Plasma Levels Of Lipoprotein Cholesterol Research Articles

The role of systemic inflammation in remnant cholesterol associated cardiovascular risk: insights from the EPIC-Norfolk study.

Both plasma levels of remnant cholesterol and low-density lipoprotein cholesterol (LDL-C) levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischemic stroke. This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8±9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels (95% Confidence Interval (CI): 22.1, 37.4, p<0.001), whereas LDL-C was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, p<0.001) for MACE, compared to a HR of 1.21 (95% CI: 1.13, 1.31, p<0.001) for LDL-C. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, p<0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL-C. Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors as Adjunct Therapy to Statins: A New Frontier in Cardiovascular Risk Reduction.

Lowering low-density lipoprotein cholesterol (LDL-C) plasma levels is crucial for the prevention of primary and secondary cardiovascular diseases (CVDs). Many patients struggle to obtain goal LDL-C levels, despite the availability of several lipid-lowering medications, because of limited efficaciousness and unfavorable side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting has drawn interest recently as a novel approach to further lower cardiovascular (CV) risk. The number of receptors accessible to remove LDL-C from the bloodstream is reduced when PCSK9 attaches to LDL-C receptors and directs them toward lysosomal destruction. LDL receptor activity is increased by PCSK9 inhibition, which attracts therapeutic intervention. Despite concurrent statin therapy, phase 3 clinical trials have demonstrated encouraging outcomes with monoclonal antibodies against PCSK9, such as evolocumab and alirocumab, resulting in significant reductions in LDL-C levels. This study intends to investigate recent advancements in the field to evaluate PCSK9 inhibitors' safety, effectiveness, and potential for preventing CVD. The investigation will also review potential future paths and wider effects of using PCSK9 inhibitors in therapeutic settings.

Genetic Susceptibility to Hidradenitis Suppurativa and Predisposition to Cardiometabolic Disease

Hidradenitis suppurativa (HS) is associated with an increased prevalence of cardiovascular diseases compared with the general population. Any association between polygenic risk for HS, risk of incident cardiometabolic outcomes, and the plasma proteome is unclear. To investigate the genetic correlation between HS and cardiometabolic disease. This cohort study used a polygenic risk score (PRS) for HS to examine the risks of coronary artery disease (CAD) and diabetes and identify changes in the plasma proteome in individuals of European ancestry from the UK Biobank. Participants were enrolled from January 1, 2006, to December 31, 2010. End of follow-up was January 1, 2023. Correlations were assessed between HS susceptibility and cardiometabolic traits using linkage disequilibrium score regression. Odds ratios were assessed in logistic regressions. The risk of incident CAD and diabetes was estimated in cause-specific survival models designed as time-to-event analyses. The PRS for HS. Main outcomes were CAD and diabetes diagnosis measured by logistic regressions and incident disease measured by Cox proportional hazards regression models adjusted for sex, age, body mass index, and smoking status. The study included 391 481 individuals (median [IQR] age, 58 [51-64] years; 209 235 [53%] female). Genetic variants for HS correlated significantly with variants associated with CAD, diabetes, and plasma levels of high-density lipoprotein cholesterol, triglycerides, and C-reactive protein. Compared with the low-risk group, a high PRS for HS (≥75th percentile) conferred odds ratios of 1.09 (95% CI, 1.06-1.12; P < .001) for CAD and 1.13 (95% CI, 1.10-1.17; P < .001) for diabetes. Estimates remained consistent when examining only incident CAD and diabetes. The PRS for HS was significantly associated with altered expression of 58 plasma proteins. Integrating this proteomic profile and the PRS for HS in a machine learning model improved prediction of CAD and diabetes compared with a reference model based on sex, age, and body mass index. These findings suggest that a high genetic risk of HS is associated with increased risk of subsequent CAD and diabetes and altered composition of the plasma proteome. Additional investigation into the identified proteins and their potential roles as drug targets is warranted.

