Plasma Low-density Lipoprotein Cholesterol Research Articles

Therapeutic Effects of Statins: Promising drug for Topical and Transdermal Administration.

Statins are HMG-CoA reductase inhibitors and decrease plasma low-density lipoprotein cholesterol (LDL-C) levels. They are well tolerated, and because of their LDL-C-lowering effect, they are utilized to decrease the risk of atherosclerosis and cardiovascular disease. However, statins have pleiotropic effects, including immunomodulatory, anti-inflammatory, antioxidant, and anticancer. Currently, oral administration is the only Food and Drug Administration (FDA)-approved route of administration for statins. However, other administration routes have demonstrated promising results in different pre-clinical and clinical studies. For instance, statins also seem beneficial in dermatitis, psoriasis, vitiligo, hirsutism, uremic pruritus, and graft-versus-host disease. Topically applied statins have been studied to treat seborrhea, acne, rhinophyma, and rosacea. They also have beneficial effects in contact dermatitis and wound healing in animal studies, (HIV) infection, osseointegration, porokeratosis, and some ophthalmologic diseases. Topical and transdermal application of statins is a non-invasive drug administration method that has shown significant results in bypassing the first-pass metabolism in the liver, thereby reducing possible adverse effects. This study reviews the multifaceted molecular and cellular impacts of statins, their topical and transdermal application, novel delivery systems, such as nanosystems for topical and transdermal administration and the challenges concerning this approach.

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Correction of plasma fat-soluble vitamin levels by blood lipids in elderly patients with coronary heart disease

This study aims to investigate the correlation between plasma fat-soluble vitamin levels and blood lipid in elderly patients with coronary heart disease (CHD). A total of 120 participants were enrolled, including 60 CHD patients and 60 controls without CHD. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantified plasma levels of vitamins A, D, E, and K. Data analysis was conducted using the statistical analysis system module of MetaboAnalyst 5.0. The CHD group showed significantly higher levels of plasma total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) compared to controls. The CHD group exhibited significantly higher plasma levels of VA and VE, positively correlating with TC, TG, and LDL-C. After adjusted by TG levels, the CHD group had significantly lower plasma levels of VA and VE, negatively correlating with TC, TG, and LDL-C. The CHD group also had significantly lower concentrations of VD3, independent of TG modification, compared to controls. VD3 negatively correlated with TC, TG, and LDL-C. Elderly individuals with CHD display abnormal blood lipid metabolism, and fat-soluble vitamins adjusted by TG levels can more accurately and timely response to implicit fat-soluble vitamins deficiency in CHD patients.

Clustering of health behaviors and their associations with cardiometabolic risk factors among adults at high risk for type 2 diabetes in India: A latent class analysis.

We aimed to identify clusters of health behaviors and study their associations with cardiometabolic risk factors in adults at high risk for type 2 diabetes in India. Baseline data from the Kerala Diabetes Prevention Program (n = 1000; age 30-60 years) were used for this study. Information on physical activity (PA), sedentary behavior, fruit and vegetable intake, sleep, and alcohol and tobacco use was collected using questionnaires. Blood pressure, waist circumference, 2-h plasma glucose, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were measured using standardized protocols. Latent class analysis was used to identify clusters of health behaviors, and multilevel mixed-effects linear regression was employed to examine their associations with cardiometabolic risk factors. Two classes were identified, with 87.4% of participants in class 1 and 12.6% in class 2. Participants in both classes had a high probability of not engaging in leisure-time PA (0.80 for class 1; 0.73 for class 2) and consuming <5 servings of fruit and vegetables per day (0.70 for class 1; 0.63 for class 2). However, participants in class 1 had a lower probability of sitting for >=3 h per day (0.26 vs 0.42), tobacco use (0.10 vs 0.75), and alcohol use (0.08 vs 1.00) compared to those in class 2. Class 1 had a significantly lower mean systolic blood pressure (β = -3.70 mm Hg, 95% confidence interval [CI] -7.05, -0.36), diastolic blood pressure (β = -2.45 mm Hg, 95% CI -4.74, -0.16), and triglycerides (β = -0.81 mg/dL, 95% CI -0.75, -0.89). Implementing intervention strategies, tailored to cluster-specific health behaviors, is requiredfor the effective prevention of cardiometabolic disorders among high-risk adults for type 2 diabetes.

Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling.

