apoC-III Levels Research Articles

Potential biomarkers identified by tandem mass tags based quantitative proteomics for diagnosis and classification of Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A comparative proteomics analysis was performed on the cerebrospinal fluid (CSF) from 10 patients with GBS and 10 patients with noninflammatory neurological disease (NND) using the tandem mass tags technique. The differentially expressed proteins were analyzed by bioinformatics, and then the candidate proteins were validated by the enzyme-linked immunosorbent assay method in another cohort containing 160 samples (paired CSF and plasma of 40 patients with GBS, CSF of 40 NND patients and plasma of 40 healthy individuals). In all, 298 proteins were successfully identified in the CSF samples, of which 97 differentially expressed proteins were identified in the GBS and NND groups. Three key molecules were identified as candidate molecules for further validation. The CSF levels of TGOLN2 and NCAM1 decreased in GBS patients compared with NND patients, whereas the CSF levels of APOC3 increased. The enzyme-linked immunosorbent assay results were consistent with our proteomics analysis. Interestingly, in the validation cohort, serum APOC3 levels in the GBS group were consistent with those in the CSF samples and significantly higher than those in the healthy control group. Our preliminary data suggest that the CSF protein expression profile of patients with GBS is different from that of patients with NND. Moreover, alterations of TGOLN2, NCAM1and APOC3 may be used as novel biomarkers for identifying patients with GBS.

Serum PCSK9 Correlates with PTX3 and Apolipoproteins B, A1, and C3 Concentrations in Patients with Type 2 Diabetes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the regulation of LDL metabolism. There is evidence that circulating PCSK9 is a cardiovascular risk factor. In this study, we determined factors associated with circulating PCSK9 in a group of patients with type 2 diabetes mellitus (DM2). Material included 116 consecutive patients with DM2 from outpatient diabetes clinic. Circulating PCSK9, PTX3, apolipoprotein (apo) B100, apo B48, and apo C3 levels were determined by ELISA, apo A1 by immunoturbidimetry. The mean (sd) age of patients was 59.1 (11.1) years, the mean (sd) values of serum PCSK9 were 255.4 (106.97) ng/ml. Circulating PCSK9 correlated negatively with age (r = −0.21, p < 0.05) and HbA1c (r = −0.21, p < 0.05) and positively with BMI (r = 0.21, p < 0.05), total cholesterol (r = 0.59), LDL-cholesterol (r = 0.50), triglyceride (r = 0.35), apo B100 (r = 0.43), apo A1 (r = 0.43) (p < 0.001 for all), apo C3 (r = 0.29, p < 0.01), and apo B48 (r = 0.25, p < 0.01) concentration and FLI (r = 0.26, p < 0.01). Strong correlation between PTX3 and PCSK9 levels was observed (r = 0.47, p < 0.001). Multiple stepwise backward regression analysis with PCSK9 as dependent variable revealed that PTX3, apo B100, apo A1, apo B48, and BMI were significantly positive and the presence of NAFLD and HbA1c negatively associated with PCSK9 concentrations. These variables together explain 57% of PCSK9 variability; the strongest relationship was observed between PCSK9 and PTX3 and apo B100. Our results indicate that circulating PCSK9 is significantly associated with inflammation marker PTX3 as well as atherogenic lipids and apolipoproteins C3, B100, and B48, which might be of value in understanding interactions between development of atherosclerosis and inflammatory state in DM2 patients.

Disease activity in patients with rheumatoid arthritis increases serum levels of apolipoprotein C-III.

Rheumatoid arthritis (RA) has been unequivocally associated with an increased burden of accelerated atherosclerosis, which, at least in part, is a consequence of the inflammation present in the disease. Apolipoprotein C-III (ApoC3) is a key molecule in triglycerides metabolism that has been linked to cardiovascular (CV) disease. Our objective was to study how ApoC3 is related to the characteristics of RA, paying special attention to its relationship with the inflammatory activity of the disease. Cross-sectional study that included 430 patients with RA. In these patients, data related to the disease, classic CV risk factors, complete lipid profile, and serum ApoC3 levels were evaluated. A multivariable regression analysis was performed to study the relationship of the characteristics of RA with ApoC3. Abdominal circumference, obesity, type 2 diabetes, and circulating triglycerides were significantly associated with higher ApoC3 serum levels. Furthermore, C-reactive protein and erythrocyte sedimentation rate, as well as the disease activity score -DAS28- were significantly related to a higher circulating ApoC3 after multivariable analysis. Patients included in the moderate or high disease activity groups had higher ApoC3 serum levels compared to those in remission (beta coefficient 1.28 [95% confidence interval 0.16-2.39] mg/dl, p=0.025) when adjusting for confounders. The use of prednisone, disease-modifying anti-rheumatic drugs and anti-tumour necrosis factor therapies was associated with lower values of ApoC3. The activity of the disease in patients with RA is independently associated with higher serum levels of ApoC3.

Plasma Proteomics Characteristics of Subclinical Vitamin E Deficiency of Dairy Cows During Early Lactation.

