Lower Plasma Cholesterol Levels Research Articles

Evaluation the antihyprlipidemic effect of apigenin flavonoid in mice

The study’s aim was to examine the antihyperlipidemic effect of apigenin in mice as a model. Healthy adult albino mice of either sex were selected to use for this study. Four groups of animals were formed of 5 mice each. Animals Group 1 served as a negative control and fed the standard diet and tap water. Groups 2,3 and 4 were fed fatty diet and 1% water with H2O2 for 90 days to induce hyperlipidemia. After hyperlipidemic induction, group 2 served as a positive control, whereas group 3 was treated orally with apigenin 50 mg/kg/day for 14 constitutive days. Group 4 was treated by rosuvastatin (an antihyprlipidemic drug) orally at 7 mg/kg for 14 constitutive days. Blood samples were collected from all of the animals at the beginning of the study to measure the lipid profile. Then these were rechecked again after 12 weeks of feeding a high-fat diet, and then at the end of the experiment for the treated groups. The results demonstrated that the apigenin at 50mg/kg significantly reduced hyperlipidemia manifested by decreased TC, LDL-C, Triglyceride and elevation of HDL-C in comparison with the positive control group. The results, obtained by apigenin were the in accordance with those of the standard drug rosuvastatin for TC and LDL-C. This study concluded that apigenin lowered plasma cholesterol and triglycerides levels in mice.

SR-B1's Next Top Model: Structural Perspectives on the Functions of the HDL Receptor.

Purpose of ReviewThe binding of high-density lipoprotein (HDL) to its primary receptor, scavenger receptor class B type 1 (SR-B1), is critical for lowering plasma cholesterol levels and reducing cardiovascular disease risk. This review provides novel insights into how the structural elements of SR-B1 drive efficient function with an emphasis on bidirectional cholesterol transport.Recent FindingsWe have generated a new homology model of full-length human SR-B1 based on the recent resolution of the partial structures of other class B scavenger receptors. Interrogating this model against previously published observations allows us to generate structurally informed hypotheses about SR-B1’s ability to mediate HDL-cholesterol (HDL-C) transport. Furthermore, we provide a structural perspective as to why human variants of SR-B1 may result in impaired HDL-C clearance.SummaryA comprehensive understanding of SR-B1’s structure–function relationships is critical to the development of therapeutic agents targeting SR-B1 and modulating cardiovascular disease risk.

Hepatic TM6SF2 Is Required for Lipidation of VLDL in a Pre-Golgi Compartment in Mice and Rats.

Background & AimsSubstitution of lysine for glutamic acid at residu 167 in Transmembrane 6 superfamily member 2 (TM6SF2) is associated with fatty liver disease and reduced plasma lipid levels. Tm6sf2-/- mice replicate the human phenotype but were not suitable for detailed mechanistic studies. As an alternative model, we generated Tm6sf2-/- rats to determine the subcellular location and function of TM6SF2.MethodsTwo lines of Tm6sf2-/- rats were established using gene editing. Lipids from tissues and from newly secreted very low density lipoproteins (VLDLs) were quantified using enzymatic assays and mass spectrometry. Neutral lipids were visualized in tissue sections using Oil Red O staining. The rate of dietary triglyceride (TG) absorption and hepatic VLDL-TG secretion were compared in Tm6sf2-/- mice and in their wild-type littermates. The intracellular location of TM6SF2 was determined by cell fractionation. Finally, TM6SF2 was immunoprecipitated from liver and enterocytes to identify interacting proteins.ResultsTm6sf2-/- rats had a 6-fold higher mean hepatic TG content (56.1 ± 28.9 9 vs 9.8 ± 3.9 mg/g; P < .0001) and lower plasma cholesterol levels (99.0 ± 10.5 vs 110.6 ± 14.0 mg/dL; P = .0294) than their wild-type littermates. Rates of appearance of dietary and hepatic TG into blood were reduced significantly in Tm6sf2-/- rats (P < .001 and P < .01, respectively). Lipid content of newly secreted VLDLs isolated from perfused livers was reduced by 53% (TG) and 62% (cholesterol) (P = .005 and P = .01, respectively) in Tm6sf2-/- mice. TM6SF2 was present predominantly in the smooth endoplasmic reticulum and endoplasmic reticulum–Golgi intermediate compartments, but not in Golgi. Both apolipoprotein B-48 and acyl-CoA synthetase long chain family member 5 physically interacted with TM6SF2.ConclusionsTM6SF2 acts in the smooth endoplasmic reticulum to promote bulk lipidation of apolipoprotein B–containing lipoproteins, thus preventing fatty liver disease.