The gut microbiota is closely linked to atherosclerosis. However, the role of intestinal fungi, essential members of the complex microbial community, in atherosclerosis is poorly understood. Herein, we show that gut fungi dysbiosis is implicated in patients with dyslipidemia, characterized by higher levels of Candida albicans (C.albicans), which are positively correlated with plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Furthermore, C.albicans colonization aggravates atherosclerosis progression in a mouse model of the disease. Through gain- and loss-of-function studies, we show that an intestinal hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway mediates the effect of C.albicans. Mechanistically, formyl-methionine, a metabolite of C.albicans, activates intestinal HIF-2α signaling, which drives increased ceramide synthesis to accelerate atherosclerosis. Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment.

Anti-atherogenic role of green tea (Camellia sinensis) in South Indian smokers

Ethnopharmacological relevanceGreen tea (Camellia sinensis) is a popular beverage consumed all over the world due to its health benefits. Many of these beneficial effects of green tea are attributed to polyphenols, particularly catechins. Aim of the studyThe present study focuses on underlying anti-platelet aggregation, anti-thrombotic, and anti-lipidemic molecular mechanisms of green tea in South Indian smokers. Materials and methods: We selected 120 South Indian male volunteers for this study to collect the blood and categorised them into four groups; control group individuals (Controls), smokers, healthy control individuals consuming green tea, and smokers consuming green tea. Smokers group subjects have been smoking an average 16-18 cigarettes per day for the last 7 years or more. The subjects (green tea consumed groups) consumed 100 mL of green tea each time, thrice a day for a one-year period. ResultsLC-MS analysis revealed the presence of multiple phytocompounds along with catechins in green tea extract. Increased plasma lipid peroxidation (LPO), protein carbonyls, cholesterol, triglycerides, and LDL-cholesterol with decreased HDL-cholesterol levels were observed in smokers compared to the control group and the consumption of green tea showed beneficial effect. Furthermore, docking studies revealed that natural compounds of green tea had high binding energy with 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA) when compared to their positive controls, whereas (-) epigallocatechin-3-gallate (EGCG) and (-) epicatechin-gallate (ECG) had high binding energy with sterol regulatory element-binding transcription factor 1 (SREBP1c). Further, our ex vivo studies showed that green tea extract (GTE) significantly inhibited platelet aggregation and increased thrombolytic activity in a dose dependent manner. ConclusionIn conclusion, in smokers, catechins synergistically lower oxidative stress, platelet aggregation and modify an aberrant lipid profile. Furthermore, molecular docking studies supported green tea catechins' antihyperlipidemic efficacy through strong inhibitory activity on HMG-CoA reductase and SREBP1c. The mitigating effects on cardiovascular disease risk factors in smokers that have been reported can be attributed majorly to catechins or to their synergistic effects.

Enhancing prime editor flexibility with coiled-coil heterodimers

BackgroundPrime editing enables precise base substitutions, insertions, and deletions at targeted sites without the involvement of double-strand DNA breaks or exogenous donor DNA templates. However, the large size of prime editors (PEs) hampers their delivery in vivo via adeno-associated virus (AAV) due to the viral packaging limit. Previously reported split PE versions provide a size reduction, but they require intricate engineering and potentially compromise editing efficiency.ResultsHerein, we present a simplified split PE named as CC-PE, created through non-covalent recruitment of reverse transcriptase to the Cas9 nickase via coiled-coil heterodimers, which are widely used in protein design due to their modularity and well-understood sequence-structure relationship. We demonstrate that the CC-PE maintains or even surpasses the efficiency of unsplit PE in installing intended edits, with no increase in the levels of undesired byproducts within tested loci amongst a variety of cell types (HEK293T, A549, HCT116, and U2OS). Furthermore, coiled-coil heterodimers are used to engineer SpCas9-NG-PE and SpRY-PE, two Cas9 variants with more flexible editing scope. Similarly, the resulting NG-CC-PE and SpRY-CC-PE also achieve equivalent or enhanced efficiency of precise editing compared to the intact PE. When the dual AAV vectors carrying CC-PE are delivered into mice to target the Pcsk9 gene in the liver, CC-PE enables highly efficient precise editing, resulting in a significant reduction of plasma low-density lipoprotein cholesterol and total cholesterol.ConclusionsOur innovative, modular system enhances flexibility, thus potentially facilitating the in vivo applicability of prime editing.

Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

Biomimetic MicroRNAs-Selenium-Nanocomposites for Targeted and Combined Hyperlipidemia Therapy.

