Nasal delivery of polymeric nanoDisc mobilizes a synergy of central and peripheral amyloid-ß clearance to treat Alzheimer's disease.

The disequilibrium of amyloid ß-peptide (Aß) between the central and peripheral pools has been claimed as an initiating event in Alzheimer's disease (AD). In this study, we employ discoidal high-density lipoproteins (HDL-Disc) mimicking Aß antibody for directional flux of Aß from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier-free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures Aß into microglia for central clearance or ferries Aß out of the brain for liver-mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral Aß burden by 97.3% and vascular Aß burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing Aß antibody mimics to mobilize a synergy of central and peripheral Aß clearance for AD treatment.

Effect of phospholipid transfer protein on plasma sphingosine-1-phosphate.

Plasma phospholipid transfer protein (PLTP) is a risk factor for cardiovascular diseases. Sphingosine-1-phosphate (S1P), carried by high-density lipoprotein (HDL), is a potent lipid mediator and is also associated with cardiovascular diseases. We found that germline Pltp gene knockout (KO) mice have decreased circulating S1P without influencing apoM, a major S1P carrier on HDL. We then hypothesized that, like apoM, PLTP is another S1P carrier. We established inducible Pltp-KO, Apom-KO, and Pltp/Apom double KO mice and measured plasma lipoprotein and S1P levels under different diets. We found that PLTP deficiency, and the double deficiency have a similar effect on HDL reduction. Importantly, we found that all mice have about 50% reduction in plasma S1P levels, compared to WT mice, and PLTP deficiency significantly reduces apoM levels (about 40%), while apoM deficiency has no effect on PLTP activity, indicating that PLTP depletion reduces S1P through HDL reduction. To further evaluate this HDL reduction-mediated effect, we overexpressed PLTP which also caused a reduction of HDL. We found that the overexpression reduces S1P and apoM as well as apoA-I, a major apolipoprotein on HDL. Furthermore, we found that albumin (another reported S1P carrier) deficiency in mice has no effect on plasma S1P. We also found that the influence of PLTP on HDL may not require its direct binding to the particle. In conclusion, PLTP is not a direct S1P carrier. PLTP depletion or overexpression in adulthood dramatically reduces plasma S1P through HDL reduction. ApoM, but not albumin, deficiency reduces plasma S1P levels.

Hepatitis C virus E1 recruits high-density lipoprotein to support infectivity and evade antibody recognition.

Hepatitis C virus (HCV) is a member of the Flaviviridae family; however, unlike other family members, the HCV virion has an unusually high lipid content. HCV has two envelope glycoproteins, E1 and E2. E2 contributes to receptor binding, cell membrane attachment, and immune evasion. In contrast, the functions of E1 are poorly characterized due, in part, to challenges in producing the protein. This manuscript describes the expression and purification of a soluble E1 ectodomain (eE1) that is recognized by conformational, human monoclonal antibodies. eE1 forms a complex with apolipoproteins AI and AII, cholesterol, and phospholipids by recruiting high-density lipoprotein (HDL) from the extracellular media. We show that HDL binding is a function specific to eE1 and HDL hinders recognition of E1 by a neutralizing monoclonal antibody. Either low-density lipoprotein or HDL increases the production and infectivity of cell culture-produced HCV, but E1 preferentially selects HDL, influencing both viral life cycle and antibody evasion.IMPORTANCEHepatitis C virus (HCV) infection is a significant burden on human health, but vaccine candidates have yet to provide broad protection against this infection. We have developed a method to produce high quantities of soluble E1 or E2, the viral proteins located on the surface of HCV. HCV has an unusually high lipid content due to the recruitment of apolipoproteins. We found that E1 (and not E2) preferentially recruits host high-density lipoprotein (HDL) extracellularly. This recruitment of HDL by E1 prevents binding of E1 by a neutralizing antibody and furthermore prevents antibody-mediated neutralization of the virus. By comparison, low-density lipoprotein does not protect the virus from antibody-mediated neutralization. Our findings provide mechanistic insight into apolipoprotein recruitment, which may be critical for vaccine development.

Nanoparticle-Directed Antioxidant Therapy Can Ameliorate Disease Progression in a Novel, Diet-Inducible Model of Coronary Artery Disease.