Alterations in the Hemato-biochemical, Endocrine, Somatic Cell Count and Milk Composition in Lactating Tarai Buffaloes during Different Lactation Stages

Background: Tarai buffalo is indigenous buffalo breed of Uttarakhand state, dual purpose, well adapt to hot-humid climatic condition of Tarai area. This study aimed to evaluate the alterations in the hemato-biochemical, endocrine, milk somatic cell count and milk composition in lactating Tarai buffaloes. Methods: Thirty-six healthy Tarai buffaloes were selected from four different Gujjar farms and divided into four groups consisting nine buffaloes in each group as early (60±30 days), mid (120±30 days) and late (180±30 days) lactation stages and dry buffaloes. Both blood and milk samples were collected once from each lactation stage of selected animals. Hematological parameters and milk composition were evaluated by standard procedures and methods. Biochemical and endocrine parameters were evaluated using commercially available kits as per manufacturer’s protocol. Milk somatic cell count (SCC) was done by direct microscopic counts using Newman Lampert stain. Result: It observed significantly (p less than 0.05) higher TLC value but lower plasma glucose, cholesterol, calcium, phosphorus and urea levels during early lactation stage. Significantly (p less than 0.05) declined in plasma total protein during late lactation stage and triglyceride in dry cows. Plasma hormone significantly (p less than 0.05) higher in cortisol during early lactation while higher T4 and insulin in late lactation stages. Milk fat, urea and total solids were significantly (p less than 0.05) decreased during early lactation and again increased during late lactation while milk SCC significantly (p less than 0.05) higher during early and late lactation stages.

Simvastatin regulates the proliferation, apoptosis, migration and invasion of human acute myeloid leukemia cells via miR-19a-3p/HIF-1α axis

ABSTRACT Statins are mainly used to lower plasma cholesterol level. In addition, the anti-leukemia effect of statins has been reported, but the mechanism remains unclear. This study aimed to explore the bioregulation of simvastatin and its mechanism in acute leukemia cell lines. Cell viability was detected by CCK-8 analysis. Apoptosis was detected through flow cytometry. Cell invasion and migration both were observed by transwell and wound healing separately. RT-qPCR and Western blot were used for determination of genes and proteins. We found that that simvastatin could regulate the biological functions of acute myeloid leukemia (AML) cells, including its proliferation, migration, invasion and apoptosis, which may be carried out by down-regulating miR-19a-3p. Overexpression of miR-19a-3p had the opposite effect in AML cells, suggesting simvastatin-inhibited AML by reducing miR-19a-3p expression. Following researches showed that HIF-1α was directly regulated by the target of miR-19a-3p. Simvastatin could reverse the adverse effects caused by miR-19a-3p mimics. Conversely, the increased expression of Mcl-1, the inhibition of caspase-3 could promote the growth of AML cells. In conclusion, simvastatin could inhibit the proliferation, migration, invasion and promote apoptosis in AML cells through miR-19a-3p/HIF-1α axis.

Hematological Parameters, Lipid Profile, and Cardiovascular Risk Analysis Among Genotype-Controlled Indigenous Kiwcha Men and Women Living at Low and High Altitudes.