Houttuynia cordata Thunb. Extracts Alleviate Atherosclerosis and Modulate Gut Microbiota in Male Hypercholesterolemic Hamsters

Background and Aims: Hypercholesterolemia leads to cardiovascular diseases and atherosclerosis. Previous studies have highlighted the crucial role of gut microbiota in alleviating atherosclerosis progression and reducing plasma cholesterol. However, the protective effects of Houttuynia cordata Thunb (HCT), a well-known fishy Chinese herb, against hypercholesterolemia and vasculopathy remain largely unknown. This study aims to explore the effects of HCT extracts on vascular health and gut microbiota in golden Syrian hamsters with hypercholesterolemia. Methods: The hypercholesterolemia hamster model was established by feeding with a high-cholesterol diet. Aqueous or ethanolic HCT extracts were mixed with diet and concurrently given to hamsters for Six weeks. Plasma lipid profiles were evaluated. Aortas were collected to detect fatty streak areas. Feces were collected to analyze the abundance of microorganisms in the gut microbiota. Results: HCT ethanolic extract treatment remarkedly decreased plasma levels of total cholesterol and high-density lipoprotein cholesterol in hypercholesterolemic hamsters. Notably, both aqueous and ethanolic extracts of HCT reduced atherosclerotic plaques in hamsters fed with a high-cholesterol diet. Strikingly, the effects of HCT ethanolic extract in reducing atherosclerotic plaques are greater than aqueous extract. Furthermore, at the phylum level, the relative abundance of Firmicutes was decreased in hamsters treated with aqueous and ethanolic extracts of HCT. By contrast, the abundance of Bacteroidetes was increased by HCT treatment. At the family level, HCT extract favourably modulated the relative abundance of Porphyromonadaceae and Bacteroidales_S24-7_group. These findings indicate that HCT extracts may facilitate the growth of short-chain fatty acids-producing bacteria to alter gut microbiota composition, contributing to the reduction of plasma lipid levels. Conclusions: This study offers evidence demonstrating the effects of HCT extracts on alleviating atherosclerosis and lowering plasma cholesterol levels in the male hypercholesterolemic hamster model, offering novel insights into the pharmacological effects and promoting the application of HCT. This study highlights the potential of HCT as a dietary supplement to alleviate atherosclerosis, lower plasma cholesterol, and modulate the abundance of microorganisms in gut microbiota.

Natural disease course of chronic visceral acid sphingomyelinase deficiency in adults: A first step toward treatment criteria.

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3-19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future.

Targeted lipidomics uncovers oxylipin perturbations and potential circulation biomarkers in Bietti's crystalline dystrophy.

Abnormalities in lipid metabolism have been proposed in Bietti's crystalline dystrophy (BCD). We aim to characterize the lipid profiles in a case-control study. All participants were genetically confirmed by CYP4V2 gene sequencing and underwent chorioretinopathy evaluation by calculating the percentages of AF atrophy (PAFA). Fasting blood samples of BCD patients and controls were collected, and plasma was analyzed for routine lipid profiles. Targeted lipidomic evaluation includes long chain polyunsaturated fatty acids (LCPUFA) and associated eicosanoid metabolites. Routine lipids profiles showed elevated plasma levels of triglyceride (P = 0.043) and low-density lipoprotein cholesterol (P = 0.024) in BCD patients. Lipidomic analysis showed significantly decreased levels of ω-3 LCPUFA including docosahexaenoic acid (DHA, 22:6, P = 0.00068) and eicosapentaenoic acid (EPA, 20:5, P = 0.0016), as well as ω-6 LCPUFA arachidonic acid (ARA, 20:4, P < 0.0001) in BCD patients. Eicosanoid metabolites, either derived from ω-3 and/ or ω-6 LCPUFAs via cyclooxygenase (COX) or lipoxygenase (LOX) pathways, including 5-HEPE, 12-HEPE, 13-HDHA, 15-HETE, 12-HETE, 5-HETE, 6k-PGF1a, PGE2, PGJ2, and TXB2, exhibited significant differences (P < 0.0001) between BCD patients and controls. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites including 5-HETE, 5-HEPE, 12-HEPE and LTB4. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA), as well as their downstream metabolites via the COX and LOX pathways, suggesting that these might be implicated in BCD pathogenesis and could serve as biomarkers and therapeutic targets of the disease. What is known BCD is a vision-threatening hereditary disease the causative gene of which is CYP4V2. Abnormalities in lipid metabolism have been proposed and demonstrated previously in BCD studies. The detailed pathogenesis remains unclear and controversial. What is new We observed prominent lipidomic alterations in the circulation when compared with age, gender, and bodymass index (BMI)-matched healthy controls. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA). Remarkable changes were observed in the downstream metabolites of the LCPUFA via the COX and LOX pathways. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites.

