High Plasma Cholesterol Levels Research Articles

Conditional deletion of Ccl2 in smooth muscle cells does not reduce early atherosclerosis in mice

Background and aimsC–C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout of Ccl2 reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice. MethodsSMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtype Ccl2 alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and a high-fat diet for 12 weeks. ResultsUnexpectedly, mice with SMC-specific Ccl2 deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes. ConclusionsSMC-specific deficiency of Ccl2 does not significantly affect early plaque development in hypercholesterolemic mice.

Effects of disease-modifying therapies on lipid parameters in patients with multiple sclerosis.

Cholesterol and lipids are essential components of nerve cells. Myelin synthesis and stabilization is a cholesterol-dependent process. It has been shown in several studies that high plasma cholesterol levels may be associated with clinical deterioration in Multiple Sclerosis (MS). There is scarce information about the effects of disease-modifying treatment (DMTs) on lipid profile. In this study, we aimed to investigate the effect of DMTs on plasma lipid profiles in MS patients. The records of 380 MS patients who were still under follow-up were analyzed in terms of age, sex, disease duration, EDSS scores, serum lipid levels, and used DMTs. The data of patients receiving Interferon (n=53), Glatiramer acetate (n=25), Fingolimod (n=44), Teriflunomide (n=24), Dimethyl fumarate (n=7) and Ocrelizumab (n=14) were compared with the data of control group (n=53). A total of 220 patients, 157 women, and 63 men, were included in the study. The average age of the participants in the study was 39.83±10.21 years, mean disease duration was 8.45±6.56 years, and the EDSS score was 2.25±1.97. Although, Lipid parameters were higher in MS patients using Fingolimod the difference cannot reach the statistical significance. No significant relationship was found between the DMTs that MS patients had been using for the last six months and their cholesterol levels.

CETP inhibitor evacetrapib enters mouse brain tissue.

High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5h after a 40mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.

Endothelial KCa channels: Novel targets to reduce atherosclerosis-driven vascular dysfunction.

Elevated levels of cholesterol in the blood can induce endothelial dysfunction, a condition characterized by impaired nitric oxide production and decreased vasodilatory capacity. Endothelial dysfunction can promote vascular disease, such as atherosclerosis, where macrophages accumulate in the vascular intima and fatty plaques form that impair normal blood flow in conduit arteries. Current pharmacological strategies to treat atherosclerosis mostly focus on lipid lowering to prevent high levels of plasma cholesterol that induce endothelial dysfunction and atherosclerosis. While this approach is effective for most patients with atherosclerosis, for some, lipid lowering is not enough to reduce their cardiovascular risk factors associated with atherosclerosis (e.g., hypertension, cardiac dysfunction, stroke, etc.). For such patients, additional strategies targeted at reducing endothelial dysfunction may be beneficial. One novel strategy to restore endothelial function and mitigate atherosclerosis risk is to enhance the activity of Ca2+-activated K+ (KCa) channels in the endothelium with positive gating modulator drugs. Here, we review the mechanism of action of these small molecules and discuss their ability to improve endothelial function. We then explore how this strategy could mitigate endothelial dysfunction in the context of atherosclerosis by examining how KCa modulators can improve cardiovascular function in other settings, such as aging and type 2 diabetes. Finally, we consider questions that will need to be addressed to determine whether KCa channel activation could be used as a long-term add-on to lipid lowering to augment atherosclerosis treatment, particularly in patients where lipid-lowering is not adequate to improve their cardiovascular health.

Update on Sitosterolemia and Atherosclerosis.

The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice.

BackgroundNon-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood.MethodsIn this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice.ResultsObese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice.ConclusionsUnhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.