Vitamin E (VE) is an essential fat-soluble nutrient for dairy cows. Vitamin E deficiency leads to immune suppression and oxidative stress and increases the susceptibility of cows to reproductive disorders in the early post-partum period. However, studies on plasma proteomics of VE deficiency have not been reported so far. Therefore, the purpose of this study was to understand the changes of blood protein profile in cows with subclinical VE deficiency in the early post-partum period. In this study, plasma protein levels of 14 healthy cows (>4 μg/ml α-tocopherol) and 13 subclinical VE-deficient cows (2–3 μg/ml α-tocopherol) were analyzed by tandem mass tag (TMT). The results showed that there were 26 differentially expressed proteins (DEPs) in the plasma of cows with subclinical VE deficiency compared with healthy controls. Twenty-one kinds of proteins were downregulated, and five kinds were upregulated, among which eight proteins in protein–protein interactions (PPI) network had direct interaction. These proteins are mainly involved in the MAPK signaling pathway, pantothenic acid and coenzyme A (CoA) biosynthesis, PPAR signaling pathway, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The top four DEPs in PPI (APOC3, APOC4, SAA4, PHLD) and one important protein (VNN1) by literature review were further verified by ELISA and Western blot. The expression levels of APOC3, VNN1, and SAA4 were significantly lower than those of healthy controls by ELISA. VNN1 was significantly lower than those of healthy controls by Western blot. VNN1 is closely related to dairy cow subclinical VE deficiency and can be a potential biomarker. It lays a foundation for further research on the lack of pathological mechanism and antioxidative stress of VE.

CSF apolipoprotein B levels predict future visuospatial cognitive decline and synaptic pathology in cognitively unimpaired healthy elderly with a parental history of Alzheimer’s disease

AbstractBackgroundWe examine the role of brain apolipoprotein B (apoB) as a putative CSF indicator of early tau pathology in pre‐symptomatic Alzheimer’s disease (AD).MethodAmong 129 cognitively unimpaired elderly at increased risk of AD (PREVENT‐AD cohort), we assessed blood and cerebrospinal fluid apoB, apoC3 and apoE protein levels with those of amyloid β42, total tau and phosphorylated tau. We compared results with amyloid‐b (NAV4694) and tau (flortaucipir) positron emission tomography uptake and cognitive assessment alterations over 6‐8 years. Tangle and plaque pathologies were contrasted with cortical APOB, APOC3 and APOE mRNA levels in 240 autopsied subjects enrolled in the Religious Orders Study and Memory and Aging Project (ROSMAP) studies with diagnoses of cognitively unimpaired, mild cognitive impairment, or AD.ResultAmong cognitively unimpaired participants, we observed significant correlations between baseline CSF, but not blood, apoB levels and both CSF t‐tau (R2 = 0.23, P &lt; 0.0001) and P‐tau (R2 = 0.28, P &lt; 0.0001). Similar associations were observed when using PET flortaucipir‐binding in entorhinal, parahippocampal and fusiform regions. No association was detected between CSF apoB and CSF Aβ42 levels or cerebral Ab deposition. Baseline CSF apoB levels were associated with visuospatial cognitive decline over the course of 6‐8 years (R2 = 0.13, P &lt; 0.02) and alterations in several synaptic proteins in the CSF. Contribution from peripheral apoB was found to be negligible. In ROSMAP, APOB gene expression failed to correlate with either tangle pathology or amyloid plaque deposition.ConclusionCSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at‐risk individuals predisposed to develop visuospatial cognitive decline over time.

CSF apolipoprotein B is associated with early tau pathology and selective activation of a cytokine cascade in cognitively unaffected subjects with a parental history of Alzheimer’s disease

AbstractBackgroundWe examine the role of CSF apolipoprotein B (apoB) as a putative indicator of early tau pathology in pre‐symptomatic Alzheimer’s disease (AD).MethodAmong 129 cognitively unimpaired elderly at increased risk of AD (PREVENT‐AD cohort), we assessed blood and cerebrospinal fluid apoB, apoC3 and apoE protein levels using the the Milliplex APOMAG‐62k human apolipoprotein cardiovascular disease multiplex kit (EMD‐Millipore, MA, USA) with those of amyloid β42, total tau and phosphorylated tau (the Innotest enzyme‐linked immunosorbent assay kit (Fujirebio, Ghent, Belgium). We contrasted results with alterations in several inflammation biomarkers using Luminex’s Milliplex HCYTMAG60PMX29BK xMap technology ((EMD‐Millipore, USA).ResultAmong cognitively unimpaired participants, we observed significant correlations between baseline CSF, but not blood, apoB levels and both CSF t‐tau (R2 = 0.23, P &lt; 0.0001) and P‐tau (R2 = 0.28, P &lt; 0.0001). No association was detected between CSF apoB and CSF Aβ42 levels. Using multiple brain blood barrier permeability assays, we found that the contribution from peripheral apoB to be negligible. Concomitant analyses of several key cytokines and chemokines in the CSF failed to show any association following FDR correction, except for IL‐15 (R2: 0.38, p &lt; 0.001). IL‐15, a potent inducer of reactive gliosis in both astrocytes and microglia, is normally synthesized by compromised neurons in the CNS.ConclusionCSF apoB, which is normally produced by microglia, markedly associates with early tau dysregulation and the activation of select cytokines in asymptomatic subjects, years before the onset of symptoms.