Hyperlipidemia is considered as a high-risk factor for leading to coronary heart disease. MicroRNA-148a-3p (miR-148a-3p) inhibitor is a potential therapeutic target to bind low-density lipoprotein cholesterol receptors (LDLR) for decreasing the levels of low-density lipoprotein cholesterol in plasma. However, the therapeutic effects are not ideal in the clinical translation of nucleic acids treatment, owing to the short circulation time in vivo. Therefore, a platelet membrane (PM) cloaks Se nanoparticles (SeNPs) delivery system with chitosan (CS) modifies and miR-148a-3p inhibitors encapsulated is designed (PM/CS-SeNPs/miR). The PM/CS-SeNPs/miR shows a uniform shell-core structure with a particle size of ≈90 nm. Co-delivering miR-148a-3p inhibitors and Se effectively alleviate hyperlipidemia via LDLR pathway and Toll-Like Receptor 4 (TLR-4)/NF-κB signaling pathway, respectively. Furthermore, coated by PM, PM/CS-SeNPs/miR successfully prolong circulation time to 48 h in vivo and quickly target to liver with no toxicity. This dual combination therapy with miRNAs and Se based on nanoparticles targeted delivery presents a high-performance strategy for precise hyperlipidemia treatment.

Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism.

Transmembrane 6 superfamily member 2 ( TM6SF2 ) gene was identified through exome-wide studies in 2014. A genetic variant from glutamic acid to lysine substitution at amino acid position 167 (NM_001001524.3:c.499G> A) (p.Gln167Lys/p.E167K, rs58542926) was discovered (p.E167K) to be highly associated with increased hepatic fat content and reduced levels of plasma triglycerides and LDL cholesterol. In this review, we focus on the discovery of TM6SF2 and its role in VLDL secretion pathways. Human data suggest TM6SF2 is linked to hepatic steatosis and cardiovascular disease (CVD), hence understanding its metabolic pathways is of high scientific interest. Since its discovery, completed research studies in cell, rodent and human models have defined the role of TM6SF2 and its links to human disease. TM6SF2 resides in the endoplasmic reticulum (ER) and the ER-Golgi interface and helps with the lipidation of nascent VLDL, the main carrier of triglycerides from the liver to the periphery. Consistent results from cells and rodents indicated that the secretion of triglycerides is reduced in carriers of the p.E167K variant or when hepatic TM6SF2 is deleted. However, data for secretion of APOB, the main protein of VLDL particles responsible for triglycerides transport, are inconsistent. The identification of genetic variants that are highly associated with human disease presentation should be followed by the validation and investigation into the pathways that regulate disease mechanisms. In this review, we highlight the role of TM6SF2 and its role in processing of liver triglycerides.

Evaluation of antihyperlipidemic effect of rosemary oil in streptozotocin-induced diabetic rats

Aim: In this study, the potential effects of rosemary oil on the lipid profile in streptozotocin-induced diabetic rats were examined. Materials and Methods: In this study, thirty-two adult male Wistar Albino rats were used. Working groups were consisted as follows: control group (C, n=6), rosemary group (R, n=6), diabetes group (STZ, n=10) and diabetes+rosemary group (STZ+R, n=10). The rosemary oil was administered at oral dosage of 200 mg/kg daily for duration of three weeks in the groups receiving rosemary oil. Diabetes was performed by subcutaneous injections of streptozotocin at dosage of 40 mg/kg in 0.1 M citrate buffer (pH 4.5) for two consecutive days as a single daily dose. At the end of three weeks, blood samples collected from the all animals were assessed lipid parameters. Results: In this study, plasma levels of triglyceride, total cholesterol, and LDL-cholesterol significantly elevated, alongside plasma HDL-cholesterol levels in diabetes group significantly reduced compared to the control group. However, upon the application of rosemary oil to streptozotocin-induced diabetic rats, a substantial decrease in plasma triglyceride, total cholesterol, and LDL-cholesterol levels was observed, while plasma HDL-cholesterol notably increased. Conclusion: As a result of the current findings, it is concluded that rosemary oil may have antihiperlipidemic properties and could be used as a phytomedicine for the treatment of diabetes.