Blue and Red Light Color Combinations Can Enhance Certain Aspects of Digestive and Anabolic Performance in Juvenile Steelhead Trout Oncorhynchus mykiss

The light spectrum varies with the altitude of the sun and shows different light colors in clear water. In this study, we aimed to investigate the response of juvenile steelhead trout Oncorhynchus mykiss (34.67 ± 2.69 g initial weight) under different light color conditions. The effects of different blue and red light combinations on plasma biochemical parameters, digestive enzyme activity, and RNA/DNA ratio were assessed in trout over 16 weeks. Six treatments were randomly assigned to 24 tanks with four replicates per treatment: a constant light intensity of 150 lx: 12 h white light then 12 h dark (12W); 12 h blue light then 12 h dark (12B); 12 h red light then 12 h dark (12R); 1.5 h blue light, 9 h red light, 1.5 h blue light, then 12 h dark (3B9R); 3 h blue light, 6 h red light, 3 h blue light, then 12 h dark (6B6R); and 12 h of both blue and red light then 12 h dark (T12BR). Fish exposed to the 3B9R light environment showed significantly increased plasma levels of total protein (TP), enhanced activities of midgut lipase, trypsin, and gastric lipase; and increased RNA content in the liver and muscle tissue to promote protein synthesis efficiency, thereby improving digestive and anabolic performance compared to fish in the other treatments. This indicates that steelhead trout have adapted well to such variable light conditions during long-term evolution. In contrast, trout exposed to the 6B6R light environment showed significant reductions in plasma glucose, TP, and triglyceride levels, decreased activity of gastrointestinal digestive enzymes, and reduced protein synthesis capacity in the muscle and liver, resulting in weakened digestive and anabolic performance. Furthermore, despite the high RNA content and RNA/DNA ratio in fish exposed to a 12R light environment, relatively high plasma cholesterol and triglycerides levels were observed, which might indicate oxidative stress. Therefore, this light is not considered suitable for long-term cultivation. In conclusion, the 3B9R treatment was the optimal light condition tested and can be used to improve the digestive and anabolic performance of steelhead trout.

Bile Acid Sequestrants for Hypercholesterolemia Treatment Using Sustainable Biopolymers: Recent Advances and Future Perspectives.

Bile acids, the endogenous steroid nucleus containing signaling molecules, are responsible for the regulation of multiple metabolic processes, including lipoprotein and glucose metabolism to maintain homeostasis. Within our body, they are directly produced from their immediate precursors, cholesterol C (low-density lipoprotein C, LDL-C), through the enzymatic catabolic process mediated by 7-α-hydroxylase (CYP7A1). Bile acid sequestrants (BASs) or amphiphilic resins that are nonabsorbable to the human body (being complex high molecular weight polymers/electrolytes) are one of the classes of drugs used to treat hypercholesterolemia (a high plasma cholesterol level) or dyslipidemia (lipid abnormalities in the body); thus, they have been used clinically for more than 50 years with strong safety profiles as demonstrated by the Lipid Research Council-Cardiovascular Primary Prevention Trial (LRC-CPPT). They reduce plasma LDL-C and can slightly increase high-density lipoprotein C (HDL-C) levels, whereas many of the recent clinical studies have demonstrated that they can reduce glucose levels in patients with type 2 diabetes mellitus (T2DM). However, due to higher daily dosage requirements, lower efficacy in LDL-C reduction, and concomitant drug malabsorption, research to develop an "ideal" BAS from sustainable or natural sources with better LDL-C lowering efficacy and glucose regulations and lower side effects is being pursued. This Review discusses some recent developments and their corresponding efficacies as bile removal or LDL-C reduction of natural biopolymer (polysaccharide)-based compounds.

Výhody současné léčby hypertenze a hypercholesterolemie fixní kombinací

Parallel occurrence of high blood pressure and high plasma cholesterol level is very frequent, in our population in 30 %, and brings multiplicative higher risk for atherosclerotic cardiovascular diseases. On the other hand the contemporary treatment of them reduces that risk synergically. New fixed combination pill of rosuvastatin and ramipril (Kastel) is very felicitous choice for patients with hypercholesterolemia and mild hypertension, in which two antihypertensive drugs are not required immediatelly.