Abstract 13534: Plasma Apolipoprotein C3 is Negatively Associated With High Lipoprotein(a) Plasma Levels in Healthy Volunteers

Introduction: ApoliproteinC3 (apoC3) is a small (~8.8kDa) protein, made in the liver. It is an inhibitor of lipoprotein lipase as well as the uptake of triglyceride (TG) rich lipoproteins and remnants by the liver. Overexpression contributes to atherosclerosis by increasing plasma concentration of TG-rich lipoproteins. A recent study reported the presence of apoC3 on lipoprotein(a) [Lp(a)] particles in subjects with mild to moderate aortic stenosis. Lp(a) is an apoB100 containing lipoprotein with apo(a) covalently bound and is a causal factor of ASCVD. Our goal was to investigate relationships between apoC3 and Lp(a) in a healthy population. Methods: We analyzed data from 39 healthy subjects who completed studies of lipoprotein metabolism at the Columbia University Irving Medical Center. Subjects were 18 - 75 years old, and 44% were female. Twenty were Black, 9 Hispanic, 8 White, and 2 mixed race. Lipids (total Cholesterol (C), TG, HDLC, LDLC) were measured by an automatic analyzer. Plasma apoC3, apoB100 and Lp(a) levels were measured via validated ELISA assays. Lp(a) particles were isolated from plasma by immunoprecipitation (IP) with a monoclonal antibody and Western blots were performed. Results: We did not find an association between plasma Lp(a) and apoC3 levels. In a sub-group analysis of participants (N=15), with Lp(a) levels &gt;100nmol/L, we found a significant negative association between apoC3 and Lp(a) plasma concentrations (R = -0.58, p=0.018). Based on the Western blots and ELISA analysis, we see an interaction between Lp(a) (apo(a) and apoB100 intact) and apoC3. There seem to be some differences in the Lp(a) and apoC3 interaction based on Lp(a) plasma concentration. Conclusion and Future Direction: In healthy subjects, there is no association of apoC3 with Lp(a) plasma levels. In a subset of subjects (high Lp(a)), we observed an association with apoC3 plasma levels. Our small data set suggests possible distinct roles for apoC3 in healthy individuals with high Lp(a) level. ApoC3 may be associated with specific circulating isoform sizes of Lp(a). Future studies will focus on analysis of larger cohorts and examining lipid composition in the isolated particles.

Abstract 11174: Effect of APOCIII-L Rx on Lipoprotein Size and Particle Numbers Measured by NMR in Patients with Hypertriglyceridemia: Results of the AKCEA-APOCIII-L Rx Trial

Background: APOCIII-L Rx is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apoC-III and triglyceride-rich lipoproteins (TRLs). We examined the effect of APOCIII-L Rx on a variety of lipoprotein fractions measured by nuclear magnetic resonance (NMR) spectroscopy. Methods: The AKCEA-APOCIII-L Rx trial was a dose-ranging study in 114 patients with, or at risk for, ASCVD and fasting serum triglycerides 200-500 mg/dL. Patients (n=114) received AKCEA-APOCIII-L Rx (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. Comprehensive NMR LipoProfile ® analysis was performed by LipoScience/LabCorp in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. Results: Results are reported as change from baseline to PAT for the 50 mg every 4 weeks dose versus placebo. APOCIII-L Rx resulted in a significant reduction in total TRL particle (TRLP) concentration by 51% (P&lt;0.0001) with largest reductions in large-size (by 68%, P&lt;0.0001) and medium-size (by 63%, P&lt;0.0001) TRLPs. Total LDL particle (LDLP) concentration was not changed, small LDLP numerically decreased by 39% (P= 0.0713) while medium LDLP increased by 187% (P=0.0119), accompanied by an increase in average LDL size by xx 2% (p=0.0039xx). Total HDL particle (HDLP) concentration increased by 15% (P=0.0006), represented primarily by an increase in small HDL subspecies (particle diameters &lt;8.3 mm) of 32% (P=0.0008). Lower cumulative doses of APOCIII-L Rx generally reflected a dose-dependent relationship in the above parameters. Conclusion: APOCIII-L Rx results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDLP. These findings suggest an improvement in overall atherogenic risk profile.

Clusterin, paraoxonase 1, and myeloperoxidase alterations induce high-density lipoproteins dysfunction and contribute to peripheral artery disease; aggravation by type 2 diabetes mellitus.