BACKGROUND: Oxidative stress plays a crucial role in the pathogenesis of coronary artery disease. In cardiovascular research using murine models, the generation and maintenance of models with robust coronary arterial atherosclerosis has been challenging. METHODS: We characterized a new mouse model in which the last 3 amino acids of the carboxyl terminus of the HDL (high-density lipoprotein) receptor (SR-B1 [scavenger receptor class B, member 1]) were deleted in a low-density lipoprotein receptor knockout (LDLR-/-) mouse model (SR-B1ΔCT/LDLR-/-) fed an atherogenic diet. We also tested the therapeutic effects of an oxidative stress-targeted nanoparticle in atherogenic diet-fed SR-B1ΔCT/LDLR-/- mice. RESULTS: The SR-B1ΔCT/LDLR-/- mice fed an atherogenic diet had occlusive coronary artery atherosclerosis, impaired cardiac function, and a dramatically lower survival rate, compared with LDLR-/- mice fed the same diet. As SR-B1ΔCT/LDLR-/- mice do not exhibit female infertility or low pup yield, they are far easier and less costly to use than the previously described SR-B1-based models of coronary artery disease. We found that treatment with the targeted nanoparticles improved the cardiac functions and corrected hematologic abnormalities caused by the atherogenic diet in SR-B1ΔCT/LDLR-/- mice but did not alter the distinctive plasma lipid levels. CONCLUSIONS: The SR-B1ΔCT/LDLR-/- mice developed diet-inducible, fatal atherosclerotic coronary artery disease, which could be ameliorated by targeted nanoparticle therapy. Our study provides new tools for the development of cardiovascular therapies.

Association between metabolic syndrome and white matter integrity in young and mid-age post-9/11 adult Veterans.

Metabolic syndrome has been associated with reduced brain white matter integrity in older individuals. However, less is known about how metabolic syndrome might impact white matter integrity in younger populations. This study examined metabolic syndrome-related global and regional white matter integrity differences in a sample of 537 post-9/11 Veterans. Metabolic syndrome was defined as ≥3 factors of: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. T1 and diffusion weighted 3 T MRI scans were processed using the FreeSurfer image analysis suite and FSL Diffusion Toolbox. Atlas-based regions of interest were determined from a combination of the Johns Hopkins University atlas and a Tract-Based Spatial Statistics-based FreeSurfer WMPARC white matter skeleton atlas. Analyses revealed individuals with metabolic syndrome (n = 132) had significantly lower global fractional anisotropy than those without metabolic syndrome (n = 405), and lower high-density lipoprotein cholesterol levels was the only metabolic syndrome factor significantly related to lower global fractional anisotropy levels. Lobe-specific analyses revealed individuals with metabolic syndrome had decreased fractional anisotropy in frontal white matter regions compared with those without metabolic syndrome. These findings indicate metabolic syndrome is prevalent in this sample of younger Veterans and is related to reduced frontal white matter integrity. Early intervention for metabolic syndrome may help alleviate adverse metabolic syndrome-related brain and cognitive effects with age.

Impaired high-density lipoprotein function and endothelial barrier stability in severe anaphylaxis.

BACKGROUND: Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases. OBJECTIVE: This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins A1 and B in sera from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis. METHODS: Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient sera, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Last, the effect of anaphylactic-derived high-density lipoprotein (HDL) particles on the endothelial barrier was studied. Detailed methods are provided in the Methods section in this article's Online Repository available at www.jacionline.org. RESULTS: Serum samples from severe anaphylactic reactions show statistically significant low levels of HDL cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A1 and B, which points to their possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human serum cell assays, we observed impaired capacity of apolipoprotein B-depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier. CONCLUSION: These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

Ligand-dependent interactions between SR-B1 and S1PR1 in macrophages and atherosclerotic plaques.