Mopping up crystals to keep the blood flowing.

Despite substantial progress in the prevention and treatment of cardiovascular diseases, mortality and morbidity remain unacceptably high; stroke and myocardial infarction are still one of the biggest killers worldwide.1 One hallmark of a ruptured atherosclerotic plaque causing a clinical event is the presence of cholesterol crystals (CC) that are fuelled by high plasma cholesterol levels. These deposits are extremely pro-inflammatory which contributes to plaque inflammation, instability and rupture.

Colchicine reduces atherosclerotic plaque vulnerability in rabbits

Background and aimsThe anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis. MethodsTwenty-two rabbits were fed a 0.5% cholesterol-enriched diet for 10 weeks and then randomized to receive either oral saline (n=11) or colchicine (350 μg/kg/day; n=11) for 6 weeks, with 0.2% cholesterol-diet during the treatment period. We performed intravascular ultrasound imaging (at start and end of treatment) and histology analyses of the descending thoracic aorta. Leucocyte activation was assessed in vitro on blood samples obtained during treatment. ResultsColchicine prevented positive aortic vascular remodelling (p=0.029 vs placebo). This effect was even more marked at high plasma cholesterol level (third quartile of plasma cholesterol, p=0.020). At high cholesterol level, both atherosclerotic plaque and media areas on histomorphology were reduced by colchicine compared to placebo (p=0.031 and p=0.039, respectively). Plaque fibrosis and macrophage area were reduced by colchicine (Masson's trichrome stain: p=0.038; RAM-11: p=0.026). The plaque vulnerability index, assessed by histology, was reduced by colchicine (p=0.040). Elastin/type I collagen ratio in media was significantly higher with colchicine compared to placebo (p=0.013). At a high level of plasma cholesterol, in vitro LPS challenge revealed a decrease in monocyte activation following treatment with colchicine (p<0.001) and no change in the placebo group (p=0.353). ConclusionsColchicine decreases plaque vulnerability with reductions in plaque inflammation, medial fibrosis, outward vascular remodelling and ex vivo monocyte activation.

The effects of olive oil and cholesterol enriched diets on aortic fatty streak development and lipid peroxidation in rabbits.

High plasma cholesterol levels, mainly low-density lipoprotein-cholesterol (LDL) is a widely recognized major risk factor for coronary heart disease (CHD). According to epidemiologic studies' findings, people from the Mediterranean countries have lower CHD rates than other countries; in these countries the usual diet is high in olive oil. The present study compares the effects of a cholesterol-enriched diet with or without adding olive oil on serum lipoproteins, lipid peroxidation, and atherosclerosis development. Twenty Dutch male rabbits were categorized into four groups (one group as control, and others as experimental). They received one of control (CON), olive oil-rich (OIL), cholesterol-rich (CHOL), and cholesterol + olive oil (COIL) diet for 12 weeks. Fasting blood samples from the heart were collected at the beginning and the end of the experimental period. Means of serum lipids were not significantly different at the beginning of the experimental period. After the intervention, significant differences were shown in total cholesterol (TC) (CON: 27.75 ± 4.83, OIL: 19.75 ± 2.62, CHOL: 1757.20 ± 149.62, COIL: 2906.40 ± 421.01; P < 0.001), high-density lipoprotein-cholesterol (HDL-C) (CON: 16 ± 1.47, OIL: 10.25 ± 1.70, CHOL: 22.2 ± 3.83, COIL: 28.60 ± 6.27; P = 0.04), triglyceride (CON: 65 ± 12.21, OIL: 71.75 ± 6.23, CHOL: 244.2 ± 44.45, COIL: 775.6 ± 105.07; P < 0.001), and MDA between groups (CON: 0.57 ± 0.10, OIL: 0.63 ± 0.15, CHOL: 5.62 ± 0.18, COIL: 2.06 ± 0.64; P < 0.001). The comparison of CHOL and the COIL groups showed a higher mean of malondialdehyde (MDA) in group CHOL (4.47 ± 0.28 vs 1.1 ± 0.6; P < 0.001). Aortic lesion was not observed in CON and OIL groups. Aortic lesion degree was significantly lower in the COIL group compared to the CHOL (2.4 ± 0.6 vs 3.66 ± 0.33; P = 0.02). These findings showed the preventive effect of olive oil on atherosclerosis development. However, it is independent of the plasma lipoprotein effect, and olive oil probably acts on arteries directly.

