Alimentos funcionales y nutracéuticos en el tratamiento de la hipercolesterolemia: posicionamiento de la Sociedad Española de Arteriosclerosis 2023 / Functional foods and nutraceuticals in the treatment of hypercholesterolemia: Statement of the Spanish Society of Arteriosclerosis 2023

Para el tratamiento de la hipercolesterolemia, además de aconsejar una alimentación saludable, puede ser conveniente recomendar alimentos funcionales o nutracéuticos con efecto hipolipemiante. Dado el progresivo incremento en el número de estos productos y su creciente utilización por la población, la Sociedad Española de Arteriosclerosis (SEA) ha creído conveniente revisar la información disponible, seleccionar los resultados de los estudios científicamente más sólidos y posicionarse sobre la utilidad de los mismos, para recomendar a los profesionales sanitarios y a la población general su potencial utilidad en términos de eficacia y sus posibles beneficios y limitaciones. Se han identificado los siguientes escenarios clínicos en los que se podrían utilizar estos productos y que se analizarán con más detalle en este documento: 1. Tratamiento hipolipemiante en sujetos con intolerancia a estatinas. 2. Tratamiento hipolipemiante «a la carta» en personas en prevención primaria. 3. Prevención cardiovascular a largo plazo en personas sin indicación de tratamiento hipolipemiante. 4. Pacientes con tratamiento hipolipemiante optimizado que no alcanzan objetivos terapéuticos. (AU)

In the management of hypercholesterolemia, besides advising a healthy, plant-based diet, it may be useful to recommend functional foods or nutraceutical with cholesterol-lowering properties. Given the progressive increase in the number of these products and their rising use by the population, the Spanish Society of Arteriosclerosis (SEA) has considered it appropriate to review the available information, select the results of the scientifically more robust studies and take a position on their usefulness, to recommend to health professionals and the general population their potential utility in terms of efficacy and their possible benefits and limitations. The following clinical scenarios have been identified in which these products could be used and will be analyzed in more detail in this document: (1) Hypolipidemic treatment in subjects with statin intolerance. (2) Hypolipidemic treatment «a la carte» in individuals in primary prevention. (3) Long-term cardiovascular prevention in individuals with no indication for lipid-lowering therapy. (4) Patients with optimized lipid-lowering treatment who do not achieve therapeutic objectives. (AU)

Dietary Sterols and Sterol Oxidation Products on Atherosclerosis: An Insight Provided by Liver Proteomic and Lipidomic.

SCOPE: The development of atherosclerosis is closely associated with disorder of lipid metabolism. Dietary sterols and their oxidation products play a role in the pathogenesis of atherosclerosis. However, their effects on liver lipid metabolism during the atherosclerosis remain unknown. METHODS AND RESULTS: Here, we apply lipidomic and proteomic analysis on liver of ApoE-/- mice feed with phytosterols, cholesterol oxidation products (COPs), or phytosterol oxidation products (POPs) to profile lipid species and reveal the underlying mechanism. Dietary exposure of phytosterols, COPs, and POPs all reduce the accumulation of liver triglyceride (TG), but COPs and POPs accelerate the fibrosis of liver. Lipidomic analysis reveals that phytosterols mainly decrease the levels of phosphatidylinositol (PI), while COPs and POPs both increase the level of digalactosyldiacylglycerol (DGDG) and reduce TG with long-chain polyunsaturated fatty acids. Besides, COPs up-regulated levels of lipids associate with atherosclerosis risk, such as phosphatidylcholines (PC), phosphatidylethanolamine (PE) and ceramides (Cer). POPs down-regulate the level of acyl carnitine (AcCa). Furthermore, proteomic analysis shows that COPs promote oxidative phosphorylation and POPs inhibit the beta oxidation of fatty acids. CONCLUSIONS: This study reveals that phytosterols, COPs, and POPs differently change the composition and metabolism of glycerophospholipids, sphingolipids, and glycerolipids in liver of ApoE-/- mice.

Safety and tolerability of a natural supplement containing glucosinolates, phytosterols and citrus flavonoids in adult women: a randomized phase I, placebo-controlled, multi-arm, double-blinded clinical trial.