Introduction: Human adaptation to high altitude is due to characteristic adjustments at every physiological level. Differences in lipid profile and cardiovascular risk factors in altitude dwellers have been previously explored. Nevertheless, there are no reports available on genotype-controlled matches among different altitude-adapted indigenous populations.Objective: To explore the possible differences in plasma lipid profile and cardiovascular risk among autochthonous Kiwcha people inhabitants of low and high-altitude locations.Methodology: A cross-sectional analysis of plasmatic lipid profiles and cardiovascular risk factors in lowland Kiwchas from Limoncocha (230 m) and high-altitude Kiwchas from Oyacachi (3,800 m).Results: In the low altitude group, 66% were women (n = 78) and 34% (n = 40) were men, whereas in the high altitude group, 59% (n = 56) were women and 41% (n = 41%) were men. We found the proportion of overweight and obese individuals to be higher among low altitude dwellers (p < 0.05). Red blood cells (RBCs), hemoglobin concentration, and SpO2% were higher among high altitude dwellers and the erythrocyte size was found to be smaller at high altitude. The group located at low altitude also showed lower levels of plasma cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), but most of these differences are not influenced by gender or elevation.Conclusions: Living at an altitude elicits well-known adaptive physiological changes such as erythrocyte count, hemoglobin concentration, hematocrit level, and serum glucose level. We also report clinical differences in the plasma lipid profile, with higher levels of cholesterol, HDL, and LDL in inhabitants of the Andes Mountain vs. their Amazonian basin peers. Despite this, we did not find significant differences in cardiovascular risk.

Toxicological Evaluation of Kenaf Seed Supercritical Carbon Dioxide-Oil in Male Sprague Dawley Rats

Kenaf seed supercritical carbon dioxide oil (KSO-SFE) is known for its numerous health benefits such as high antioxidant activity, lower plasma cholesterol level, chemopreventive to cervical and colon cancer. As there has been no report of toxicological evaluation, present study was conducted to assess the toxicity effects of KSO-SFE at 500, 1000, 1500 mg/kg body weight/day on male Sprague Dawley rats for 90 days. Parameters measured were body and organs weight, hematology, serum biochemistry, and histopathology of liver and kidneys. Induction with KSO-SFE showed lower creatinine level at all doses when compared with control group. Whereas lower plasma cholesterol level has been observed at 1000 and 1500 mg/kg bw/day, respectively. These slight changes were considered no toxicological significance. No mortality or treatment-related adverse effects in any of the parameters measured throughout the administration period even at the highest dose (1500 mg/kg bw). Based on these results, the no-adverse-effect level (NOAEL) for KSO-SFE under the condition of this study corresponds to the highest dose (1500 mg/kg bw/day).

Rosuvastatin Reduces L-Type Ca2+ Current and Alters Contractile Function in Cardiac Myocytes via Modulation of β-Adrenergic Receptor Signaling.

Rosuvastatin is one of the most used statins to lower plasma cholesterol levels. Although previous studies have reported remarkable cardiovascular effects of rosuvastatin (RSV), the mechanisms of these effects are largely unknown. In this study, we investigated the acute effects of RSV on L-type Ca2+ currents and contractile function of ventricular myocytes under basal conditions and during β-adrenergic stimulation. The effects of RSV were investigated in freshly isolated adult rat ventricular myocytes. L-type Ca+2 currents and myocyte contractility were recorded using patch-clamp amplifier and sarcomere length detection system. All experimental recordings were performed at 36 ± 1°C. L-type Ca+2 currents were significantly reduced with the administration of 1μM RSV (~ 24%) and this reduction in Ca2+ currents was observed at almost all potential ranges applied. Suppression of L-type Ca2+ current by RSV was prevented by adenylyl cyclase (AC) and protein kinase A (PKA) inhibitors SQ 22536 and KT5720, respectively. However, inhibition of Rho-associated kinases (ROCKs) by Y-27632 or nitric oxide synthase (NOS) by L-NAME failed to circumvent the inhibitory effect of RSV. Finally, we examined the effect of RSV during β-adrenergic receptor stimulation by isoproterenol and observed that RSV significantly suppresses the β-adrenergic responses in both L-type Ca2+ currents and contraction parameters. In conclusion, RSV modulates the β-adrenergic signaling cascade and thereby mimics the impact of β-adrenergic receptor blockers in adult ventricular myocytes through modulation of the AC-cAMP-PKA pathway.

