Conclusions: In patients with CAD, the level of HDL-C cannot reflect HDL function, but hsCRP is independently associated with HDL dysfunction. The impaired correlation between HDL-C and CEC is possibly due to an inflammation-induced HDL subclass remodeling. Trial registration: Chinese Clinical Trial Registry, ChiCTR1900020873. Registered on 21 January 2019 - Retrospectivelyregistered.

The human ether-à-go-go-related gene (hERG) potassium channel mediates the repolarization of ventricular action potentials. Mutations in the KCNH2 cause long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. Here, we functionally analyzed a mutation of hERG potassium channel (p.L51P), gaining novel insights into clinical genotype-phenotype relationships. Potassium currents were recorded by whole-cell patch clamping in HEK293 cells transiently transfected with wild-type and/or mutant hERG potassium channel. Immunofluorescence assay and confocal imaging were undertaken to study the effects of L51P mutation on channel trafficking. The models of the protein structure of hERG and its mutations are predicted by Amber16 software. Molecular dynamics (MD) of individual protein were performed with Particle Mesh Ewald (PME). The production of MD simulations of hERG-WT and hERG-Mut at constant pressure and temperature were carried out with SHAKE. L51 was a conservative amino acid, located in the Per-Arnt-Sim (PAS) domain of the amino terminus. L51P caused loss of function via impairing channel activation. L51P was predicted to destroy hydrophobic structure in the PAS domain, thus causing the failure of channel opening. In summary, the present study identifies L51P as a novel mutation of hERG potassium channel. L51P mutation mechanistically impairs channel activation, reducing channel functionality.

In the recent outbreak of novel coronavirus infection worldwide, the risk of thrombosis and bleeding should be concerned. We aimed to observe the dynamic changes of D-dimer levels during disease progression to evaluate their value for thrombosis. In this study, we report the clinical and laboratory results of 57 patients with confirmed COVID-19 pneumonia and 46 patients with confirmed community-acquired bacterial pneumonia (CAP). And their concentrations of D-dimer, infection-related biomarkers, and conventional coagulation were retrospectively analyzed. The Padua prediction score is used to identify patients at high risk for venous thromboembolism (VTE). The results found that, on admission, both in COVID-19 patients and CAP patients, D-dimer levels were significantly increased, and compared with CAP patients, D-dimer levels were higher in COVID-19 patients (P < 0.05). Besides, we found that in COVID-19 patients, D-dimer were related with markers of inflammation, especially with hsCRP (R = 0.426, P < 0.05). However, there was low correlation between VTE score and D-dimer levels (Spearman’s R = 0.264, P > 0.05) weakened the role of D-dimer in the prediction of thrombosis. After treatments, D-dimer levels decreased which was synchronous with hsCRP levels in patients with good clinical prognosis, but there were still some patients with anomalous increasing D-dimer levels after therapy. In conclusion, elevated baseline D-dimer levels are associated with inflammation but not with VTE score in COVID-19 patients, suggesting that it is unreasonable to judge whether anticoagulation is needed only according to D-dimer levels. However, the abnormal changes of D-dimer and inflammatory factors suggest that anticoagulant therapy might be needed. Electronic supplementary material The online version of this article (10.1007/s11239-020-02171-y) contains supplementary material, which is available to authorized users.

Background Remnant cholesterol (RC) can partly explain the residual risk in atherosclerotic cardiovascular disease (ASCVD). A consensus method of measuring RC levels has not been established yet. In clinical practice, RC levels are usually calculated from the standard lipid profile, which are not true RC. Nuclear magnetic resonance (NMR) can measure RC levels directly. This study aimed to characterize RC at fasting and non-fasting states in more details and establish the performance of calculated RC and NMR-measured RC. Methods Blood samples at fasting state and at 2 h and 4 h postprandial states were collected in 98 subjects. Lipid parameters including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), subfractions 3, 4, and 5 of very low-density lipoprotein cholesterol (VLDL3-C, VLDL4-C, and VLDL5-C, respectively), and intermediate-density lipoprotein cholesterol (IDL-C) were measured by enzymatic method and NMR. RC levels calculated from the standard lipid profile or measured by NMR were referred here as RCe or RCn. Results The RCe and RCn levels were different, but both of them increased after a meal (P Conclusions RC calculated from the standard lipid profile as TC minus LDL-C minus HDL-C is different from the NMR-measured RC. According to different TG levels, RC could overestimate or underestimate the actual RC level. Developing a consensus clinical method to measure RC levels is necessary, so that results from different studies and platforms can be more directly compared. Trial registration Chinese Clinical Trial Registry, ChiCTR1900020873. Registered in 21 January 2019 - Retrospectively registered.