Peripheral artery disease (PAD) is an atherosclerotic disorder affecting arteries of the lower limbs, the major risk factors including dyslipidemia and diabetes mellitus (DM). We aimed to identify alterations of the proteins in high-density lipoproteins (HDL) associated with HDL dysfunction in PAD patients. HDL2 and HDL3 were isolated from plasma of PAD patients with/without DM (PAD-DM/PAD) and healthy subjects (N). Apolipoprotein AI (ApoAI), ApoAII, ApoCIII, clusterin (CLU), paraoxonase 1 (PON1), myeloperoxidase (MPO), and ceruloplasmin (CP) were measured in HDL2 /HDL3 and plasma. Oxidation and glycation of the analyzed proteins were assessed as malondialdehyde-protein adducts (MDA) and advanced glycation end-products (AGE), respectively. The anti-inflammatory effect of HDL3 was estimated as its potential to reduce monocyte adhesion to tumor necrosis factor α-activated endothelial cells. We show that in PAD patients compared to N subjects: (i) HDL2 presented increased levels of MDA-PON1, AGE-PON1, AGE-ApoAI, ApoAII, ApoCIII, and CP levels, and decreased PON1 levels; (ii) HDL3 had increased levels of MDA- and AGE-CLU and -ApoAI, MDA-PON1, ApoCIII, CLU, MPO, CP, and reduced PON1 levels. All these alterations were exacerbated by DM. These changes were more pronounced in HDL3 , which had reduced anti-inflammatory potential in PAD and became pro-inflammatory in PAD-DM. In PAD patients' plasma, CLU levels and MPO specific activity increased, while PON1 specific activity decreased. In conclusion, HDL function is altered in PAD patients due to multiple modifications of associated proteins that are aggravated by DM. Plasma CLU, MPO, and PON1 could constitute indicators of HDL dysfunction and contribute to risk stratification in PAD patients.

A lifestyle intervention with an energy-restricted Mediterranean diet and physical activity enhances HDL function: a substudy of the PREDIMED-Plus randomized controlled trial

Consumption of a Mediterranean diet, adequate levels of physical activity, and energy-restricted lifestyle interventions have been individually associated with improvements in HDL functions. Evidence of intensive interventions with calorie restriction and physical activity is, however, scarce. To determine whether an intensive lifestyle intervention with an energy-restricted Mediterranean diet plus physical activity enhanced HDL function compared to a non-hypocaloric Mediterranean eating pattern without physical activity. In 391 older adults with metabolic syndrome (mean age, 65 years; mean BMI, 33.3kg/m2) from 1 of the Prevención con Dieta Mediterránea-Plus trial centers, we evaluated the impact of a 6-month intervention with an energy-restricted Mediterranean diet plus physical activity (intensive lifestyle; n=190) relative to a nonrestrictive Mediterranean diet without physical activity (control; n=201) on a set of HDL functional traits. These included cholesterol efflux capacity, HDL oxidative/inflammatory index, HDL oxidation, and levels of complement component 3, serum amyloid A, sphingosine-1-phosphate, triglycerides, and apolipoproteins A-I, A-IV, C-III, and E in apoB-depleted plasma. The intensive-lifestyle intervention participants displayed greater 6-month weight reductions (-3.83kg; 95% CI: -4.57 to -3.09 kg) but no changes in HDL cholesterol compared with control-diet participants. Regarding HDL functional traits, the intensive lifestyle decreased triglyceride levels (-0.15mg/g protein; 95% CI: -0.29 to -0.014 mg/g protein) and apoC-III (-0.11mg/g protein; 95% CI: -0.18 to -0.026 mg/g protein) compared to the control diet, with weight loss being the essential mediator (proportions of mediation were 77.4% and 72.1% for triglycerides and apoC-III levels in HDL, respectively). In older adults with metabolic syndrome, an energy-restricted Mediterranean diet plus physical activity improved the HDL triglyceride metabolism compared with a nonrestrictive Mediterranean diet without physical activity. This trial is registered at isrctn.com as ISRCTN89898870.

TMT-Based Plasma Proteomics Reveals Dyslipidemia Among Lowlanders During Prolonged Stay at High Altitudes.

Acute exposure to high altitude perturbs physiological parameters and induces an array of molecular changes in healthy lowlanders. However, activation of compensatory mechanisms and biological processes facilitates high altitude acclimatization. A large number of lowlanders stay at high altitude regions from weeks to months for work and professional commitments, and thus are vulnerable to altitude-associated disorders. Despite this, there is a scarcity of information for molecular changes associated with long-term stay at high altitudes. In the present study, we evaluated oxygen saturation (SpO2), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) of lowlanders after short- (7 days, HA-D7) and long-term (3 months, HA-D150) stay at high altitudes, and used TMT-based proteomics studies to decipher plasma proteome alterations. We observed improvements in SpO2 levels after prolonged stay, while HR, SBP, and DBP remained elevated as compared with short-term stay. Plasma proteomics studies revealed higher levels of apolipoproteins APOB, APOCI, APOCIII, APOE, and APOL, and carbonic anhydrases (CA1 and CA2) during hypoxia exposure. Biological network analysis also identified profound alterations in lipoprotein-associated pathways like plasma lipoprotein assembly, VLDL clearance, chylomicron assembly, chylomicron remodeling, plasma lipoprotein clearance, and chylomicron clearance. In corroboration, lipid profiling revealed higher levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) for HA-D150 whereas high density lipoproteins (HDL) levels were lower as compared with HA-D7 and sea-level indicating dyslipidemia. We also observed higher levels of proinflammatory cytokines IL-6, TNFα, and CRP for HA-D150 along with oxidized LDL (oxLDL), suggesting vascular inflammation and proartherogenic propensity. These results demonstrate that long-term stay at high altitudes exacerbates dyslipidemia and associated disorders.