Green Tea; Best Way to Struggle Lipid

Introduction: Tea is one of the most common famous drink used daily in many countries in the world. Green tea contains polyphenolic compounds as catechins, that contains epigallocatechin gallate (EGCG). The lowering of plasma cholesterol levels and blood pressure as well as improvement of insulin sensitivity and endothelial function by green tea. Aim of the work: Study the effect of green tea on obesity, blood lipid level and its effect on fatty liver. Materials and Methods: All animal procedures were approved by the ethical committee of Faculty of Medicine, Tanta University. Thirty male Albino rats in the range of 230–280 g body weight was used in this study. All subjects were kept in an animal room of Physiology Department of Faculty of Medicine, Tanta University, in a controlled temperature and 12:12 h light/dark cycle with free access to food and water. The animals were divided into 3 groups of 10 animals each. Group-1: the sham group (sham operated, no obesity). Group-2: the vehicle group (obesity induced rats treated with normal saline). Group-3: the ghrelin group (obesity induced rats treated with EGCG). Results: Body weight, fat deposits, adiposity index and serum cholesterol increased significantly in a time-dependent manner in obese and control animals but were higher in the obese group (HFD > SD). High fat diet caused significant increases in the serum cholesterol level indicating high body lipid and obesity but when EGCG was administered after the beginning of high fat diet, these elevations were significantly depressed. Conclusion: In conclusion, since the administration of EGCG increase lipolysis and the accumulation of neutrophils in the damaged hepatic tissue, this agent appears to play a cytoprotective role in the liver insulted by fatty infiltration with obesity. It seems likely that Green tea (EGCG) is put in consideration as a potential therapeutic agent against obesity and hyperlipidemia.

Recent insights into low-density lipoprotein metabolism and therapy.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are causal to atherosclerosis and, thus, the reduction of LDL-C represents a major objective for the prevention of cardiovascular disease. Aim of this review is to provide an overview on novel strategies to lower LDL-C. Although inhibiting liver cholesterol biosynthesis by statins is used as the main therapeutic approach to increase hepatic LDL-receptor expression and lower plasma cholesterol levels, novel insights into lipid and lipoprotein biology have led to the development of additional lipid-lowering therapies that can be used in combination with or as an alternative to statins in patients with statin-intolerance. New approaches include bempedoic acid, proprotein convertase subtilisin/kexin type 9 inhibitors, and angiopoietin-like protein 3 inhibitors. In the last decade, several novel therapeutic approaches have been tested and some of them have been approved as lipid-lowering agents. Some drugs are already available in clinical practice, whereas others are at late stages of development.

Development and in vitro appraisal of Soluplus® and/or Carbopol® 971 buccoadhesive patches releasing atorvastatin

ABSTRACT Atorvastatin (ATR) is frequently prescribed to lower plasma cholesterol levels. However, features such as marginal aqueous solubility, high protein binding (>95%), and low bioavailability (12–14%) have opposed its oral use. Therefore, unidirectional controlled-release mucoadhesive patches of ATR, using Carbopol® (CP) as a mucoadhesive polymer, Soluplus® (SL) as a novel water-solubilizer carrier, and ethylene/vinyl acetate as a backing layer, were proposed as a potential strategy for buccal delivery. Various ratios of CP to SL were employed to prepare eight patches. Physicochemical properties, viscosity, mucoadhesion, and drug permeation were investigated. Patch A1 (3:1, CP:SL) emerged as the most promising system, with appropriate flexibility and uniform thickness, weight, and drug content. Additionally, the appropriate surface pH, positive mucoadhesion properties, and swelling level were observed. Flow curves of the polymer mixtures were fitted perfectly to the Carreau-Yasuda and Casson models. The amount of drug diffused, and flux were 51.57% and 0.82 mg/cm2/h, respectively, with a four-fold increase in permeability across the cellulose membrane (P = 1.80 cm/h) when compared with the reference patch composed of 0% SL. It can be postulated that micellar structures of SL were able to solubilize the poorly soluble ATR and control its release across the uncoiled buccoadhesive CP network.