20( S )-Protopanaxatriol Improves Atherosclerosis by Inhibiting Low-Density Lipoprotein Receptor Degradation in ApoE KO Mice.

Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.

Discovery of novel cholesteryl ester transfer protein (CETP) inhibitors by a multi-stage virtual screening

Cholesteryl ester transfer protein (CETP) is a promising therapeutic target for cardiovascular diseases. It effectively lowers the low-density lipoprotein cholesterol levels and increases the high-density lipoprotein cholesterol levels in the human plasma. This study identified novel and highly potent CETP inhibitors using virtual screening techniques. Molecular docking and molecular dynamics (MD) simulations revealed the binding patterns of these inhibitors, with the top 50 compounds selected according to their predicted binding affinity. Protein–ligand interaction analyses were performed, leading to the selection of 26 compounds for further evaluation. A CETP inhibition assay confirmed the inhibitory activities of the selected compounds. The results of the MD simulations revealed the structural stability of the protein–ligand complexes, with the binding site remaining significantly unchanged, indicating that the five compounds (AK-968/40709303, AG-690/11820117, AO-081/41378586, AK-968/12713193, and AN-465/14952302) identified have the potential as active CETP inhibitors and are promising leads for drug development.Graphical

고콜레스테롤 식이 쥐에서 2,3- 및 3,4-dihydroxybenzoic acids의 항동맥경화 효과 비교

This study compared the anti-atherosclerosis effects of the long-term ingestion of 2,3-dihydroxybenzoic acid (2,3-DHBA) and 3,4-dihydroxybenzoic acid (3,4-DHBA). Six group diets [normal diet (ND), high-fat diet (HFD), 2,3- and 3,4-DHBA high and low diets] were administered to Sprague-Dawley rats for six weeks. The final body weights of the six groups were similar. The total cholesterol, high, and low-density lipoprotein cholesterol levels in the blood plasma of the HFD group were higher than those in the ND group. The plasma levels in the 2,3- and 3,4-DHBA groups were similar to those in the HFD group. HFD, 2,3- and 3,4-DHBA groups showed accumulation of lipid droplets in liver tissues, and the aorta of the HFD group was thicker than that of the ND group, but the recovered aortic thickness of 2,3- and 3,4-DHBA groups was similar to that of the ND group. In addition, in vitro and in vivo antioxidant activities were the highest in the 3,4-DHBA group. Therefore, the daily intake of 2,3-DHBA and 3,4-DHBA may have anti-atherosclerosis effects.

Long-Term Efficacy and Tolerability of PCSK9 Targeted Therapy: A Review of the Literature.

Increased plasma levels of low-density lipoprotein cholesterol (LDL-C) are causally associated with atherosclerotic cardiovascular disease (ASCVD), and statins that lower LDL-C have been the cornerstone of ASCVD prevention for decades. However, guideline-recommended LDL-C targets are not achieved in about 60% of statin users. Proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapy effectively lowers LDL-C levels and has been shown to reduce ASCVD risk. A growing body of scientific and clinical evidence shows that PCSK9-targeted therapy offers an excellent safety and tolerability profile with a low incidence of side effects in the short term. In this review, we present and discuss the current clinical and scientific evidence pertaining to the long-term efficacy and tolerability of PCSK9-targeted therapy.