Plasma apoC-III levels predict coronary severity and cardiovascular risks in stable coronary artery disease patients with diabetes or pre-diabetes: a prospective cohort study

Abstract Background Apolipoprotein C-III (apoC-III) has been proposed to be involved in lipid and glucose metabolism and related to cardiovascular risks. The aim of this study is to investigate the association of apoC-III levels with coronary severity and cardiovascular outcomes in coronary artery disease (CAD) patients under different glucose metabolism status. Methods A total of 4342 consecutive patients with newly angiography-proven stable CAD were enrolled and categorized into three groups according to apoC-III levels and further stratified by glucose metabolism status [diabetes mellitus (DM), pre-DM, normal glucose regulation (NGR)]. Patients were followed for the occurrence of cardiovascular events (CVEs). Plasma apoC-III concentration was measured by enzyme immunoassay and coronary severity was assessed by number of diseased vessels, Gensini score and syntax score. The relationships of apoC-III levels with coronary severity and CVEs were evaluated. Results 389 (9.0%) CVEs were developed during a follow-up of 5.1 years. Plasma apoC-III levels were increased in prediabetic and diabetic patients with stable CAD. Elevated apoC-III levels were associated with more severe coronary lesion and the risk for CVEs. No significant differences in incident CVEs and coronary severity were observed between pre-DM and NGR groups. When combined glucose metabolism status and apoC-III levels as stratifying factors, patients with the highest apoC-III levels and pre-diabetic or diabetic patients with any levels of apoC-III had more sever coronary lesion and higher risk of subsequent CVEs compared to those with the lowest apoC-III levels and NGR. Conclusion Our data firstly found that elevated apoC-III levels were greatly associated with coronary severity and adverse cardiovascular events in stable CAD patients with pre-DM and DM, which suggested apoC-III may be a prognostic predictor among CAD patient with impaired glucose metabolism. Funding Acknowledgement Type of funding sources: None.

Intra-population differences of apolipoproteins in the aqueous humor

BackgroundEvidence suggests that proteins related to lipid metabolism, such as apolipoproteins, play an important role in the maintenance of normal vision. While several members of the apolipoprotein family are abundant in human aqueous humor (AH), their study remains difficult due to the AH’s small volume, low protein concentration, and the invasive nature of sample collection. In this study, we report the use of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to discover associations between AH apolipoproteins and race, gender, and ocular structure in patients with and without primary open angle glaucoma (POAG).MethodsAH samples were collected from 231 patients undergoing phacoemulsification or glaucoma incisional surgery at the Medical College of Georgia, Augusta University and subsequently analyzed via LC-MS/MS. The number of peptide spectrum matches (PSMs) for each protein was used as a semi-quantitative measure of relative protein levels. Parameters related to ocular structure were determined using Optical Coherence Tomography (OCT) and Heidelberg Retinal Tomography (HRT). These data sets were probed for relationships between apolipoprotein levels and POAG, demographics (gender and race), and ocular structure.ResultsA total of ten apolipoproteins were detected in the 231 collected AH samples, with six detected in 100% of the samples, one detected in almost 57% of the samples and three detected in less than 10% of the samples. The levels of APOA1, APOC3, and APOD were higher among POAG subjects. Stratification by gender and race revealed demographic-specific variations. The levels of five apolipoproteins (APOA1, APOA2, APOA4, APOC3, and APOD) were higher in female POAG patients, whereas no apolipoprotein levels were altered in male POAG patients. The levels of APOA1, APOA2, APOA4, and APOD were increased in glaucomatous African American patients, whereas APOE and APOH levels were decreased in glaucomatous Caucasian patients. We also found distinct associations between apolipoprotein levels and OCT and HRT parameters in patients with and without POAG.ConclusionsThe intra-population variation in apolipoprotein levels highlights the heterogeneity of glaucoma as a disease, suggesting the importance of personalized treatments. Gender and race-specific alterations may be associated with higher risks of POAG in females and members of the African American population.