Background: Aged people is more susceptible and vulnerable to COVID-19 pneumonia. As the “super-elderly” group, octogenarian COVID-19 patients is not rare in current world-wide common healthy event.Object: To describe clinical features in octogenarian with severe COVID-19. And try to find out the differences with other non-octogenarian adult patients.Materials and Methods: We studied a small cohort of octogenarian COVID-19 patients at a hospital in Wuhan from 10 February to 15 March. We recorded interested clinical data including chest CT in the octogenarian patients. In order to know the differences of clinical characteristics between octogenarian and other adult patients, we included the number of non-octogenarian patients cohort as ratio of 1:3.Result: For octogenarian patients, the age is 83.33±3.08 and 4 are female (4/6,66.7%). For non-octogenarian patients, the age is 60.72±8.28 years and 5 are female(5/18, 27.8%). and 59% were men. Compared non-octogenarian patients, octogenarian patients’ hospital stay duration is significantly longer (p=0.0052*). WBC is obvious elevated in octogenarian(p=0.0494*). BUN (p=0.0377*) and Cr (p=0.0112*) is with obvious differences between two group patients. No obvious differences in CT findings between two groups.Conclusion: The severe COVID-19 pneumonia octogenarian may have more chance to combined with bacterial infection. Octogenarian has worse baseline kidney function than non-octogenarian. In individual cases, the broader lesion and more lesion types may be found in octogenarian CT image.

We here studied the clinical features, cardiac structure, and functional changes and prognosis of hypertrophic cardiomyopathy (HCM) patients with hypertension (HTN). A total of 90 HCM patients with HTN and 172 patients without HTN were divided into a hypertensive group and non-hypertensive group. The clinical characteristics, cardiac structure and function, and prognosis of the two groups were compared. Our study found that HCM patients with HTN had fewer syncope events in their medical histories (8% vs. 22%, P P P P P P = 0.065). In conclusion, we found that the clinical phenotypes of HCM patients with HTN differed from those of patients with HCM alone, suggesting that HTN may play a pathogenic role in the pathogenesis of hypertensive hypertrophic cardiomyopathy patients.

Background: The protein-lipid composition, namely the “quality” of lipoprotein particles, has been shown to be increasingly associated with cardiovascular disease (CVD). The high heterogeneity of lipoproteins makes it necessary to study the “quality” of each high-resolution subgroup. However, the targeted separation, detection, and exploration of the heterogeneous on omic-scale for lipoprotein remain challenging and rarely touched. Methods: We established a high-resolution proteomics and lipidomics (HiPL) method. Briefly, the lipoprotein particles were separated into nine fractions (Lipo-HiPL) using anion-exchange chromatography (AEC), in which HDL, LDL, and VLDL were fractionated into three more fractions respectively. Furthermore, the HDL subclasses were delicately purified within nine fractions (HDL-HiPL), covering diverse protein-lipid heterogeneity. Then the integration of proteomic and lipidomic analysis of these high-resolution subgroups revealed proteome-lipidome connectivity (PLC) in lipoprotein and HDL particles. Findings: We used the high fat high cholesterol (HFHC)-fed rabbit model before atherosclerotic lesions occurred to evaluate the applicability of our method preliminarily, and then we applied Lipo-HiPL and HDL-HiPL methods to acute coronary syndrome (ACS) patients before and after PCI and standardized drug treatment. We found that LiPL-HiPL method had enough sensitivity to illustrate dramatic changes of lipoproteins in HFHC died rabbits. However, in ACS patients, the HDL-HiPL method with a higher resolution could better reflect the molecular dynamics and PLC features of HDL than Lipo-HiPL. Moreover, the HDL “quality” revealed by PLC related more closely to clinical status in ACS patients than direct proteome and lipidome quantification. Interpretation: Proteome-lipidome connectivity (PLC) as novel HDL “quality” features could be highly associated with atherosclerotic cardiovascular diseases. Funding Statement: This work was supported by a grant from the Ministry of Science and Technology (2017YFA0505500), and grants from the National Natural Science Foundation of China (81561128018, 81670426 and 81870336). Declaration of Interests: None. Ethics Approval Statement: The study was approved by the Medical Ethics Committee of the Second Xiangya Hospital of Central South University. All patients gave written informed consent before blood sample collection. Rabbit studies were performed according to animal protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Michigan.