OBJECTIVE: To evaluate the safety and tolerability of an oral herbal supplement containing glucosinolates, phytosterols, and citrus flavonoids (Warmi®, Lima Perú;) in otherwise healthy adult women. METHODS: This was a phase-I, randomized parallel three arms, double-blinded, and a placebo-controlled clinical trial. A total of 55 participants aged 18-40 were randomly assigned to one of three groups to receive for three months: (1) an oral herbal supplement of 1650 mg/day; (2) an oral herbal supplement of 3300 mg/day; or (3) an oral placebo 3300 mg/day. The primary endpoints were oral safety and tolerability of the supplement. The secondary endpoint was its effect on vital functions, anthropometrics, and laboratory tests. We used an exploratory approach by covariance analysis (ANCOVA) adjusted for the variables' baseline value for the secondary outcomes. RESULTS: All women completed three months of follow-up, reporting no side effects. Our exploratory analysis revealed that treatment with the herbal supplement of 1650 mg/day was associated with increased glucose and uric acid levels. In comparison, the herbal supplement 3300 mg/day was associated with reduced breathing rate, increased basal temperature, and systolic blood pressure, both compared to the placebo group. However, despite significant differences, none of these was clinically significant. CONCLUSION: The oral herbal supplement had a favorable safety and tolerability profile in studied women. There is a need to study its potential as an option to treat menopausal symptoms.

Phytosterol consumption and markers of subclinical atherosclerosis: Cross-sectional results from ELSA-Brasil.

BACKGROUND AND AIMS: Phytosterol (PS) consumption is associated with lower total and LDL-cholesterol (LDL-c) concentrations, but its impact on cardiovascular risk is unclear. This study assessed the effect of usual intake of PS on markers of subclinical atherosclerosis in the Longitudinal Study of Adult Health (ELSA-Brasil). METHODS AND RESULTS: This cross-sectional study included 2560 participants of ELSA-Brasil, aged 48 (43-54) years, with available food frequency questionnaires (FFQ), coronary artery calcium (CAC) scores, carotid intima media thickness (cIMT), and carotid-femoral pulse wave velocity (cf-PWV), at baseline. Several logistic and linear regression models were used, and significance level was set at a P < 0.05. Mean values (SD) for PS consumption were 256 (198) mg/day, CAC 22.78 (110.54) Agatston Units, cf-PWV 9.07 (1.60) m/s and cIMT 0.57 (0.12) mm. PS consumption in Q4 was associated with lower total- and LDL-c levels, and with higher percentiles of cf-PWV (P < 0.001). Proportion of subjects in Q4 of PS consumption was 1.5 times higher among individuals in cf-PWV Q4, than in Q1 (P = 0.002, for comparisons among quartiles). There was a trend (P = 0.003) for higher cf-PWV with higher PS intake. In crude logistic and linear regressions, PS intake was associated with cf-PWV. In the adjusted models, these associations disappeared. No associations were found between PS and cIMT or CAC. CONCLUSIONS: In this large and apparently healthy cross-sectional sample from ELSA-Brasil, usual PS consumption was associated with lower total- and LDL-cholesterol, but not with markers of subclinical atherosclerosis.

Protective effects of a unique combination of nutritionally active ingredients on risk factors and gene expression associated with atherosclerosis in C57BL/6J mice fed a high fat diet.

Atherosclerosis, an inflammatory disorder of the vasculature and the underlying cause of cardiovascular disease, is responsible for one in three global deaths. Consumption of active food ingredients such as omega-3 polyunsaturated fatty acids, flavanols and phytosterols has many beneficial effects on cardiovascular disease. However, their combined actions on the risk factors for atherosclerosis remains poorly understood. We have previously shown that a formulation containing each of these active components at physiologically relevant doses modulated several monocyte/macrophage processes associated with atherosclerosis in vitro, including inhibition of cytokine-induced pro-inflammatory gene expression, chemokine-driven monocyte migration, expression of M1 phenotype markers, and promotion of cholesterol efflux. The objectives of the present study were to investigate whether the protective actions of the formulation extended in vivo and to delineate the potential underlying mechanisms. The formulation produced several favourable changes, including higher plasma levels of HDL and reduced levels of macrophages and myeloid-derived suppressor cells in the bone marrow. The mRNA expression of liver-X-receptor-α, peroxisome proliferator-activated receptor-γ and superoxide dismutase-1 was induced in the liver and that of interferon-γ and the chemokine (C-X-C motif) ligand 1 decreased, thereby suggesting the potential mechanisms for many beneficial effects. Other changes were also observed such as increased plasma levels of triglycerides and lipid peroxidation that may reflect potential activation of brown fat. This study provides new insights into the protective actions and the potential underlying mechanisms of the formulation in vivo, particularly in relation to risk factors together with changes in systemic inflammation and hepatic lipid alterations associated with atherosclerosis and metabolic syndrome, and supports further assessments in human trials.