HDLs carry sphingosine-1-phosphate (S1P) and stimulate signaling pathways in different cells including macrophages and endothelial cells, involved in atherosclerotic plaque development. HDL signaling via S1P relies on the HDL receptor scavenger receptor class B, type I (SR-B1) and the sphingosine-1-phosphate receptor 1 (S1PR1), which interact when both are heterologously overexpressed in the HEK293 cell line. In this study, we set out to test if SR-B1 and S1PR1 interacted in primary murine macrophages in culture and atherosclerotic plaques. We used knock-in mice that endogenously expressed S1PR1 tagged with eGFP-(S1pr1eGFP/eGFP mice), combined with proximity ligation analysis to demonstrate that HDL stimulates the physical interaction between SR-B1 and S1PR1 in primary macrophages, that this is dependent on HDL-associated S1P and can be blocked by an inhibitor of SR-B1's lipid transfer activity or an antagonist of S1PR1. We also demonstrate that a synthetic S1PR1-selective agonist, SEW2871, stimulates the interaction between SR-B1 and S1PR1 and that this was also blocked by an inhibitor of SR-B1's lipid transport activity. Furthermore, we detected abundant SR-B1/S1PR1 complexes in atherosclerotic plaques of S1pr1eGFP/eGFP mice that also lacked apolipoprotein E. Treatment of mice with the S1PR1 antagonist, Ex26, for 12 h disrupted the SR-B1-S1PR1 interaction in atherosclerotic plaques. These findings demonstrate that SR-B1 and S1PR1 form ligand-dependent complexes both in cultured primary macrophages and within atherosclerotic plaques in mice and provide mechanistic insight into how SR-B1 and S1PR1 participate in mediating HDL signaling to activate atheroprotective responses in macrophages.

Lipoprotein lipids and apolipoproteins in primary immune thrombocytopenia: Results from a clinical characteristics and causal relationship verification, potential drug target identification by Mendelian randomization analyses.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease. Cellular and systemic lipid metabolism plays a significant role in the regulation of immune cell activities. However, the role of lipoprotein lipids and apolipoproteins in ITP remains elusive. The automatic biochemistry analyser was used to measure the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA-I), apoB, apoE and lipoprotein a [LP(a)]. Genetic variants strongly associated with circulating lipoprotein lipids and apolipoproteins (LDL-C, apoB, TG, HDL-C and apoA-I) were extracted to perform Mendelian randomization (MR) analyses. Finally, drug-target MR and passive ITP mice model was used to investigate the potential druggable targets of ITP. Levels of HDL-C, apoA-I, decreased and LP(a) increased in ITP patients compared with healthy controls. Low HDL-C was causally associated with ITP susceptibility. Through drug-target MR and animal modelling, ABCA1 was identified as a potential target to design drugs for ITP. Our study found that lipid metabolism is related to ITP. The causative association between HDL-C and the risk of ITP was also established. The study provided new evidence of the aetiology of ITP. ABCA1 might be a potential drug target for ITP.

Apolipoprotein A1 deficiency in mice primes bone marrow stem cells for T cell lymphopoiesis.

The bone marrow has emerged as a potentially important target in cardiovascular disease as it generates all leukocytes involved in atherogenesis. In the current study, we evaluated whether a change in bone marrow functionality underlies the increased atherosclerosis susceptibility associated with high-density lipoprotein (HDL) deficiency. We found that HDL deficiency in mice due to the genetic lack of hepatocyte-derived apolipoprotein A1 (APOA1) was associated with an increase in the Lin-Sca-1+Kit+ (LSK) bone marrow stem cell population and lymphoid-primed multipotent progenitor numbers, which translated into a higher production and systemic flux of T cell subsets. In accordance with APOA1 deficiency-associated priming of stem cells to increase T lymphocyte production, atherogenic diet-fed low-density lipoprotein receptor knockout mice transplanted with bone marrow from APOA1-knockout mice displayed marked lymphocytosis as compared to wild-type bone marrow recipients. However, atherosclerotic lesion sizes and collagen contents were similar in the two groups of bone marrow recipients. In conclusion, systemic lack of APOA1 primes bone marrow stem cells for T cell lymphopoiesis. Our data provide novel evidence for a regulatory role of HDL in bone marrow functioning in normolipidemic mice.

HDLs extract lipophilic drugs from cells.

High-density lipoproteins (HDLs) prevent cell death induced by a variety of cytotoxic drugs. The underlying mechanisms are however still poorly understood. Here, we present evidence that HDLs efficiently protect cells against thapsigargin (TG), a sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) inhibitor, by extracting the drug from cells. Drug efflux could also be triggered to some extent by low-density lipoproteins and serum. HDLs did not reverse the non-lethal mild ER stress response induced by low TG concentrations or by SERCA knockdown, but HDLs inhibited the toxic SERCA-independent effects mediated by high TG concentrations. HDLs could extract other lipophilic compounds, but not hydrophilic substances. This work shows that HDLs utilize their capacity of loading themselves with lipophilic compounds, akin to their ability to extract cellular cholesterol, to reduce the cell content of hydrophobic drugs. This can be beneficial if lipophilic xenobiotics are toxic but may be detrimental to the therapeutic benefit of lipophilic drugs such as glibenclamide.