The mechanism for an abnormal pattern of triglyceride (TG) metabolism in response to a meal still needs further investigation. Extensive pieces of evidence have shown that apolipoprotein CIII (apoCIII) is a critical modulator of plasma TG metabolism mostly by inhibiting the hydrolysis of TG. Little is known about the role of apoCIII contained in high density lipoprotein (HDL) in plasma TG metabolism after a meal.Fasting and 4-hour postprandial peripheral venous blood were collected in 91 subjects selected from our hospital. Serum lipid parameters, apoCIII levels and HDL subcomponents were tested by standard laboratory procedures, ELISA, and nuclear magnetic resonance (NMR), respectively. The t-test, and Non-parametric tests were performed to examine differences between groups, Pearson's correlation and multiple regression analysis were used to assess the correlations between apoCIII (HDL-associated or nonHDL-associated) and postprandial TG.There was a significant increase in TG after a meal compared to fasting status [155.40(96.70-251.07) mg/dl.vs.118.53(83.38-173.29)mg/dl, p 0.001]. However, the total apoCIII levels were unchanged before (11.56(7.89-16.22) mg/dl) and after a meal (11.66(7.75-16.02)mg/dl, p = 0.124), while a significant increase in HDL-associated apoCIII (HDL-apoCIII) was observed from fasting (5.25(3.92-7.83)mg/dl) to post-meal (6.46(4.57-8.76)mg/dl, p = 0.001). Unlike nonHDL-apoCIII, HDL-apoCIII was positively correlated with both fasting and postprandial plasma TG in subjects with baseline plasma TG 118.53 mg/dl (R = 0.503, p 0.001 for fasting, R = 0.584, p 0.001 for postprandial). Besides, in the subjects who had an abnormal TG response to a meal, which was defined as postprandial plasma TG increase of30% compared to baseline TG levels, postprandial HDL-apoCIII was also increased significantly [5.37(3.52-7.02)mg/dl.vs.6.64(4.61-8.86)mg/dl, p = 0.001]. The enrichment of apoCIII in HDL led to changes of TG, cholesterol, free cholesterol, phospholipid and apoAII contents in HDL particles defined by NMR.Enrichment of apoCIII in HDL particles potentially plays an independent role in postprandial hypertriglyceridemia.

Despite great advances in lipid-lowering therapy, the gender-based disparities in lipid goal success among Chinese coronary heart disease (CHD) patients receiving lipid-lowering treatment remained uncharacterized. Furthermore, little is known about potential causes for this gender imbalance. This cross-sectional trial included 25 697 patients treated with lipid-lowering agents from 122 centres between April 2012 and October 2012; data for 9420 participants with CHD were analysed in the present study; all underwent clinical examination and had their latest fasting lipid profiles while on lipid-lowering therapy recorded. Logistic regression was used to explore possible factors associated with gender disparity in goal attainment rates, and to what extent each factor contributes. Of 9420 CHD patients (42.5% women) evaluated, women had a significantly lower overall low-density lipoprotein cholesterol (LDL-C) success rate than men (46.2 vs. 62.7%, P < 0.0001). Among CHD patients with diabetes, only 31.5% of women and 46.4% of men ( P < 0.0001) attained the optional LDL-C target of

Aim: Previous studies have demonstrated that the dysregulated-secretion of adipokines by adipocytes may contribute to obesity-associated atherosclerosis (As) and high density lipoprotein (HDL) may protect against atherogenesis through multiple pathways. This study was to explore the effect of HDL on the oxLDL uptake in inflammatory adipocytes stimulated by endotoxin lipopolysaccharide (LPS) and the possible mechanism. Methods and Results: 3T3-L1 adipocytes were cultured and induced to differentiation and maturation. Acute inflammation in adipocytes was induced by LPS (100 ng/ml) for 6 hours. The adipocytes were pretreated with HDL in various concentrations (10, 50, 100 μg/ml) for 16 hours or with specific PPARγ antagonist (GW9662, 10 μM) or agonist (Rosiglitazone, 10 μM) for 30 min before administration of LPS. The results showed that LPS significantly increased the release of inflammation-related adipokines, such as monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8 and IL-6, while decreasing the release of leptin and adiponectin. Meanwhile, LPS reduced the uptake and degradation of 125 I-oxLDL, and down-regulated the expression of PPARγ and CD36. Pretreatment with HDL dose-dependently affected the release of IL-8 and IL-6 and the reduced uptake and degradation of oxLDL of adipocytes stimulated by LPS, accompanied with marked upregulation of PPARγ and CD36 expression. Pretreatment with GW9662 markedly inhibited the upregulation of CD36 expression mediated by HDL (100 μg/ml), while the effects of Rosiglitazone were opposite to GW9662. Conclusions: HDL may increase oxLDL uptake of inflammatory adipocytes stimulated by LPS via upregulation of PPARγ/CD36 pathway, which may be a new mechanism of anti-atherosclerosis mediated by HDL.