EXPERIMENTAL MODELS OF THE ATHEROSCLEROSIS ON RABBITS

Atherosclerosis is the main cause of cardiovascular diseases, which, despite a number of new advances in their diagnosis and treatment, still occupy a leading position. Experimental modeling of atherosclerosis in laboratory animals plays an important role in the study of the fundamental pathophysiological processes and pathology of atherosclerosis. Rabbits are among the most suitable animals for simulating atherosclerosis, as they are widely available, inexpensive to maintain, and easy to manipulate. The key advantage of rabbits over other animals is that their lipid metabolism is practically similar to that of humans. The aim of the study was to analyze literature data on experimental models of atherosclerosis in rabbits. The review shows that the history of the study of atherosclerosis by means of experimental models is very rich and originates from the works of the well-known Russian pathologists A.I. Ignatovsky, N.N. Anichkov, S.S. Khalatov (1908-1915), who developed a cholesterol model of the formation of atherosclerosis in rabbits. The principle of this model is to feed laboratory animals with food containing elevated levels of lipids and cholesterol. The composition of the cholesterol (atherogenic) diet may vary, determining the existence of modifications of this model. Most often, a diet with a cholesterol content of 0.3-0.5% is used, in cases where it is necessary to accelerate the development of atherosclerosis, a short-term use of a diet with a 1% cholesterol content is allowed. In addition to cholesterol, it is recommended to use vegetable oils (soybean, coconut or corn) in the atherogenic diet as they improve the absorption of cholesterol in the intestine. In 1980, Japanese researcher Y. Watanabe deduced a new model of atherosclerosis formation - on hereditarily determined hyperlipidemic rabbits Watanabe (WHHL-rabbits). WHHL rabbits contain a genetic mutation in the gene encoding low-density lipoprotein receptors, which results in these animals having high plasma cholesterol levels with a normal diet. Thanks to modern genetic technologies, various genetic models of atherosclerosis in rabbits have also been created: transgenic and “knocked out” rabbits. The main method for obtaining transgenic rabbits is pronuclear microinjection, which allows the introduction of a transgene (additional DNA fragment) into their genome. To date, using this technology, it has been possible to introduce more than a dozen genes responsible for lipid metabolism. The principle of creating knocked out rabbits consists in specific inactivation using genome editing technologies (ZFN, TALEN, CRISPR / Cas9) of a certain working gene. Experimental models of atherosclerosis in rabbits have not lost their significance and continue to be used to study the fundamental morphological (pathological) and pathological mechanisms underlying atherosclerosis, to search for new diagnostic biomarkers and potential targets for therapeutic effects, as well as to conduct preclinical trials of newly developed drugs.

EFFECT OF HONEYBEE VENOM (APIS MELLIFERA) ON RESPIRATORY FUNCTIONS OF HYPERCHOLESTEROLEMIC MALE ALBINO RATS

Hypercholesterolemia can be defined as the presence of high plasma cholesterol levels, with normal plasma triglycerides, as a consequence of the rise of cholesterol and apolipoprotein B (apoB)-rich lipoproteins, called low-density lipoprotein (LDL)and characterized by very high levels on the blood cholesterol which is a risk factor of cardiovascular health. Medicines which formed from chemical compounds cause serious side effects that cause an imbalance in the body’s functions. Therefore, using of natural substances may be an innovative method for the treatment of diseases, as they do not have any side effects on human health. Bee venom can be used as a drug due to its beneficial effects on many disorders, such as neurological, cardiovascular, hematological, musculoskeletal, and dermatological disorders. In the present work, we found that treatment of hypercholesterolemic rats with bee venom (BV) revealed significant increases in Hb, Hct, and RBCs count and showed a significant increase in PaO2, % O2 saturation, O2 carrying capacity. These results suggest that BV can enhance respiratory functions of blood and can be used in respiratory diseases to enhance the respiration and hematological parameters. Also, BV could be used as a prophylactic agent (food protector) to protect us from the harmful effects of cholesterol.