HDL-C and apolipoprotein A-I are independently associated with skeletal muscle mitochondrial function in healthy humans.

Prior animal and cell studies have demonstrated a direct role of high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-I) in enhancing skeletal muscle mitochondrial function and exercise capacity. However, the relevance of these animal and cell investigations in humans remains unknown. Therefore, a cross-sectional study was conducted in 48 adults (67% female, 8% Black participants, age 39 ± 15.4 yr old) to characterize the associations between HDL measures, ApoA-I, and muscle mitochondrial function. Forearm muscle oxygen recovery time (tau) from postexercise recovery kinetics was used to assess skeletal muscle mitochondrial function. Lipoprotein measures were assessed by nuclear magnetic resonance. HDL efflux capacity was assessed using J774 macrophages, radiolabeled cholesterol, and apolipoprotein B-depleted plasma both with and without added cyclic adenosine monophosphate. In univariate analyses, faster skeletal muscle oxygen recovery time (lower tau) was significantly associated with higher levels of HDL cholesterol (HDL-C), ApoA-I, and larger mean HDL size, but not HDL cholesterol efflux capacity. Slower recovery time (higher tau) was positively associated with body mass index (BMI) and fasting plasma glucose (FPG). In multivariable linear regression analyses, higher levels of HDL-C and ApoA-I, as well as larger HDL size, were independently associated with faster skeletal muscle oxygen recovery times that persisted after adjusting for BMI and FPG (all P < 0.05). In conclusion, higher levels of HDL-C, ApoA-I, and larger mean HDL size were independently associated with enhanced skeletal muscle mitochondrial function in healthy humans.NEW & NOTEWORTHY Our study provides the first direct evidence supporting the beneficial role of HDL-C and ApoA-I on enhanced skeletal muscle mitochondrial function in healthy young to middle-aged humans without cardiometabolic disease.

Modulation of lipid profile by secretory phospholipase A2 group IIA: Verification with a transgenic mouse model.

We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.

Measurement of cumulative high-sensitivity C-reactive protein and monocyte to high-density lipoprotein ratio in the risk prediction of type 2 diabetes: a prospective cohort study.

BACKGROUND: Converging data have suggested that monocytic inflammation and C-reactive protein (CRP) are biologically intertwined processes and are involved in diabetogenesis. This study aimed to investigate the association between systemic inflammation assessed by joint cumulative high-sensitivity C-reactive protein (CumCRP) and monocyte to high-density lipoprotein ratio (CumMHR) and incident type 2 diabetes (T2D) and their predictive value for T2D in a general population. METHODS: A total of 40,813 nondiabetic participants from a prospective real-life cohort (Kailuan Study, China) were followed biennially from 2010/2011 until December 31, 2020. Multivariable Cox regression analyses were conducted to evaluate the adjusted hazard ratios (aHRs) of incident diabetes. RESULTS: During a median follow-up of 7.98 (IQR: 5.74-8.87) years, 4848 T2D cases developed. CumMHR and CumCRP were alone or jointly associated with incident T2D after adjusting for potential confounders. Elevated CumMHR levels significantly increased the risk of incident diabetes in each CumCRP strata (P-interaction: 0.0278). Participants with concomitant elevations in CumMHR and CumCRP levels had the highest risk (aHR: 1.71, 95% CI 1.52-1.91) compared to both in the low strata. Notably, the coexposure-associated T2D risk was modified by age, sex, hypertension, dyslipidemia, and prediabetes status. C-statistics increased from 0.7377 to 0.7417 when CumMHR and CumCRP were added into the multivariable-adjusted model, with a net reclassification improvement (%) of 12.39 (9.39-15.37) (P < 0.0001). CONCLUSIONS: Cumulative hsCRP and MHR were both independently and jointly associated with an increased risk of T2D and their addition to established risk factors should improve risk prediction and reclassification of diabetes.

Association between human herpesvirus 8 and lipid profile in northwest China: A cross-sectional study.