A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice.

Dyslipidemia is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TG-rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519-D95aA against N-terminal ANGPTL3 (NT-ANGPTL3), which potently inhibits NT-ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519-D95aA shows higher apolipoprotein B (ApoB) and TG-lowering, and similar LDL-C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519-D95aA-ANGPTL3 complex (10 hydrogen bonds, -65.51 kcal/mol) is more stable than the Evinacumab-ANGPTL3 complex (4 hydrogen bonds, -63.76 kcal/mol). Importantly, F1519-D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519-D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519-D95aA is a novel fully human anti-NT-ANGPTL3 antibody with potent plasma ApoB, TG, and LDL-C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases.

Relationships of apolipoprotein E genotypes with a cluster of seven in persons with type 2 diabetes.

The objective of the study was to determine if there would be statistically significant differences or trends among apolipoprotein E genotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4) for each member of the cluster of seven associated with type 2 diabetes (T2D). The cluster of seven includes abdominal obesity, hypertension, platelet hyperaggregability, hyperglycemia, dyslipidemia (decreased plasma levels of high-density lipoprotein cholesterol (HDL-C) and increased plasma levels of triglycerides)), increased low-density lipoprotein (LDL) oxidation, and increased inflammation. Forty-six patients with well-controlled T2D participated in the study. Abdominal obesity (assessed by waist circumference), hypertension (measured by manual sphygmomanometry), platelet hyperaggregability (measured by bleeding time), hyperglycemia (by enzymatic kit and spectrophotometry), decreased plasma levels of HDL-C and increased plasma levels of triglycerides (by enzymatic kit and spectrophotometry), increased LDL oxidation (measured by LDL conjugated dienes using spectrophotometry) and increased inflammation measured by C-reactive protein (CRP) (by EIA kit) were determined. All genotypes, except 2/2 were found in the population studied. Abdominal obesity did not vary significantly across the five genotypes. However, glucose levels trended progressively higher going from 2/3 to 2/4 to 3/4 to 4/4. Systolic blood pressure was higher in 3/4 compared to 2/4 and trended higher in 3/4 compared to 3/3. Diastolic blood pressure trended higher in 3/3 vs 2/4 and significantly higher in 3/4 compared to 2/4. Triglycerides trended higher in 3/4 vs 3/3 while HDL-C came close to trending downward in 4/4 compared to 2/4. Bleeding time was unaffected by genotype. Plasma LDL conjugated dienes trended higher in 3/4 vs 2/4 and were significantly higher in 3/4 vs 3/3. CRP trended higher in 4/4 vs 2/3. We can conclude that those with at least one 4 allele in the presence of another allele being 2, 3 or 4 is potentially (in the case of trends) deleterious or is deleterious in terms of hyperglycemia, hypertension (systolic and diastolic blood pressure), dyslipidemia, LDL conjugated dienes and CRP levels.

Various apolipoprotein E genotypes relate to responsiveness to flaxseed lignan complex in older persons with type 2 diabetes mellitus.

Objective. The objective of the study was to determine if there would be statistically significant differences or trends among apolipoprotein E genotypes in the responsiveness of members of a cluster of seven measures in older persons with type 2 diabetes mellitus (T2DM) consuming flaxseed lignan complex (FLC). The cluster of seven are abdominal obesity, hypertension, platelet hyperaggregability, hyperglycemia, dyslipidemia (decreased plasma levels of high-density lipoprotein cholesterol (HDLc), and increased plasma levels of triglycerides), increased low-density lipoprotein (LDL) oxidation and increased inflammation. All cluster members exacerbate T2DM. Methods. Sixteen patients with well-controlled T2DM participated in this double-blind randomized, placebo-controlled crossover study consisting of four visits. Apolipoprotein E genotyping was done at visit one. The cluster of seven, diet, exercise, smoking and medication use were assessed at each visit. Results. The 3/4 genotype showed a stronger downward trend in systolic blood pressure compared to the 3/3 genotype with no trend or significant difference in the 2/4 genotype. There was a downward trend in diastolic blood pressure in genotype 3/3 compared genotype 2/4, which showed no significant difference or trend. Only genotype 3/4 showed a significant drop in diastolic pressure compared to genotypes 2/4 and 3/3. HDLc only showed a downward trend in 3/4 relative to genotypes 2/4 and 3/3. LDL apolipoprotein B oxidation (LDL-Box) only showed an upward trend in 3/3 compared to genotypes 2/4 and 3/4. There were no other significant differences or trends by genotype in the cluster of seven. Conclusions. It appears that those with the 2/4 genotype may not benefit from FLC, those with 3/3 and 3/4 genotypes may benefit only in terms of systolic and diastolic pressures, those with the apo E 3/4 genotype should perhaps avoid FLC to manage HDLc, and those with the 3/3 genotype should perhaps avoid FLC to manage LDL apolipoprotein B oxidation.