Urban tourism is a worldwide form of tourism and is one of the most important social and economic impetus for urban development. The urban tourism market has been increasingly dominated by the demand for personalized experiences. Accordingly, this study aims to design personalized itineraries with hotel selection for multi-day urban tourists. A two-level heuristic approach is proposed, which embeds genetic algorithm, variable neighborhood search, and differential evolution algorithm into the structure of memetic algorithm. A case study in Xiamen, a coastal city in Southeast China, is carried out to evaluate the performance of our approach. Results of paired sample t-tests show that our proposed approach is remarkably superior to existing methods. In addition, compared with previous methods, our approach can design more reasonable and personalized itineraries for tourists.

Exchangeable apolipoproteins play an important role in systemic lipid metabolism, especially for lipoproteins with which they are associated. Recently, emerging evidence has suggested that exchangeable apolipoproteins, such as apolipoprotein A4 (apoA4), apolipoprotein A5 (apoA5), apolipoprotein C3 (apoC3) and apolipoprotein E (apoE), also exert important effects on intracellular lipid homeostasis. There is a close link between lipid metabolism in adipose tissue and liver because the latter behaves as the metabolic sensor of dysfunctional adipose tissue and is a main target of lipotoxicity. Given that the energy balance between these two major lipogenic organs is intimately involved in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD), we here review recent findings concerning the intracellular function of exchangeable apolipoproteins in triglyceride metabolism in adipocytes and hepatocytes. These apolipoproteins may act as mediators of crosstalk between adipose tissue and liver, thus influencing development of obesity and hepatosteatosis. This review provides new insights into the physiological role of exchangeable apolipoproteins and identifies latent targets for therapeutic intervention of obesity and its related disorders.

Introduction: Localized pericardium restriction is a rare disease and likely to be unrecognized owing to the atypical manifestation, even after diagnostic avenues are exhausted. Recognizing the red flags of the disease could timely spark a preliminary suspicion of the disease and thus contribute to the early application of relevant examinations. Case presentation: We will here report a case of a 21-year-old young man with a giant right ventricular outflow tract. He was presented to our hospital for further evaluation of progressive right heart failure which had been previously diagnosed as cardiomyopathy. Unlike patients with right heart failure owing to the restrictive cardiomyopathy, our patient's tissue Doppler revealed an increased early diastolic septal mitral annular velocity. In addition, the disproportion between the severity of right heart failure and the degree of myocardial dysfunction could not be completely explained by other myocardial disease, suggesting that alternative diagnosis of the patient should be sought. Subsequently, cardiac computed tomography, which revealed the focally calcific pericardium encircling the left ventricle, gave us a clue to the diagnosis of localized constrictive pericarditis. Cardiac catheterization, showing the “dip and plateau” sign, further confirmed this diagnosis. The patient underwent successful pericardiectomy. Nowadays, he is able to undertake ordinary physical activity. Conclusion: Localized constrictive pericarditis should be suspected in patients for whom the severity of heart failure and deformity of heart might not be completely explained by valvular heart disease or myocardial disease.

Apolipoprotein (apo) O is a novel apolipoprotein that is present predominantly in high density lipoprotein (HDL). However, overexpression of apoO does not impact on plasma HDL levels or functionality in human apoA-I transgenic mice. Thus, the physiological function of apoO is not yet known. In the present study, we investigated relationships between plasma apoO levels and high-sensitive C-reactive protein (hs-CRP) levels, as well as other lipid parameters in healthy subjects (n = 111) and patients with established acute coronary syndrome (ACS) (n = 50). ApoO was measured by the sandwich dot-blot technique with recombinant apoO as a protein standard. Mean apoO level in healthy subjects was 2.21 ± 0.83 µg/ml whereas it was 4.94 ± 1.59 µg/ml in ACS patients. There were significant differences in plasma level of apoO between two groups (P < 0.001). In univariate analysis, apoO correlated significantly with lg(hsCRP) (r = 0.48, P < 0.001) in ACS patients. Notably, no significant correlation between apoO and other lipid parameters was observed. Logistic regression analysis showed that plasma apoO level was an independent predictor of ACS (OR = 5.61, 95% CI 2.16–14.60, P < 0.001). In conclusion, apoO increased in ACS patients, and may be regarded as an independent inflammatory predictor of ACS patients.