A randomized, placebo-controlled, double-blind study on the effects of SZL on patients with mild to moderate depressive disorder with comparison to fluoxetine

Ethnopharmacological relevanceKaixinsan (KXS) decoction, as an herbal formula, was used to treat the diseases, such as insomnia, amnesia, emotional disorders in ancient china. It has been demonstrated to be active in various animal models resembling human depression with multitarget effects. However, effective verification on the clinical application of KXS is still lacking. Supplements in this knowledge field are urgently needed. Aim of the studyThis very first study evaluated the efficacy and tolerability of ShenZhiLing (SZL) tablets (KXS preparation), compared with fluoxetine (FLX, positive comparator), in patients with mild to moderate depressive disorder. Materials and methodsIn this randomized, double-blind, parallel-group study, 156 patients with mild to moderate depression without taken any antidepressants in the past 6 months or 4 continuous weeks were randomized to receive either 3.2 g/d SZL plus 20 mg/d FLX placebo (SZL group) or 20 mg/d FLX plus 3.2 g/d SZL placebo (FLX group), for 8 weeks. Their clinical presentations and some metabolic indexes were assessed during the 8 weeks' visiting period. ResultsPatients in SZL group showed a statistically significant improvement after 8 weeks of treatment in HAM-D17 score (18.79±2.09 to 4.43±4.71, p<0.001) and self-rating depression scale (SDS) score (58.49±8.89 to 39.84±12.09, p<0.001), but not in N-back total respond time (1145.55±608.26 to 1128.47±387.49, p>0.05). In addition, no significant difference at 8 weeks of treatment was found between SZL and FLX groups in SDS score (39.84±12.09 vs. 36.63±12.44) and N-back respond time (1128.47±387.49 vs. 1089.43±352.08) as well as reduction of HAM-D17 score (14.79±4.88 vs. 15.24±4.29) (p>0.05 for all). However, the serum APOB, APOC3 and ALB levels and LDL-C/HDL-C ratio decreased significantly in patients after SZL treatment, while only APOB/APOA1 ratio decreased significantly in FLX group. Other metabolic indexes did not alter significantly after treated with SZL or FLX. ConclusionThe efficacy and safety profile of SZL are comparable to that of fluoxetine in patients with mild to moderate depression. The beneficial effect of SZL is probably associated with improvement of lipid metabolic balance.

Cardiovascular Disease Risk in Children With Chronic Kidney Disease: Impact of Apolipoprotein C-II and Apolipoprotein C-III.

Cardiovascular disease (CVD) is an evolving process that begins in the early stages of chronic kidney disease (CKD) in children. Several surrogate markers, such as ambulatory blood pressure monitoring (ABPM), left ventricular (LV) mass, and arterial stiffness assessment, allow for the early detection of subclinical CVD in pediatric CKD. Four groups of plasma samples (n = 3/group) from congenital anomalies of the kidney and urinary tract (CAKUT), as well as non-CAKUT patients with or without BP abnormalities, were studied to screen differentially expressed proteins using isobaric tags for relative and absolute protein quantification (iTRAQ)-based proteomics. As a result, 20 differentially expressed proteins associated with hypertension in children with CKD were discovered. Among them, apolipoprotein C-II (apoC-II) was found to have the highest abundance among the CKD patients with hypertension. As such, we hypothesized that apoC-II and apolipoprotein C-III (apoC-III) levels were related to BP abnormalities and CVD in children suffering from mild-to-moderate CKD. We examined their associations with surrogate markers of CV risk in 88 pediatric patients with CKD stages G1–G4. Children with CKD stages G2–G4 had a higher plasma apoC-II level than G1 patients (6.35 vs. 5.05 mg/dl, p < 0.05). We observed that ABPM abnormalities, LV mass, and arterial stiffness parameters were greater in CKD children who had stages G2–G4 than in those who had stage G1 (all p < 0.05). Plasma levels of apoC-II and apoC-III were positively correlated with total cholesterol, triglyceride, and low-density lipoprotein (LDL) (all p < 0.001). In multivariate linear regression analyses, apoC-II was correlated with a high LV mass index and an abnormal ABPM profile, and apoC-III was correlated with 24-h hypertension (r = 0.303, p = 0.003) and asleep hypertension (r = 0.379, p < 0.001). Early evaluations of apoC-II and apoC-III, ABPM, and surrogate markers of CV risk will aid in early preventative interventions to reduce the risk of CV in youths suffering from CKD.

Association between ANGPTL3, 4, and 8 and lipid and glucose metabolism markers in patients with diabetes.

Lipid management, especially with respect to triglyceride (TG) metabolism, in patients with diabetes is not sufficient with current therapeutic agents, and new approaches for improvement are needed. Members of the angiopoietin-like protein (ANGPTL) family, specifically ANGPTL3, 4, and 8, have been reported as factors that inhibit lipoprotein lipase (LPL) activity and affect TGs. The present study investigated the association between lipid and glucose metabolism markers and the mechanism by which these proteins affect lipid metabolism. A total of 84 patients hospitalized for diabetes treatment were evaluated. Lipid and glucose metabolism markers in blood samples collected before breakfast, on the day after hospitalization, were analyzed. ANGPTL8 showed a significant positive correlation with TG values. HDL-C values displayed a significant positive correlation with ANGPTL3 but a negative correlation with ANGPTL4 and ANGPTL8. The results did not indicate a significant correlation among ANGPTL3, 4, and 8 levels. Thus, it is possible that the distribution of these proteins differs among patients. When patients were divided into groups according to the levels of ANGPTL3 and ANGPTL8, those with high levels of both ANGPTL3 and ANGPTL8 also had high levels of TG and small dense LDL-C/LDL-C (%). Multiple regression analysis indicated that low LPL, high ApoC2, high ApoC3, high ApoE, and high ANGPTL8 levels were the determinants of fasting hypertriglyceridemia. By contrast, no clear association was observed between any of the ANGPTLs and glucose metabolism markers, but ANGPTL8 levels were positively correlated with the levels of HOMA2-IR and BMI. Patients with high levels of both ANGPTL3 and ANGPTL8 had the worst lipid profiles. Among ANGPTL3, 4, and 8, ANGPTL8 is more important as a factor determining plasma TG levels. We anticipate that the results of this research will facilitate potential treatments targeting ANGPTL8 in patients with diabetes.