Association of cigarette smoking with cardiometabolic risk factors: A cross-sectional study.

Despite strong and consistent epidemiological evidence linking cigarette smoking to several cardiovascular diseases (CVDs), the association between smoking intensity and CVD risk factors remains unclear. This study aimed to explore the possible effects of cigarette smoking on cardiometabolic risk in healthy individuals. This cross-sectional study was conducted between November 2022 and June 2023. Consecutive sampling was performed to include 160 healthy participants: 100 smokers with 60 males and 40 females; and 60 age- and sex-matched non-smokers with 36 males and 24 females. Blood samples were taken from each participant to assess their cardiometabolic function: lipid profile, von Willebrand factor (vWF), high-sensitivity cardiac troponin I (hs-cTnI), and fibrinogen levels; and liver function using an automated enzymatic method. In addition, blood sugar level, body mass index (BMI), and blood pressure were recorded. Smokers had significantly higher vWF functional activity and hs-cTnI but significantly lower albumin and total bilirubin levels than non-smokers (65.87 ± 19.07 vs 56.45 ± 6.59, respectively, p<0.001; 0.0382 ± 0.0077 vs 0.0147 ± 0.0105, respectively, p<0.001; and 4.63 ± 0.32 vs 4.74 ± 0.28, respectively, p=0.026). The number of cigarettes consumed daily was associated positively and significantly with plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, vWF functional activity, and hs-cTnI but were negatively associated with total bilirubin. Moreover, heavy smokers had a significantly higher BMI and waist-to-hip ratio among male smokers than non-smokers. Cigarette smoking was associated with increased dyslipidemia, BMI, and central obesity, in addition to higher vWF functional activity. Altogether, increased hs-cTnI levels in smokers indicate a higher susceptibility to CVD.

Gallic acid rescues uranyl acetate induced-hepatic dysfunction in rats by its antioxidant and cytoprotective potentials

BackgroundThe liver was identified as a primary target organ for the chemo-radiological effects of uranyl acetate (UA). Although the anti-oxidant and anti-apoptotic properties of gallic acid (GA) make it a promising phytochemical to resist its hazards, there is no available data in this area of research.MethodsTo address this issue, eighteen rats were randomly and equally divided into three groups. One group was received carboxymethyl cellulose (vehicle of GA) and kept as a control. The UA group was injected intraperitoneally with UA at a single dose of 5 mg/kg body weight. The third group (GA + UA group) was treated with GA orally at a dose of 100 mg/kg body weight for 14 days before UA exposure. UA was injected on the 15th day of the experiment in either the UA group or the GA + UA group. The biochemical, histological, and immunohistochemical findings in the GA + UA group were compared to both control and UA groups.ResultsThe results showed that UA exposure led to a range of adverse effects. These included elevated plasma levels of aspartate aminotransferase, lactate dehydrogenase, total protein, globulin, glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very-low-density lipoprotein and decreased plasma levels of high-density lipoprotein cholesterol. The exposure also disrupted the redox balance, evident through decreased plasma total antioxidant capacity and hepatic nitric oxide, superoxide dismutase, reduced glutathione, glutathione-S-transferase, glutathione reductase, and glutathione peroxidase and increased hepatic oxidized glutathione and malondialdehyde. Plasma levels of albumin and alanine aminotransferase did not significantly change in all groups. Histopathological analysis revealed damage to liver tissue, characterized by deteriorations in tissue structure, excessive collagen accumulation, and depletion of glycogen. Furthermore, UA exposure up-regulated the immuno-expression of cleaved caspase-3 and down-regulated the immuno-expression of nuclear factor-erythroid-2-related factor 2 in hepatic tissues, indicating an induction of apoptosis and oxidative stress response. However, the pre-treatment with GA proved to be effective in mitigating these negative effects induced by UA exposure, except for the disturbances in the lipid profile.ConclusionsThe study suggests that GA has the potential to act as a protective agent against the adverse effects of UA exposure on the liver. Its ability to restore redox balance and inhibit apoptosis makes it a promising candidate for countering the harmful effects of chemo-radiological agents such as UA.