Studies of the past decade have increased our understanding of the role of adipose tissue dysfunction in obesity and obesity-related insulin resistance and type 2 diabetes. Although adipose tissue is the body's largest pool of free cholesterol, adipocytes have limited activity in cholesterol synthetic pathway. Thus, the majority of adipocyte cholesterol originates from circulating lipoproteins. To maintain cholesterol homeostasis, adipocytes have developed multiple pathways for cholesterol efflux. Several transcriptional factors, such as sterol regulatory element-binding proteins and liver X receptors may be responsible for the regulation of cholesterol homeostasis in adipocytes. Most notably, because altering cholesterol balance profoundly modifies adipocyte metabolism in a way resembling that seen in hypertrophied adipocytes, cholesterol imbalance is recognized as a characteristic for enlarged adipocytes per se in the obese state. In addition, plasma membrane cholesterol normalization by chromium picolinate can fully restore insulin-stimulated glucose transport, further supporting the role of the adipocyte cholesterol imbalance in obesity and insulin resistance.

The proband, a 25-year-old female, was presented to our institution with exertional dyspnoea and oedema in lower extremities. Her electrocardiogram showed prominent dilated atria 2 years ago ( Panel A ), followed by sustained atrial fibrillation 1 year later. Transthoracic echocardiography revealed preserved systolic function, massive biatrial enlargement, and moderate left ventricular hypertrophy (LVH) …

Background Despite clear guideline recommendations, there is a paucity of data regarding the prevalence and type of persistent lipid profile abnormalities in patients on stable lipid-lowering therapy in China. Methods This cross-sectional trial included 25,697 patients treated with lipid-lowering agents from 122 centres between April 2012 and October 2012; all underwent clinical examination and had their latest fasting lipid profiles while on lipid-lowering therapy recorded. Logistic regression was performed to assess predictors for lipid abnormalities classified according to current Chinese guidelines. Findings Overall, 29.1% of patients had no lipid abnormalities, and 38.5% of patients did not achieve the therapeutic goal for low-density lipoprotein cholesterol (LDL-C), either as a single lipid anomaly or associated with low high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, or both. Subjects with low risk were more likely than those with very high and high risk to be at target LDL-C levels. Furthermore, 10.4% of very high-risk patients and 11.1% of high-risk patients who attained the LDL-C goal failed to attain non-HDL-C goals. Diabetes was shown to be a strong predictor of failure in attaining non-HDL-C and both goals (OR 3.03; 3.22, 95% CI 2.58–3.55; 2.73–3.79, respectively). Conclusion Although great improvements have been made over the past decade, the large majority of very high-risk and high-risk patients treated with lipid-lowing agents still had one or more manifestations of dyslipidaemia. Further clinical evidence is needed to clarify whether adding other lipid-lowering agents to a statin will be associated with additional cardiovascular risk reduction.

To construct human apolipoprotein O (apolipoprotein O, ApoO) expression vector and obtain recombinant fusion protein thioredoxin (Trx)-ApoO by pET prokaryotic expression system.The ApoO gene fragment from the human liver cDNA library was amplified by PCR. The resulting product was cloned into pET-32a(+) vector and sequenced. The confirmed cDNA was cloned into plasmid E.coli DH10B and then transformed into E.coli BL 21 (DE3) where it was induced to express protein by isopropyl β-D-1-thiogalactopyranoside (IPTG). The fusion protein was purified by Ni-NTA resin.The ApoO gene was cloned by PCR and a 519 bp DNA fragment was shown on the agarose electrophoresis. The cloned gene was sequenced and demonstrated to have the same sequence as that of human ApoO gene in GenBank which justified a successful construction of recombinant plasmid. ApoO cDNA gene fragment was induced by IPTG, and a 34 kD recombinant fusion protein Trx-ApoO was tested on sodium dodecyl sulfate polyacrylamide (SDS-PAGE).Human ApoO gene is successfully cloned and its recombinant fusion protein Trx-ApoO is expressed.

Background: Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells. Methods: HepG2 cells were treated either with oleic acid or tumor necrosis factor-α for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole-genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR. Results: ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection. Conclusions: It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells, and UCP2 may act as a mediator between lipid metabolism and inflammation in apoO-silenced HepG2 cells.