Impact of different fructose concentrations on metabolic and behavioral parameters of male and female mice

Clinical evidence has shown that a high consumption of sugar-sweetened beverages is a risk factor for developing obesity and metabolic syndrome. There has also been increasing interest in the potential effects of high-fructose intake on behavior. The present study evaluated sex differences in behavioral and metabolic characteristics in response to chronic fructose intake in mice. Swiss mice (3-months-old) had access to tap water or fructose-water solution (at 15% or 30% w/v) ad libitum for nine weeks. After the 8 weeks, the mice were submitted to a battery of behavioral tests. A glucose tolerance test was performed one day after these behavioral tests, and the next day blood was collected for biochemical analysis. At a 15% concentration, fructose-intaking resulted in higher plasma cholesterol levels and glucose intolerance in mice that paralleled with a passive stress-coping behavior in the female mice and lower self-care behavior in the male and the female mice. At a 30% concentration, fructose-intaking resulted in higher body mass gain and higher plasma cholesterol and triglycerides levels in the male and the female mice, whereas glucose intolerance was more pronounced in the male mice. Spatial memory impairments and lower self-care behavior were observed in the male and the female mice, while passive stress-coping behavior was observed only in the female mice. Collectively, high-fructose intake induces metabolic and behavioral alterations in mice, with the males being more susceptible to glucose metabolism dysfunctions and the females to depressive-like endophenotypes.

P41 Pharmacokinetics-based estimation of evolocumab dosing for homozygous familial hypercholesterolemia (HoFH) in patients aged 6 to 12 years old

BackgroundHomozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterised by high plasma cholesterol levels and premature development of atherosclerotic cardiovascular disease.1Evolocumab is a high-cost monoclonal antibody to PCSK-9, an enzyme critical in cholesterol homeostasis. It is a subcutaneous injection commissioned for HoFH in children ≥12 years with persistently raised LDL-cholesterol (LDL-C) despite maximal tolerated lipid-lowering therapy.2 3 There is an unmet clinical need to allow patients ≥6 years meeting the same treatment threshold to access evolocumab and attenuate progression to invasive lipid apheresis or liver transplantation. However, as there are no published studies with PCSK-9 inhibitors in children &lt;12 years, no established dosing regimen exists.Aims and objectivesPropose a safe, efficacious and cost-effective dose of evolocumab to be administered to eligible patients aged 6 to 12 years old with HoFH.Review all patients at 12 weeks to determine if 30% target LDL-C reduction is achieved thereby warranting treatment continuation in line with commissioning criteria.Review all patients at 12 months to establish if LDL-C reduction sustained.Assess all patients for incidence and nature of treatment-related adverse effects.MethodProposed evolocumab dosing determined using four criteria: potential dosing adjustments required based on population physiological and pharmacokinetic data, drug safety profile, practicalities of administration and cost implications.Clinic letters for all patients were reviewed 12 weeks and 12 months after treatment commenced.ResultsIn children &lt;12 years dosing was proposed to start at 140 mg every 2 weeks, as this is the lowest administrable dose but is clinically equivalent to the 420 mg monthly dose (if information is extrapolated from heterozygous familial hypercholesterolemia studies4) and more cost-effective in terms of number of injections required. Furthermore, dose reduction in younger patients unlikely to be required as blood volume-dependent clearance of monoclonal antibodies and synthetic rates of PCSK-9 production do not significantly vary with age. Wide therapeutic index is implied as doses can be increased to 420 mg every 2 weeks and PCSK-9 has a limited physiological role with negligible ‘off target’ toxicity due to its inhibition.2 3 Therapeutic drug monitoring is not currently an option. Evolocumab was initiated using the proposed dose regimen in two eligible patients. Patient 1 had a 65% reduction in LDL-C (5.9 mmol/L to 1.9 mmol/L) at week 12, marginally subsiding at 12 months (2.7 mmol/L). No adverse effects reported and patient not yet progressed to lipid apheresis or liver transplantation. Patient 2 had only a 7% reduction in LDL-C (6.97 mmol/L to 6.48 mmol/L) at week 12 therefore evolocumab was stopped. No adverse effects were experienced. Lipid apheresis was continued throughout treatment.Conclusions and DiscussionExtrapolated dose of 140 mg every 2 weeks was safe and well-tolerated. Larger patient numbers are needed to further determine efficacy and safety, particularly due to promising significant and sustained LDL-C reduction in one patient. Licensed dose increases due to poor response in patients ≥12 years warrant investigation in younger population to allow potential treatment escalation for refractory patients. Therapeutic drug monitoring and antibody level testing are possible future research opportunities.ReferencesCuchel M, Bruckert E., Ginsberg HN, Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J, 2014;35:2146–57.Amgen Ltd., Summary of Product Characteristics for Repatha Sureclick. 2016. Available from www.medicines.org.uk [accessed: 24/05/2018]. Last updated 08/03/2018.NHS England, NHSE statement on evolocumab for the treatment of homozygous familial hypercholesterolaemia (circular). September 2016.National Institute for Health and Care Excellence, Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia [TA394]. 2016. Available from www.nice.org.uk [accessed:22/06/2018].