Differences among Lactiplantibacillus plantarum strains isolated from different fermented foods in their potential cholesterol-lowering properties

Elevated levels of plasma low-density lipoprotein (LDL) cholesterol have been associated with incident atherosclerotic cardiovascular disease. Animal studies and clinical trials have demonstrated that several Lactiplantibacillus plantarum strains are effective in reducing plasma LDL cholesterol levels. However, it is unclear whether the habitats from which Lactiplantibacillus plantarum strains are isolated have an impact on their potential cholesterol-lowering properties. In this study, 107 Lactiplantibacillus plantarum strains isolated from three habitats (20 isolated from fermented dairy products, 23 from fermented grape must, and 64 from fermented vegetables) were compared for their potential cholesterol-lowering properties on an origin scale. These properties included acid resistance, bile tolerance, surface hydrophobicity, and bile acid deconjugation. The results showed that the fermented dairy products-derived strains were the most bile-tolerant and hydrophobic, the fermented grape must-derived strains were the most effective at hydrolyzing conjugated bile acids, and the fermented vegetables-derived strains were the most acid-resistant. Bile salt hydrolase (BSH) genes were detected in 97.2% of the total strains and 100% of the fermented dairy products-derived strains by standard PCR with agarose gel electrophoresis detection. In the 104 bsh genes-containing strains, 92.3% had detectable BSH activity (n = 96). These BSH-positive strains exhibited a greater substrate preference for glycine-conjugated bile acids than taurine-conjugated bile acids. Overall, the fermented dairy products-derived strains appeared to have greater cholesterol-lowering potential than those isolated from the other two habitats. This study provided valuable information regarding where to obtain Lactiplantibacillus plantarum strains with greater cholesterol-lowering potential.

Nomogram for predicting the risk of nonalcoholic fatty liver disease in older adults in Qingdao, China: A cross-sectional study.

To explore the risk factors for non-alcoholic fatty liver disease (NAFLD) and to establish a non-invasive tool for the screening of NAFLD in an older adult population. A total of 131,161 participants were included in this cross-sectional study. Participants were randomly divided into training and validation sets (7:3). The least absolute shrinkage and selection operator method was used to screen risk factors. Multivariate logistic regression was employed to develop a nomogram, which was made available online. Receiver operating characteristic curve analysis, calibration plots, and decision curve analysis were used to validate the discrimination, calibration, and clinical practicability of the nomogram. Sex and age subgroup analyses were conducted to further validate the reliability of the model. Nine variables were identified for inclusion in the nomogram (age, sex, waist circumference, body mass index, exercise frequency, systolic blood pressure, fasting plasma glucose, alanine aminotransferase, and low-density lipoprotein cholesterol). The area under the receiver operating characteristic curve values were 0.793 and 0.790 for the training set and the validation set, respectively. The calibration plots and decision curve analyses showed good calibration and clinical utility. Subgroup analyses demonstrated consistent discriminatory ability in different sex and age subgroups. This study established and validated a new nomogram model for evaluating the risk of NAFLD among older adults. The nomogram had good discriminatory performance and is a non-invasive and convenient tool for the screening of NAFLD in older adults.

Research Progress in the Clinical Treatment of Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant inheritable disease with severe disorders of lipid metabolism. It is mainly marked by increasing levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), xanthoma, corneal arch, and early-onset coronary heart disease (CHD). The prevalence of FH is high, and it is dangerous and clinically underdiagnosed. The clinical treatment for FH includes both pharmacological and non-pharmacological treatment, of which non-pharmacological treatment mainly includes therapeutic lifestyle change and dietary therapy, LDL apheresis, liver transplantation and gene therapy. In recent years, many novel drugs have been developed to treat FH more effectively. In addition, the continuous maturity of non-pharmacological treatment techniques has also brought more hope for the treatment of FH. This paper analyzes the pathogenic mechanism and the progress in clinical treatment of FH. Furthermore, it also summarizes the mechanism and structure-activity relationship of FH therapeutic drugs that have been marketed. In a word, this article provides a reference value for the research and development of FH therapeutic drugs.

Consumption of a variety of plant foods, ultra-processed foods, and risk for chronic disease: A dietary intervention