Moderate over-feeding of different sources of metabolizable energy and protein improved gestational insulin resistance markers and maternal metabolic status of sheep around lambing

The objective of this study was to determine the effect of moderate over-nutrition of energy (using flaxseed as a source of n-3 fatty acids) and protein (using rumen-protected lysine and methionine) around parturition on prepartal insulin resistance (IR) and periparturient metabolic status and performance of ewes. For this purpose, 32 apparently healthy ewes (2.5 ± 1 years old, 42.19 ± 1.65 kg body weight (BW)) were randomly selected out of 200 pregnant Zell ewes on d 50 before the expected lambing. After receiving a ten-day adaptation diet, eight ewes were randomly allocated to one of the following four dietary treatments: 1) the adaptation diet that meets the metabolizable energy (ME) and protein (MP) requirements of ewes during late pregnancy as recommended by National Research Council = NRC (2007) (Control = CON). 2) A diet with 10% higher levels of ME than NRC (2007) recommendations using corn grain as a source of extra ME (HEC). 3) A diet with 10% higher levels of ME compared to NRC (2007) recommendations using flaxseed for additional ME (HEF). 4) A diet with a 10% higher level of MP than NRC (2007) recommendations using rumen-protected lysine and methionine as a source of extra MP (PRO). While the dietary treatments did not affect animals’ dry matter intake (DMI), the CON ewes lost more BW starting from d 10 to d 30 relative to parturition compared to others (P < 0.05). Milk protein and fat yield (g/d) were significantly higher for PRO and HEF compared to HEC and CON ewes (P < 0.05). Moderately over-fed ewes with MP and ME had an improved insulin sensitivity (IS) compared to CON ones. The source of additional ME also impacted IR indices because HEC showed an enhancement in IS than HEF animals (P < 0.05). A lower IS in CON ewes was parallel with higher concentrations of plasma urea at prepartum (P < 0.01), lower levels of plasma cholesterol, triglyceride (P < 0.01) and glucose post-partum (P < 0.05), and a tendency for higher levels of beta-hydroxybutyrate (BHB) and non-esterified fatty acids (NEFA) in CON ewes during both pre- and post-partum periods. There were negative correlations between plasma urea, BHB, and NEFA with IR markers on d 7 prepartum in line with these results. Comparing data, we could not find a significant change in metabolic status among ewes fed with either PRO or HEF/HEC. In conclusion, the inclusion of 10% extra MP and ME could improve late gestation maternal IS and the metabolic status of dams around lambing.

Effects of BAFF Neutralization on Atherosclerosis Associated With Systemic Lupus Erythematosus.

Cardiovascular disease (CVD) is the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus, and anti-BAFF therapy has been approved for use in SLE. Since mature B cells also promote atherosclerosis, we undertook this study to evaluate, in a mouse model and in SLE patients, whether BAFF neutralization has an atheroprotective effect in SLE. The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis/lupus-prone apolipoprotein E-knockout D227K mouse model and in a cohort of SLE patients. Mice were treated with a blocking anti-BAFF monoclonal antibody (mAb), while fed a standard chow diet. Carotid plaque and carotid intima-media thickness were assessed by ultrasound at baseline and during follow-up in SLE patients who were asymptomatic for CVD. Anti-BAFF mAb in ApoE-/- D227K mice induced B cell depletion, efficiently treated lupus, and improved atherosclerosis lesions (21% decrease; P = 0.007) in mice with low plasma cholesterol levels but worsened the lesions (17% increase; P = 0.06) in mice with high cholesterol levels. The atheroprotective effect of the BAFF-BAFF receptor signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLE patients, blood BAFF levels were associated with subclinical atherosclerosis (r = 0.26, P = 0.03). Anti-BAFF mAb treatment had a differential effect on the intima-media thickness progression in SLE patients depending on body mass index. Depending on the balance between lipid-induced and B cell-induced proatherogenic conditions, anti-BAFF could be detrimental or beneficial, respectively, to atherosclerosis development in SLE.