An in vitro investigation of the effects of Urolithins A and B on low-density lipoprotein uptake and its regulatory genes

Abstract Background Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerosis. A major pathway of LDL-C clearance from bloodstream is its uptake by hepatic LDL receptors (LDLRs), which is mainly restricted by proprotein convertase subtilisin/kexin type-9 (PCSK9). Purpose This study aimed to evaluate the possible role of Urolithin A (UA) and Urolithin B (UB) on the induction of LDL uptake and the expression of its regulatory genes. Methods Curcumin (20 uM), berberine (50 uM), UA (80 uM) and UB (80 uM) were used as the treatments in the experimental tests. LDL uptake in HepG2 cells was detected by LDL uptake cell-based assay kit and the degrees of LDL uptake as well as the distribution of cell surface LDLR were assessed using fluorescent microscopy. Moreover, the mRNA expression levels of LDLR and PCSK9 genes in HepG2 cells were assessed using qPCR. Results The LDL uptake as well as cell-surface LDLR were higher in cells treated with UA in comparison with cells treated with UB, and even in relation to the cells treated with curcumin and berberine as positive controls. In addition, cells treated with UB showed approximately 2 times greater LDLR expression level compared with curcumin (FC: 2.144, P=0.013) and berberine (FC: 2.761, P=0.006). However, UA treatment resulted in a significantly lower expression levels of LDLR compared with curcumin (FC: 0.274, P&amp;lt;0.001) and berberine (FC: 0.352, P=0.009). UB demonstrated approximately 8 times greater LDLR expression levels when compared with UA (FC:7.835, P=0.001) (Figure 1A). Compared with UB, as well as curcumin and berberine as positive controls, UA was more efficient in reducing PCSK9 expression levels. Although UB did not show any significant differences compared with curcumin and berberine, it illustrated higher levels of PCSK9 expression when compared with UA group (FC: 3.694, P&amp;lt;0.001) (Figure 1B). Conclusion The present results support that UA was more effective than UB in promoting LDL uptake as well as cell surface LDLR in HepG2 cells. This effect seems to be mostly mediated through the suppression of PCSK9 expression but not induction of LDLR expression. Figure 1. HepG2 (A) LDLR and (B) PCSK9 fold change expression in treatment groups. All data were normalized to control group (PBS).

ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.

Effect of PCSK9 inhibition on plasma levels of small dense low density lipoprotein-cholesterol and 7-ketocholesterol