Phytosterol supplementation in the treatment of dyslipidemia in children and adolescents: a systematic review / Suplementação de fitoesteróis no tratamento da dislipidemia em crianças e adolescentes: uma revisão sistemática

ABSTRACT Objective: To carry out a systematic review on the effects of phytosterol supplementation on the treatment of dyslipidemia in children and adolescents. Data sources: Review in the SciELO, Lilacs, Bireme, PubMed and Web of Science databases, with no time limit. Descriptors: phytosterols or plant sterols and dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, in English and Portuguese. The articles included were published in Portuguese, English or Spanish and evaluated the effect of phytosterol supplementation in pediatric patients with dyslipidemia. Documents that involved adults or animals, review papers, case studies and abstracts were excluded. Two authors performed independent extraction of articles. Of 113 abstracts, 19 were read in full and 12 were used in this manuscript. Data synthesis: Phytosterol supplementation to reduce cholesterol levels has been shown to be effective in reducing LDL-cholesterol levels by approximately 10%, with reductions above 10% in LDL-cholesterol levels observed after 8 to 12 weeks of intervention. Studies have not shown significant changes in HDL-cholesterol and triglyceride levels. Based on the absence of adverse effects, its use seems to be safe and of good tolerance in children and adolescents. Conclusions: Phytosterol supplementation seems to be of great therapeutic aid for the treatment of hypercholesterolemia in children and adolescents. Further studies assessing the long-term effect of phytosterol supplementation are necessary.

RESUMO Objetivo: Realizar uma revisão sistemática sobre os efeitos da suplementação de fitoesteróis no tratamento da dislipidemia em crianças e adolescentes. Fontes de dados: Revisão nos bancos SciELO, Lilacs, Bireme, Pubmed e Web of Science, sem limite de tempo. Descritores: phytosterols or plant sterols, dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, nas línguas inglesa e portuguesa. Os artigos incluídos foram publicados nos idiomas português, inglês ou espanhol e avaliaram o efeito da suplementação de fitoesteróis em pacientes pediátricos com dislipidemia. Estudos que envolviam adultos ou animais, trabalhos de revisão, estudos de caso e resumos foram excluídos. A extração independente de artigos foi realizada por dois autores. Do total de 113 resumos, 19 foram lidos na íntegra, e 12 utilizados neste manuscrito. Síntese de dados: A suplementação de fitoesteróis para a redução dos níveis de colesterol mostrou-se eficiente, de forma a promover a redução de aproximadamente 10% dos níveis de LDL-colesterol, sendo observadas reduções acima de 10% em 8 a 12 semanas de intervenção. Os estudos não mostraram alterações significantes nos níveis de HDL-colesterol e triglicérides. Com base na ausência de efeitos adversos, seu uso parece ser seguro e de boa tolerância em crianças e adolescentes. Conclusões: A suplementação com fitoesteróis parece ser de grande auxílio terapêutico para o tratamento da hipercolesterolemia em crianças e adolescentes. São necessários mais estudos que avaliem o efeito em longo prazo da suplementação de fitoesteróis.

Phytosterol supplementation in the treatment of dyslipidemia in children and adolescents: a systematic review.

OBJECTIVE: To carry out a systematic review on the effects of phytosterol supplementation on the treatment of dyslipidemia in children and adolescents. DATA SOURCES: Review in the SciELO, Lilacs, Bireme, PubMed and Web of Science databases, with no time limit. Descriptors: phytosterols or plant sterols and dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, in English and Portuguese. The articles included were published in Portuguese, English or Spanish and evaluated the effect of phytosterol supplementation in pediatric patients with dyslipidemia. Documents that involved adults or animals, review papers, case studies and abstracts were excluded. Two authors performed independent extraction of articles. Of 113 abstracts, 19 were read in full and 12 were used in this manuscript. DATA SYNTHESIS: Phytosterol supplementation to reduce cholesterol levels has been shown to be effective in reducing LDL-cholesterol levels by approximately 10%, with reductions above 10% in LDL-cholesterol levels observed after 8 to 12 weeks of intervention. Studies have not shown significant changes in HDL-cholesterol and triglyceride levels. Based on the absence of adverse effects, its use seems to be safe and of good tolerance in children and adolescents. CONCLUSIONS: Phytosterol supplementation seems to be of great therapeutic aid for the treatment of hypercholesterolemia in children and adolescents. Further studies assessing the long-term effect of phytosterol supplementation are necessary.

A Randomized, Double-Blinded, Placebo-Controlled, Clinical Study of the Effects of a Nutraceutical Combination (LEVELIP DUO®) on LDL Cholesterol Levels and Lipid Pattern in Subjects with Sub-Optimal Blood Cholesterol Levels (NATCOL Study).