Atorvastatin Enhances Foam Cell Lipophagy and Promotes Cholesterol Efflux Through the AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway.

Foam cells are the main pathological components of atherosclerosis. Therapies reducing foam cell formation can effectively prevent atherosclerotic diseases and cardiovascular events. Beyond lowering plasma cholesterol levels, the pleiotropic functions of statins in atherosclerosis have not been fully elucidated. In the present study, atorvastatin reduced cholesterol content and increased cholesterol efflux from foam cells in a concentration-dependent manner. Atorvastatin (10 μM) inhibited foam cell formation within 48 hours. Furthermore, we found that atorvastatin inhibited foam cell formation by promoting lipophagy, which was manifested by increased autophagy-related gene 5 (Atg5) expression, elevated ratio of microtubule-associated protein1 light chain 3 (LC3) II to LC3I, reduced p62 expression, and increased LC3 and lipid droplets colocalization in foam cells treated with atorvastatin. The autophagy inducer, rapamycin (Rap), did not increase the lipophagy enhancement effect of atorvastatin, but the autophagy inhibitor, 3-methyladenine, suppressed the effect of atorvastatin on Atg5 expression and the LC3II/LC3I ratio, as well as the increased p62 expression, suppressed lipophagy, attenuated cholesterol efflux and increased cholesterol content in foam cells. Further analysis revealed that atorvastatin promoted lipophagy by upregulating adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation, and downregulating mammalian target of rapamycin phosphorylation, whereas the AMPK inhibiter, compound C, attenuated these effects. In conclusion, atorvastatin reduced lipid accumulation and promoted cholesterol efflux by enhancing lipophagy in foam cells and thereby inhibited foam cell formation. The enhanced lipophagy of foam cells was exerted through the AMPK/mammalian target of rapamycin signaling pathway.

Inulin Supplementation Disturbs Hepatic Cholesterol and Bile Acid Metabolism Independent from Housing Temperature.

Dietary fibers are fermented by gut bacteria into the major short chain fatty acids (SCFAs) acetate, propionate, and butyrate. Generally, fiber-rich diets are believed to improve metabolic health. However, recent studies suggest that long-term supplementation with fibers causes changes in hepatic bile acid metabolism, hepatocyte damage, and hepatocellular cancer in dysbiotic mice. Alterations in hepatic bile acid metabolism have also been reported after cold-induced activation of brown adipose tissue. Here, we aim to investigate the effects of short-term dietary inulin supplementation on liver cholesterol and bile acid metabolism in control and cold housed specific pathogen free wild type (WT) mice. We found that short-term inulin feeding lowered plasma cholesterol levels and provoked cholestasis and mild liver damage in WT mice. Of note, inulin feeding caused marked perturbations in bile acid metabolism, which were aggravated by cold treatment. Our studies indicate that even relatively short periods of inulin consumption in mice with an intact gut microbiome have detrimental effects on liver metabolism and function.

ILRUN, a Human Plasma Lipid GWAS Locus, Regulates Lipoprotein Metabolism in Mice.