Human herpesvirus 8 (HHV-8) infection shows obvious regional and ethnic differences. Although studies have shown that these differences may be associated with lipid metabolism, to date, no large-scale studies have explored this. This study explored the seropositivity rate of HHV-8 among 2516 residents from 10 regions of northwest China and then the correlates of HHV-8 infection with lipid profile. The HHV-8 serological positivity rate was 15.6% among all residents. The HHV-8 seroprevalence ranged 11.2-27.6% among different ethnicities. Across different BMI levels, the positive rates of HHV-8 were 27.6%, 16.9%, and 13.6% for a BMI < 18.5, 18.5-24.9, and ≥25, respectively. HHV-8 seropositivity rate was lower for hypertensive people (12.6%) than for non-hypertensive people (16.7%). Univariate logistic regression analyses revealed that age, hypertension, systolic blood pressure, BMI, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) significantly correlated with HHV-8 seropositivity (p < 0.05). Multivariate logistic regression analysis after adjusting for confounding factors showed that HDL-C (odds ratio [OR]: 0.132, 95% confidence interval [CI], 0.082-0.212; p < 0.001) and BMI (OR: 0.959, 95% CI 0.933-0.986; p = 0.003) were associated with HHV-8 seropositivity. Subgroup analyses concerning ethnicity, sex, or age demonstrated a consistent relationship with HDL-C. The results of HHV-8 seropositivity and BMI were inconsistent in the subgroups. However, Spearman's correlation analysis between HHV-8 serum antibody titer and HDL-C levels showed no linear relationship among HHV-8 seropositive individuals (ρ = -0.080, p = 0.058). HHV-8 serum antibody titers were also not significantly correlated with BMI (ρ = -0.015, p = 0.381). Low HDL-C levels may be an independent risk factor for HHV-8 infection, but there is no significant correlation between HDL-C levels and HHV-8 antibody titers.

Improvement of high-density lipoprotein atheroprotective properties in patients with systemic lupus erythematosus after belimumab treatment.

OBJECTIVE: Chronic inflammatory diseases, like Systemic Lupus Erythematosus (SLE), carry an increased risk for atherosclerosis and cardiovascular events, accompanied by impairment of atheroprotective properties of high-density lipoprotein (HDL). In SLE, serum BAFF (B cell-activating factor), a cytokine implicated in disease progression, has been correlated with subclinical atherosclerosis. We investigated the impact of treatment with belimumab -an anti-BAFF monoclonal antibody- on HDL atheroprotective properties and composition in SLE patients. METHODS: Serum samples were collected from 35 SLE patients with active disease despite conventional therapy, before and after 6-month add-on treatment with belimumab, and 26 matched healthy individuals. We measured cholesterol efflux and antioxidant capacities, paraoxonase-1 activity, serum amyloid A1, myeloperoxidase and lipid peroxidation product levels of HDL. LC-MS/MS was performed to analyze the HDL lipidome. RESULTS: Following treatment with belimumab, cholesterol efflux and antioxidant capacities of HDL were significantly increased in SLE patients and restored to levels of controls. HDL-associated paraoxonase-1 activity was also increased, whereas lipid peroxidation products were decreased following treatment. HDL cholesterol efflux and antioxidant capacities correlated negatively with the disease activity. Changes were noted in the HDL lipidome of SLE patients following belimumab treatment, as well as between SLE patients and healthy individuals, and specific changes in lipid species correlated with functional parameters of HDL. CONCLUSIONS: HDL of SLE patients with active disease displays impaired atheroprotective properties accompanied by distinct lipidomic signature compared with controls. Belimumab treatment may improve the HDL atheroprotective properties and modify the HDL lipidomic signature in SLE patients, thus potentially mitigating atherosclerosis development.

Coupling capillary electrophoresis with mass spectrometry for the analysis of oxidized phospholipids in human high-density lipoproteins.

The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20 mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20 kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10 V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0 µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52 µg/mL, and the concentration limit of quantitation was 4.60 µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.

The triglyceride glucose: high-density lipoprotein cholesterol ratio is associated with coronary artery calcification evaluated via non-gated chest CT.