Аtherosclerosis-like changes in the rabbit aortic wall induced by immunization with native high-density lipoproteins.

IntroductionA high level of total cholesterol or low‐density lipoprotein (LDL) cholesterol is considered the main cause of atherosclerosis and cardiovascular disease. For this reason, experimental atherosclerosis is induced by creating high blood cholesterol in animals. However, the hypothesis that atherosclerotic processes are mostly caused by immune (autoimmune) mechanisms has recently been gaining traction. At the same time, no experimental model has been developed that clearly demonstrates the autoimmune mechanism by which atherosclerosis develops and reproduces the full picture of atherosclerosis solely by means of an immune response, without resorting to additional interventions such as a high‐cholesterol diet or the use of genetic models of hyperlipidemia. Previously, we were able to induce atherosclerosis‐like lesions in the aorta and the development of pericardial fat in rats by immunizing them with human native lipoproteins. The purpose of this study was to test whether atherosclerosis can be induced in normocholesterolaemic rabbits by immunizing them with human native high‐density lipoproteins (hnHDL).MethodsRabbits were immunized with hnHDL. Aortic wall structure, plasma cholesterol level, and antibodies against HDL were studied.ResultsImmunization with hnHDL was found to cause atherosclerosis‐like lesions in the rabbit aorta such as adipocytic and chondrocytic metaplasia, proteoglycan deposits, leukocytic infiltration. Atherosclerosis‐like lesions developed in the aorta of hnHDL‐immunized rabbits against a background of normal blood LDL‐cholesterol level. Therefore, a high plasma cholesterol level is not the sole cause of atherosclerosis. The immune response against HDL is an independent cause of atherogenesis.ConclusionsA rabbit model of atherosclerosis caused by immunization with hnHDL can be widely used to examine the mechanisms occurring during atherogenesis.