Single-nucleotide polymorphisms near the ILRUN (inflammation and lipid regulator with ubiquitin-associated-like and NBR1 [next to BRCA1 gene 1 protein]-like domains) gene are genome-wide significantly associated with plasma lipid traits and coronary artery disease (CAD), but the biological basis of this association is unknown. To investigate the role of ILRUN in plasma lipid and lipoprotein metabolism. ILRUN encodes a protein that contains a ubiquitin-associated-like domain, suggesting that it may interact with ubiquitinylated proteins. We generated mice globally deficient for Ilrun and found they had significantly lower plasma cholesterol levels resulting from reduced liver lipoprotein production. Liver transcriptome analysis uncovered altered transcription of genes downstream of lipid-related transcription factors, particularly PPARα (peroxisome proliferator-activated receptor alpha), and livers from Ilrun-deficient mice had increased PPARα protein. Human ILRUN was shown to bind to ubiquitinylated proteins including PPARα, and the ubiquitin-associated-like domain of ILRUN was found to be required for its interaction with PPARα. These findings establish ILRUN as a novel regulator of lipid metabolism that promotes hepatic lipoprotein production. Our results also provide functional evidence that ILRUN may be the casual gene underlying the observed genetic associations with plasma lipids at 6p21 in human.

No effects of PCSK9-inhibitor treatment on spatial learning, locomotor activity, and novel object recognition in mice

Monoclonal anti-proprotein convertase subtilisin/kexin type 9 (PSCK9) neutralizing antibodies effectively lower plasma cholesterol levels and decrease cardiovascular events but also raised some concern that cognitive function could worsen as a side effect. Here, we performed experiments in mice to characterize the effect of anti-PCSK9 antibodies on behavior and cognitive function in detail.APOE*3Leiden.CETP mice and B6129SF1/J wildtype mice were fed a Western type diet and treated with the fully human anti-PCSK9 antibody CmAb1 (PL-45134; 10mg*kg-1 s.c.) or vehicle for 6 weeks. Locomotor activity, anxiety levels, recognition memory, and spatial learning were investigated using the open field, novel object recognition test, and Morris water maze, respectively.Serum cholesterol levels in APOE*3Leiden.CETP mice after treatment with anti-PCSK9 antibody were significantly lower compared to controls whereas cholesterol levels in B6129SF1/J wildtype mice remained unchanged at low levels. No apparent differences were found regarding locomotor activity, anxiety, recognition memory, and spatial learning between animals treated with anti-PCSK9 antibody or vehicle in APOE*3Leiden.CETP and B6129SF1/J wildtype mice.In this study, we found no evidence that treatment with anti-PCSK9 antibodies lead to differences in behavior or changes of cognition in mice.

Investigation of HMG-CoA reductase inhibitory and antioxidant effects of various hydroxycoumarin derivatives.

Cardiovascular diseases are one of the primary causes of deaths worldwide, and the development of atherosclerosis is closely related to hypercholesterolemia. As the reduction of the low-density lipoprotein cholesterol level is critical for treating these diseases, the inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is essentially responsible for cholesterol biosynthesis, stands out as a key solution to lower plasma cholesterol levels. In this study, we synthesized several dihydroxycoumarins and investigated their antioxidant and in vitro HMG-CoA reductase inhibitory effects. Furthermore, we carried out in silico studies and examined the quantum-chemical properties of the coumarin derivatives. We also performed molecular docking experiments and analyzed the binding strength of each coumarin derivative. Our results revealed that compound IV displayed the highest HMG-CoA reductase inhibitory activity (IC50 = 42.0 µM) in vitro. Cupric-reducing antioxidant capacity and ferric-reducing antioxidant power assays demonstrated that coumarin derivatives exhibit potent antioxidant activities. Additionally, a close relationship was found between the lowest unoccupied molecular orbital energy levels and the antioxidant activities.

LDL-Cholesterol-Lowering Therapy.

The causal relation between elevated levels of LDL-C and cardiovascular disease has been largely established by experimental and clinical studies. Thus, the reduction of LDL-C levels is a major target for the prevention of cardiovascular disease. In the last decades, statins have been used as the main therapeutic approach to lower plasma cholesterol levels; however, the presence of residual lipid-related cardiovascular risk despite maximal statin therapy raised the need to develop additional lipid-lowering drugs to be used in combination with or in alternative to statins in patients intolerant to the treatment. Several new drugs have been approved which have mechanisms of action different from statins or impact on different lipoprotein classes.

Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Ldlr-/- Mice.

A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr-/- mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr-/- mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c+ foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin-coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c+ macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr-/- mice.