Oxidized forms of cholesterol (oxysterols) are implicated in atherogenesis and can accumulate in the body via direct absorption from food or through oxidative reactions of endogenous cholesterol, inducing the formation of LDL particles loaded with oxidized cholesterol. It remains unknown whether drastic reductions in LDL-cholesterol (LDL-C) are associated with changes in circulating oxysterols and whether small dense LDL (sdLDL) are more likely to carry these oxysterols and susceptible to the effects of PCSK9 inhibition (PCSK9i). We investigate the effect of LDL-C reduction accomplished via PCSK9i on changes in plasma levels of sdLDL-cholesterol (sdLDL-C) and a common, stable oxysterol, 7-ketocholesterol (7-KC), among 134 patients referred to our Preventive Cardiology clinic. Plasma lipid panel, sdLDL-C, and 7-KC measurements were obtained from patients before and after initiation of PCSK9i. The intervention caused a significant lowering of LDL-C (-55.4 %). The changes in sdLDL-C levels (mean reduction 51.4 %) were highly correlated with the reductions in LDL-C levels (R = 0.829, p < 0.001). Interestingly, whereas changes in plasma free 7-KC levels with PCSK9i treatment were much smaller than (-6.6 %) and did not parallel those of LDL-C and sdLDL-C levels, they did significantly correlate with changes in triglycerides and very low-density lipoprotein-cholesterol (VLDL-C) levels (R = 0.219, p = 0.025). Our findings suggest a non-preferential clearance of LDL subparticles as a consequence of LDL receptor upregulation caused by PCSK9 inhibition. Moreover, the lack of significant reduction in 7-KC with PCSK9i suggests that 7-KC may be in part carried by VLDL and lost during lipoprotein processing leading to LDL formation.

Rhabdomyolysis or Severe Acute Hepatitis Associated with the Use of Red Yeast Rice Extracts: an Update from the Adverse Event Reporting Systems.

Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for atherosclerotic cardiovascular disease (ASCVD), and lowering LDL-C reduces the risk of cardiovascular adverse events. Among natural approaches known for their lipid-lowering properties, red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In August 2018, the European Food Safety Authority (EFSA) concluded in its assessment of the use of RYR (further amended in June 2022) that monacolins from RYR raise significant safety concerns when used as a food supplement at a dose of 10 mg/day. In particular, individual cases of serious adverse effects of monacolins from RYR have been reported at intakes as low as 3 mg/day. The EFSA Panel pointed out several uncertainties regarding the available data. We conducted an in-depth and updated analysis of the serious adverse events, with a focus on rhabdomyolysis and acute hepatitis, associated with the consumption of RYR. An analysis of the Food and Drug Administration reporting systems revealed a very small number of cases of rhabdomyolysis or severe acute hepatitis associated with RYR use. In addition, only a few case reports of these serious adverse events associated with RYR use have been published. Based on data from adverse event reporting systems and available case reports, the occurrence of rhabdomyolysis or severe acute hepatitis that could be associated with the use of RYR appears to be extremely rare compared to the occurrence with statins, which is rare to common.

Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study.

Historically, the biopharmaceutical industry has used titer to characterize the magnitude of an anti-drug antibody (ADA) response. While reporting levels of antibodies in terms of titer is generally understood and accepted by regulatory and medical communities, titer values are inherently variable given the multiple serial dilutions and reporting a value either directly before or interpolated at the assay cut point on the lower plateau of the assay curve range. Using S/N is an appealing alternative approach to titer as it simplifies analysis with less dilutions, significantly reducing testing, time, and resources and provides a more precise value potentially differentiating low-level ADA responses. Current bridging electrochemiluminescence (ECL) ADA assays using Meso Scale Discovery (MSD) platform are also significantly more sensitive and drug tolerant with wider assay ranges compared to historic ELISA platforms; therefore, ADA response based on S/N may help differentiate and identify those ADA samples that are more likely to be clinically relevant. Bococizumab is a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), which reduces plasma levels of low-density lipoprotein (LDL) cholesterol. Bococizumab was discontinued during Phase 3 clinical development based in part on the high rate of ADA and wide variation in LDL cholesterol responses among patients. The impact of anti-bococizumab antibodies on pharmacokinetic (PK) and pharmacodynamic (PD) endpoints was originally assessed using titer. Retrospective analysis of anti-bococizumab ADA responses using S/N ratios illustrates that S/N is an acceptable alternative to titer for characterizing the magnitude of ADA response and interpretation of clinically relevant ADA.