BackgroundThe reliance on ultra-processed foods (UPF) as a source of energy has increased over the last decade. Consumption of UPF is associated with increased calorie intake and increased risk for chronic disease. An intentional increase of a variety of non-ultra-processed plant foods may decrease UPF intake and reduce risk for chronic disease. MethodsThe objective of this study was to determine whether an intervention to increase in the number of varieties of non-ultra-processed plant foods consumed each week along with grocery reimbursement was associated with reduced intake of UPF and reduced risk of chronic disease. An 8-week dietary intervention with the intention for subjects (22 were recruited and started the study, while 19 subjects completed the study) to consume at least 30 varieties of non-ultra-processed plant foods per week was conducted. Subjects watched a weekly educational module, received recipes and grocery lists, and received reimbursement for non-ultra-processed plant foods that were purchased. Diet assessments were conducted by 24-h recall and 3-day diet records. Fasting plasma glucose, C-reactive protein, LDL and HDL cholesterol, and anthropomorphic measurements were assessed at four time points. ResultsThe number of different types of non-ultra-processed plant foods consumed each week was significantly increased after the 8-week intervention compared to before (34.7 ± 10.8 vs 23.1 ± 12.1; p < 0.001). The number of ultra-processed foods consumed per day was significantly lower during the intervention compared to the control period (5.32 ± 1.65 vs 6.54 ± 2.04; p = 0.02). There were no significant changes to biochemical or anthropomorphic following the 8-week intervention. DiscussionEducating individuals on the importance of the variety of plant foods intake along with reducing the financial barrier for purchasing plant foods may be an effective way to reduce reliance on ultra-processed foods. More research is needed to determine whether an increase in varieties of plant foods and reduction in ultra-processed food intake impacts risk for chronic disease.

Lipidomic signatures discriminate subtle hepatic changes in the progression of porcine nonalcoholic steatohepatitis.

Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts (CS, MAT1A, and SPP1) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism.NEW & NOTEWORTHY A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Fenugreek Leaves and Lemon are Mild to Moderately Effective Hypolipidemic Herbs to Lower Total Plasma Cholesterol, Triglycerides, and LDL Cholesterol in Primary and Secondary Hyperlipidemic Patients

In recent decades, some researchers assert that other newer lipid measurements, including non-HDL-C, apolipoprotein (apo) A-I, apoB, and lipid ratios, are superior to traditional LDL-C in predicting adverse outcomes in general population. Some researchers even suggest that apoB can replace the standard “lipid profile” as a target for motoring and therapy in at-risk patients. High plasma lipids interact with free radicals in human body leading to develop coronary artery disease. We in this study have compared hypolipidemic effects of Fenugreek, Curcuma longa, and Lemon. Study was conducted at Jinnah Hospital Lahore-Pakistan from January 2022 to May 2022. Ninety hyperlipidemic patients of age group 19 to 70 were included in the study. Exclusion criteria were diabetic, alcoholic additives, hypertensive patients and those whose kidney or liver functions were impaired. Consent was taken from all participants. Their base line lipid profile was taken in biochemistry laboratory of the hospital. They were divided in three groups i.e. 30 patients in each group. Group-I was advised to take 500 mg of Curcuma longa (haldi) mixed in fresh milk without cream, thrice daily for two months. Group-II patients were advised to take 100 grams of Fenugreek leaves mixed with salad in each meal (thrice daily) for the period of two months. Group-III patients were advised to take 40 ml of fresh lemon juice mixed with 40 ml mineral water thrice daily for two months. They all were advised not to take heavy meal rich with any type of fat like junk food etc. One hour daily brisk walk was advised to all participants. 15 days follow up visit was scheduled for them. After two months their lipid profile was re-determined. When results were compiled and statistically analyzed by applying paired ‘t’ test, it revealed that Curcuma longa decreased total cholesterol, TG, LDL cholesterol 16.10, 20.01, and 17.59 mg/dl respectively. Fenugreek decreased total cholesterol, TGs, and LDL cholesterol 14.70, 17.33, and 17.06 mg/dl respectively. Lemon in two months therapy decreased total cholesterol, TGs, and LDL cholesterol 15.45, 10.13, and 11.97 mg/dl respectively. None of the above mentioned herbs raised HDL cholesterol significantly. It was concluded from this research work that Curcuma longa, Fenugreek leaves and Lemon are mild to moderately effective hypolipidemic herbs to lower total plasma cholesterol, triglycerides, and LDL cholesterol but have no potential to raise HDL cholesterol when analyzed biostatistically.

Diet and Lipid-Lowering Nutraceuticals in Pediatric Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia is a genetically determined disease characterized by elevated plasma total and LDL cholesterol levels from the very first years of life, leading to early atherosclerosis. Nutritional intervention is the first-line treatment, complemented with nutraceuticals and drug therapy when necessary. Nutraceuticals with a lipid-lowering effect have been extensively studied in the past few decades, and have been recently included in international guidelines as a complement to nutritional and pharmacological treatment in subjects with dyslipidemia. In this review, we explore current nutritional interventions for dyslipidemia in childhood, with a specific focus on the main nutraceuticals studied for treating severe dyslipidemia in pediatric patients. Additionally, we briefly describe their primary mechanisms of action and highlight the advantages and risks associated with the use of lipid-lowering nutraceuticals in childhood.

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study.

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein-ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research.