Relationship of Plasma ApolipoproteinC3 with Plasma Lipoprotein(a)

Introduction ApoliproteinC3 (ApoC3) is a small (~8.8kDa) protein, made in the liver. It is an inhibitor of lipoprotein lipase as well as the uptake of triglyceride (TG) rich lipoproteins and remnants by the liver. Overexpression contributes to atherosclerosis by increasing plasma concentration of TG-rich lipoproteins. Recent genetic studies suggest that ApoC3-lowering treatments may have cardiovascular benefit. ApoC3 is also known to participate in the inflammation cascade; it facilitates the interaction between monocytes and endothelial cells leading to their activation and monocyte adhesion, promoting further development of atherosclerosis. A recent study reported the presence of ApoC3 on lipoprotein(a) [Lp(a)] particles in subjects with mild to moderate aortic stenosis. Lp(a) is an ApoB100 containing lipoprotein and a causal factor of ASCVD. Most individuals have two isoforms of Apo(a), varying in the number of KIV2 repeats, and hence, have two different circulating Lp(a) molecules. High levels of Lp(a) are inversely associated with the isoform size. Our goal was to investigate relationships between ApoC3 and Lp(a) in a racially diverse healthy population. Methods We analyzed data from 39 healthy subjects who completed studies of lipoprotein metabolism at the Columbia University Medical Center. Subjects were 18 – 75 years old, and 49% were female. Fifty-one percent were Black, 23% Hispanic, 21% White, and 5% mixed race. Lipids (total Cholesterol (C), TG, HDLC, LDLC) were measured by a CDC standardized automatic analyzer. Plasma ApoC3 and Lp(a) levels were measured via validated ELISA assays. Lp(a) particles were isolated from plasma by immunoprecipitation (IP) with a monoclonal antibody (Abcam). Isolated Lp(a) samples were processed for proteomic analysis at the CUIMC – Proteomics Core. We calculated iBAQ value (total intensities/identified peptides for one protein). Excel and R-program were used for statistical analysis. Results Unlikeprevious studies, our group of healthy volunteers did not have an association between Lp(a) and ApoC3 levels. Previous studies were completed in subjects with high Lp(a). In a sub-group analysis of participants (N=15) in our study, with Lp(a) levels >100nmol/L, we found a trend in the association of ApoC3 and Lp(a) plasma concentration (R = -0.48, p=0.068). However, unlike in previous reports, it was not a positive correlation. Based on the proteomic analysis of our IP Lp(a) particles from 2 subjects with high (~ 128nmol/L) and 2 subjects with low (~ 23nmol/L) Lp(a), ApoC3/Apo(a) iBAQ ratios were similar in subjects with low Lp(a) levels, however there was not a clear relationship between ApoC3/Apo(a) ratios in subjects with high Lp(a). Conclusion and Future Direction In healthy subjects, there is no association of ApoC3 with Lp(a) plasma levels. In a subset of subjects (high Lp(a)), we observed a trend towards lower ApoC3 levels associated with high Lp(a). Our small data set suggests possible distinct roles for ApoC3 in healthy individuals with high Lp(a) level. ApoC3 may be associated with specific circulating isoform sizes of Lp(a). Future studies will focus on analysis of larger cohorts, examining the ApoC3 and Apo(a) relationships.

Elevated Levels of Apolipoprotein CIII Increase the Risk of Postprandial Hypertriglyceridemia.