BACKGROUND: Coronary artery calcification (CAC) is a common risk factor of cardiovascular disease. Although triglyceride glucose (TYG) index and high-density lipoprotein cholesterol (HDL-c) are both associated with CAC, no study has evaluated the correlation between the TYG/HDL-c ratio and CAC. In the present study, we investigated the relationships between CAC and the TYG index and the TYG/HDL-c ratio. METHODS: A total of 9585 participants who underwent computed tomography (CT) screening for lung cancer from 2018 to 2020 were included in this cross-sectional study. Demographic data, laboratory test data and medical history data were collected from medical records. TYG = Ln[fasting glucose (mg/dL)×fasting TG (mg/dL/2]. The triglyceride glucose-HDL-c ratio was calculated as TYG/HDL-c. CAC was evaluated on chest CT images. Multivariate logistic regression analysis and restricted cubic splines were used to determine the relationships among the TYG index, TYG/HDL-c ratio and risk of CAC. The receiver operating characteristic (ROC) curve was used to evaluate the performance of the TYG index and TYG/HDL-c ratio in identifying CACs in individuals aged 60 years and above. RESULTS: CAC was detected in 2515 of 9585 participants (mean age 51.8 ± 15.5 years, 61.2% men). The prevalence of CAC was significantly greater in participants with a high TYG/HDL-c ratio (32.6% in the fourth quartile vs. 19.1% in the first quartile, p < 0.001). Multivariate logistic regression revealed that both the TYG index (odds ratio (OR) = 1.06, 95% confidence interval (CI): 1.02-1.10) and the TYG/HDL-c ratio were associated with coronary artery calcification (OR = 1.32, 95% CI: 1.14-1.51). No such association was observed between the TYG index and CAC when further adjusted for the serum lipid level (OR = 1.23, 95% CI: 0.99-1.54). The TYG/HDL-c ratio was still associated with CAC after further adjustment for low-density lipoprotein cholesterol and total cholesterol (OR = 1.21, 95% CI: 1.09-1.35). TYG/HDL-c ratio was associated both with single vessel and multivessel calcification (OR = 1.14, 95%CI:1.05-1.23; OR = 1.15, 95%CI: 1.05-1.21). Similar trends were observed when we categorized individuals by TYG index and TYG/HDL-c quartiles and in subjects older than 60 years. Restricted cubic splines revealed that the TYG/HDL ratio had a better dose‒responsive relationship than did the TYG index. Subgroup analysis revealed that the association between the TYG/HDL-c ratio and coronary artery calcification was mainly observed in nondiabetic or nonhypertensive participants, regardless of low-density lipoprotein cholesterol levels. The ROC curve also revealed that the TYG/HDL-c ratio was better able to identify CAC than the TYG index was (area under the curve = 0.54 vs. 0.52, p < 0.01) in subjects older than 60 years. CONCLUSION: An increase in the TYG/HDL-c ratio is significantly positively associated with the risk of CAC, and the TYG/HDL-c ratio has a more stable association with CAC than TYG.

Sex differences in the association between insulin resistance and non-fatal myocardial infarction across glycaemic states.

BACKGROUND: Females are generally less prone to cardiovascular (CV) events than males, but this protection is trumped by diabetes. The mechanism behind the increased relative risk in females with diabetes is not fully understood. Insulin resistance (IR) is suggested to be a more important contributor to CV morbidity in females than in males. We aim to investigate differences in the association between IR indexes (Homeostatic Model Assessment of IR - HOMA-IR, visceral adiposity index - VAI, and triglycerides/high-density lipoprotein-cholesterol - TG/HDL-C index), and a first non-fatal myocardial infarction (MI) across different glycaemic states. METHODS: IR indexes were calculated in a population with (n = 696) and without (n = 707) a first non-fatal MI, free from known diabetes. MI cases were investigated at least six weeks after the event. All participants were categorized by an oral glucose tolerance test as having normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Comparison of proportion of glycaemic states by sex was tested by chi-square test. The associations between sex, a first non-fatal MI, IR indexes, and traditional CV risk factors were analysed by multivariate logistic regression models. Continuous variables were logarithmically transformed. RESULTS: Of the total population 19% were females and 81% males, out of whom 47% and 50% had a first non-fatal MI, respectively. Compared with males, females were older, less often smokers, with lower body mass index and higher total cholesterol and high-density lipoprotein cholesterol levels. The proportion of glycaemic states did not differ between the sexes (p = 0.06). Females were less insulin resistant than males, especially among cases and with normal glucose tolerance. In logistic regression models adjusted for major CV risk factors including sex, the associations between VAI and TG/HDL-C index and a first non-fatal MI remained significant only in females (odds ratios and 95% confidence intervals: 1.7, 1.0-2.9, and 1.9, 1.1-3.4 respectively). CONCLUSIONS: These results support the assumption that IR indexes based on anthropometrics and lipid panel, i.e., VAI and TG/HDL-C, could be a better measure of IR and CV-predictor for non-fatal MI in females, even without glycaemic perturbations.