Lipid-core nanocapsules containing simvastatin improve the cognitive impairment induced by obesity and hypercholesterolemia in adult rats

The development of cognitive impairment may be related to high levels of plasma cholesterol and obesity. Simvastatin (SV) and lovastatin (LV) are drugs that can potentially be used for the treatment of cognitive deficit. This study aimed to develop and characterize lipid-core nanocapsules (LNC) containing SV (SV-LNC) or LV (LV-LNC), evaluating the effects of SV-LNC in an animal model of cognitive deficit. The formulations SV-LNC and LV-LNC presented a particle average size around 200 nm, a low-polydispersity index, and negative zeta potential. Analysis of differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that there is no reaction among LNC components: LV was crystallized in the suspensions, and SV was molecularly dispersed. The encapsulation efficiency of the SV was high (98.9 ± 1.4%), while that of the LV was low (21.5 ± 1.5%).Based on these results, SV-LNC was used in the preclinical studies. Animals fed with a hyperlipidic diet (HD) developed obesity, hypercholesterolemia, and cognitive impairment, which was corroborated by the brain lesions indicated by histological analysis of some of the animals that received the high-fat diet. We observed that free simvastatin (CS3) was able to reduce the enzymatic activity of pyruvate kinase, an important enzyme for brain energy homeostasis, without affecting the memory of the animals that received a standard diet. However, it failed to improve the cognitive damage caused by a diet high in cholesterol and saturated fats. On the other hand, when simvastatin is "camouflaged" in the lipid-core nanocapsules (HNS3), this cognitive impairment improves. Thus, SV-LNC is a promising alternative therapy for the treatment of cognitive impairment.

Promising Anti-atherosclerotic Effect of Berberine: Evidence from In Vitro, In Vivo, and Clinical Studies.

Elevated levels of plasma cholesterol, impaired vascular wall, and presence of inflammatory macrophages are important atherogenic risk factors contributing to atherosclerotic plaque formation and progression. The interventions modulating these risk factors have been found to protect against atherosclerosis development and to decrease atherosclerosis-related cardiovascular disorders. Nutritional approaches involving supplements followed by improving dietary habits and lifestyle have become growingly attractive and acceptable methods used to control atherosclerosis risk factors, mainly high levels of plasma cholesterol. There are a large number of studies that show berberine, a plant bioactive compound, could ameliorate atherosclerosis-related risk factors. In the present literature review, we put together this studies and provide integrated evidence that exhibits berberine has the potential atheroprotective effect through reducing increased levels of plasma cholesterol, particularly low-density lipoprotein (LDL) cholesterol (LDL-C) via LDL receptor (LDLR)-dependent and LDL receptor-independent mechanisms, inhibiting migration and inflammatory activity of macrophages, improving the functionality of endothelial cells via anti-oxidant activities, and suppressing proliferation of vascular smooth muscle cells. In conclusion, berberine can exert inhibitory effects on the atherosclerotic plaque development mainly through LDL-lowering activity and suppressing atherogenic functions of mentioned cells. As the second achievement of this review, among the signaling pathways through which berberine regulates intracellular processes, AMP-activated protein kinase (AMPK) has a central and critical role, showing that enhancing activity of AMPK pathway can be considered as a promising therapeutic approach for atherosclerosis treatment.

The Histomorphological Study on Testicular Cells of Hypercholesterolemia Rats Treated by Polysaccharides of Sea Cucumber, Holothuria nobilis

Hypercholesterolemia is a condition characterized by the presence of high levels of plasma cholesterol. This study aims to determine the morphological change of testicular cells in hypercholesterolemia rats treated by polysaccharides of sea cucumber, Holothuria nobilis. This study used 15 Sprague Dawley rats which was divided into 4 groups: non-hypercholesterolemia group (K-), hypercholesterolemia group (K+), prevention group that were given 1% cholesterol and 400 mg/kg of body weight polysaccharides (ChP), and curative hypercholesterolemia group that treated by 400 mg/kg of body weight polysaccharides (PCh). The ChP and PCh groups were treated for 28 days. Testicular tissue was processed histologically, stained with hematoxylin-eosin and Cusson's trichrome staining, and observed using a light microscope. The results indicated that the treatment of sea cucumber polysaccharides could improve the healing process of interstitial cells (Leydig cell). However, the 28 days of hypercholesterolemia has not affected adversely on testicular spermatogenic cell development.