BackgroundTo investigate possible mechanisms of postprandial hypertriglyceridemia (PPT), we analyzed serum lipid and apolipoprotein (Apo) AI, B, CII and CIII levels before and after a high-fat meal.MethodsThe study has been registered with the China Clinical Trial Registry (registration number:ChiCTR1800019514; URL: http://www.chictr.org.cn/index.aspx). We recruited 143 volunteers with normal fasting triglyceride (TG) levels. All subjects consumed a high-fat test meal. Venous blood samples were obtained during fasting and at 2, 4, and 6 hours after the high-fat meal. PPT was defined as TG ≥2.5 mmol/L any time after the meal. Subjects were divided into two groups according to the high-fat meal test results: postprandial normal triglyceride (PNT) and PPT. We compared the fasting and postprandial lipid and ApoAI, ApoB, ApoCII and ApoCIII levels between the two groups.ResultsSignificant differences were found between the groups in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), TG-rich lipoprotein remnants (TRLRs), ApoB, ApoCIII, ApoAI/ApoB and ApoCII/ApoCIII. The insulin, HOMA-IR, TG, TC, LDL-C, non-HDL-C, TRLRs, ApoB, ApoCIII and ApoCII/ApoCIII values were higher in the PPT group, while the ApoAI/ApoB ratio was higher in the PNT group. The postprandial TG level peaked in the PNT group 2 hours after the meal but was significantly higher in the PPT group and peaked at 4 hours. TRLRs gradually increased within 6 hours after the high-fat meal in both groups. The area under the curve (AUC) of TG and TRLRs and the AUC increment were higher in the PPT group (P < 0.001). ApoCIII peaked in the PNT group 2 hours after the meal and gradually decreased. ApoCIII gradually increased in the PPT group within 6 hours after the meal, exhibiting a greater AUC increment (P < 0.001). Fasting ApoCIII was positively correlated with age, systolic and diastolic blood pressure, body mass index (BMI), waist circumference, TC, TG, LDL-C, non-HDL-C, TRLRs, and ApoB (P<0.05). ApoCIII was an independent risk factor of PPT after adjustment for BMI, waist circumference, TC, LDL-C, and ApoB (P < 0.001, OR=1.188).ConclusionsElevated ApoCIII levels may cause PPT.

Small Dense Low-Density Lipoprotein Cholesterol: A Residual Risk for Rapid Progression of Non-Culprit Coronary Lesion in Patients with Acute Coronary Syndrome.

Aim: This study investigated whether the small dense low-density lipoprotein cholesterol (sd-LDL-c) level is associated with the rapid progression (RP) of non-culprit coronary artery lesions and cardiovascular events (CE) after acute coronary syndrome (ACS). Methods: In 142 consecutive patients with ACS who underwent primary percutaneous coronary intervention for the culprit lesion, the sd-LDL-c level was measured using a direct homogeneous assay on admission for ACS and at the 10-month follow-up coronary angiography. RP was defined as a progression of any pre-existing coronary stenosis and/or stenosis development in the initially normal coronary artery. CEs were defined as cardiac death, myocardial infarction, stroke, or coronary revascularization. Results: Patients were divided into two groups based on the presence ( n =29) or absence ( n =113) of RP after 10 months. The LDL-c and sd-LDL-c levels at baseline were equivalent in both the groups. However, the sd-LDL-c, triglyceride, remnant lipoprotein cholesterol (RL-c), and apoC3 levels at follow-up were significantly higher in the RP group than in the non-RP group. The optimal threshold values of sd-LDL-c, triglyceride, RL-c, and apoC3 for predicting RP according to receiver operating characteristics analysis were 20.9, 113, 5.5, and 9.7 mg/dL, respectively. Only the sd-LDL-c level (≥ 20.9 mg/dL) was significantly associated with incident CEs at 31±17 months (log-rank: 4.123, p =0.043). Conclusions: The sd-LDL-c level on treatment was significantly associated with RP of non-culprit lesions, resulting in CEs in ACS patients. On-treatment sd-LDL-c is a residual risk and aggressive reduction of sd-LDL-c might be needed to prevent CEs.

Simultaneous Evaluation of Postchallenge Glycemia and Lipidemia in Young Women

<i>Aim:</i> To determine the effects of simultaneously ingesting glucose and fat on postchallenge glycemia and lipidemia in 12 healthy young Japanese women. <i>Methods:</i> Three test trials were administered in a randomized crossover design: glucose (1 g/kg, G trial); fat cream (0.35 g/kg as fat; F trial); glucose + fat cream (GF trial). Blood samples were taken before and at 0.5, 1, 2, 4, and 6 h post-ingestion. <i>Results:</i> The GF trial's serum glucose peak value was lower than the G trial's, and its remnant lipoprotein-cholesterol (RLP-C) increase was less than the F trial's. The GF trial's apolipoprotein (Apo) B48 increase happened faster than the F trial's. The G and GF trials' insulinogenic index (I/G30) values were negatively correlated with the area under the curve (AUC) of glucose for 2 h. Fasting insulin level and HOMA-IR were positively (and QUICKI and I/G30 were negatively) correlated with the AUC of insulin for 2 h. The F and GF trials' fasting TG, RLP-C, ApoB48, and ApoC-III levels were positively correlated with the AUC of TG and RLP-C for 6 h. The fasting ApoB48 level predicted the AUC of ApoB48 for 6 h. <i>Conclusion:</i> The glucose peak was ameliorated by co-ingesting fat. I/G30 predicted an early postchallenge (0–2 h) glucose rise. The fasting insulin level, HOMA-IR, QUICKI, and I/G30 predicted an insulin rise. The RLP-C rise by fat ingestion was ameliorated by co-ingesting glucose. Fasting TG, RLP-C, ApoB48, and ApoC-III levels predicted postchallenge TG and RLP-C rises. The fasting ApoB48 level predicted postchallenge apoB48, i.e., a rise in intestinal lipoprotein.