Fish Oil Supplementation Modifies the Proteome, Lipidome, and Function of High-Density Lipoprotein: Findings from a Trial in Young Healthy Adults.

BACKGROUND: Fish oil with the ω-3 fatty acids EPA and DHA is an FDA-approved treatment of patients with severe hypertriglyceridemia. Furthermore, EPA is an FDA-approved treatment of patients with high risk of cardiovascular disease (CVD); however, the cardioprotective mechanisms are unclear. OBJECTIVES: We aimed to determine if fish oil supplementation is cardioprotective due to beneficial modifications in HDL particles. METHODS: Seven fish oil naïve subjects without a history of CVD were recruited to take a regimen of fish oil (1125 mg EPA and 875 mg DHA daily) for 30 d, followed by a 30-d washout period wherein no fish oil supplements were taken. HDL isolated from fasting whole blood at each time point via 2-step ultracentrifugation (ucHDL) was assessed for proteome, lipidome, cholesterol efflux capacity (CEC), and anti-inflammatory capacity. RESULTS: Following fish oil supplementation, the HDL-associated proteins immunoglobulin heavy constant γ1, immunoglobulin heavy constant α1, apolipoprotein D, and phospholipid transfer protein decreased compared to baseline (P < 0.05). The HDL-associated phospholipid families sphingomyelins, phosphatidylcholines, and phosphatidylserines increased after fish oil supplementation relative to baseline (P < 0.05). Compared to baseline, fish oil supplementation increased serum HDL's CEC (P = 0.002). Fish oil-induced changes (Post compared with Baseline) in serum HDL's CEC positively correlated with plasma EPA levels (R2 = 0.7256; P = 0.015). Similarly, fish oil-induced changes in ucHDL's CEC positively correlated with ucHDL's ability to reduce interleukin 10 (R2 = 0.7353; P = 0.014) and interleukin 6 mRNA expression (R2 = 0.6322; P =0.033) in a human macrophage cell line. CONCLUSIONS: Overall, fish oil supplementation improved HDL's sterol efflux capacity through comprehensive modifications to its proteome and lipidome.

Nomogram incorporating preoperative pan-immune-inflammation value and monocyte to high-density lipoprotein ratio for survival prediction in patients with colorectal cancer: a retrospective study.

OBJECTIVE: Using the preoperative pan-immune-inflammation value (PIV) and the monocyte to high-density lipoprotein ratio (MHR) to reflect inflammation, immunity, and cholesterol metabolism, we aim to develop and visualize a novel nomogram model for predicting the survival outcomes in patients with colorectal cancer (CRC). METHODS: A total of 172 patients with CRC who underwent radical resection were retrospectively analyzed. Survival analysis was conducted after patients were grouped according to the optimal cut-off values of PIV and MHR. Univariate and multivariate analyses were performed using Cox proportional hazards regression to screen the independent prognostic factors. Based on these factors, a nomogram was constructed and validated. RESULTS: The PIV was significantly associated with tumor location (P < 0.001), tumor maximum diameter (P = 0.008), and T stage (P = 0.019). The MHR was closely related to gender (P = 0.016), tumor maximum diameter (P = 0.002), and T stage (P = 0.038). Multivariate analysis results showed that PIV (Hazard Ratio (HR) = 2.476, 95% Confidence Interval (CI) = 1.410-4.348, P = 0.002), MHR (HR = 3.803, 95%CI = 1.609-8.989, P = 0.002), CEA (HR = 1.977, 95%CI = 1.121-3.485, P = 0.019), and TNM stage (HR = 1.759, 95%CI = 1.010-3.063, P = 0.046) were independent prognostic indicators for overall survival (OS). A nomogram incorporating these variables was developed, demonstrating robust predictive accuracy for OS. The area under the curve (AUC) values of the predictive model for 1-, 2-, and 3- year are 0.791,0.768,0.811, respectively. The calibration curves for the probability of survival at 1-, 2-, and 3- year presented a high degree of credibility. Furthermore, Decision curve analysis (DCA) for the probability of survival at 1-, 2-, and 3- year demonstrate the significant clinical utility in predicting survival outcomes. CONCLUSION: Preoperative PIV and MHR are independent risk factors for CRC prognosis. The novel developed nomogram demonstrates a robust predictive ability, offering substantial utility in facilitating the clinical decision-making process.