Phytosterols and red yeast rice are largely studied cholesterol-lowering nutraceuticals, respectively inhibiting the bowel absorption and liver synthesis of cholesterol. Our aim was to test the effect of combined nutraceutical-containing phytosterols and red yeast rice vs. a placebo on the lipid profile. We performed a parallel arms, double-blind, placebo-controlled clinical trial, randomizing 88 moderately hypercholesterolemic subjects to treatment with a combined nutraceutical containing phytosterols (800 mg) and red yeast rice, standardized to contain 5 mg of monacolins from Monascus purpureus, with added niacin (27 mg) and policosanols (10 mg) (LEVELIP DUO®), or placebo. The mean LDL-Cholesterol (LDL-C) change at Week 8 was -32.5 ± 30.2 mg/dL (-19.8%) in the combined nutraceutical group and 2.5 ± 19.4 mg/dL (2.3%) in the placebo group. The estimated between-group difference of -39.2 mg/dL (95% CI: -48.6; -29.8) indicates a statistically significant difference between treatments in favor of the combined nutraceutical (p < 0.0001). Total Cholesterol (TC), non-HDL cholesterol (non-HDL-C), Apolipoprotein B, TC/HDL-C and LDL-C/HDL-C improved in a similar way in the combined nutraceutical group only. No significant changes in other clinical and laboratory parameters were observed. In conclusion, the tested combined nutraceutical was well tolerated, while significantly reducing the plasma levels of LDL-C, TC, non-HDL-C, ApoB, TC/HDL-C and LDL-C/HDL-C ratios in mildly hypercholesterolemic patients. Trial registration (ClinicalTrials.gov): NCT03739242.

Effects of Daily Consumption of an Aqueous Dispersion of Free-Phytosterols Nanoparticles on Individuals with Metabolic Syndrome: A Randomised, Double-Blind, Placebo-Controlled Clinical Trial.

Metabolic syndrome (MS) affects up to 40% of the population and is associated with heart failure, stroke and diabetes. Phytosterols (PS) could help to manage one or more MS criteria. The purpose of this study was to evaluate the therapeutic effect of daily supplementation of an aqueous dispersion of 2 g of free-phytosterols nanoparticles in individuals with MS over six months of intervention, compared with placebo. This double-blind study included 202 participants with MS randomly assigned into phytosterol (n = 102) and placebo (n = 100) groups. Participants were assessed at baseline, 4, 12 and 24 weeks. General health questions, anthropometric measurements and blood parameters were analysed. At week 24, the proportion of participants with high triglycerides (≥150 mg/dL) in the phytosterol group was 15.65% lower than in the placebo group (p-value = 0.023). Similarly, half of the participants in the phytosterol group decreased their waist circumference up to 4 cm compared with 0 cm in the placebo group (p-value = 0.0001). We reported no adverse effects (diarrhoea or vitamin D reduction); nonetheless, almost 70% of participants in the phytosterol group self-reported an improvement in bowel habits. Daily intake of free-PS nanoparticles improved some MS criteria; therefore, it might be a promising adjuvant therapy for individuals with MS (NCT02969720).

Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis.

BACKGROUND: Although a cholesterol-lowering diet and the addition of plant sterols and stanols are suggested for the lipid management of children and adults with familial hypercholesterolemia, there is limited evidence evaluating such interventions in this population. OBJECTIVES: To investigate the impact of cholesterol-lowering diet and other dietary interventions on the incidence or mortality of cardiovascular disease and lipid profile of patients with familial hypercholesterolemia. SEARCH METHODS: Relevant trials were identified by searching US National Library of Medicine National Institutes of Health Metabolism Trials Register and clinicaltrials.gov.gr using the following terms: diet, dietary, plant sterols, stanols, omega-3 fatty acids, fiber and familial hypercholesterolemia. SELECTION CRITERIA: Randomized controlled trials evaluating the effect of cholesterol-lowering diet or other dietary interventions in children and adults with familial hypercholesterolemia were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the eligibility of the included trials and their bias risk and extracted the data which was independently verified by other colleagues. RESULTS: A total of 17 trials were finally included, with a total of 376 participants across 8 comparison groups. The included trials had either a low or unclear bias risk for most of the assessed risk parameters. Cardiovascular incidence or mortality were not evaluated in any of the included trials. Among the planned comparisons regarding patients' lipidemic profile, a significant difference was noticed for the following comparisons and outcomes: omega-3 fatty acids reduced triglycerides (mean difference (MD): -0.27 mmol/L, 95% confidence interval (CI): -0.47 to -0.07, p < 0.01) when compared with placebo. A non-significant trend towards a reduction in subjects' total cholesterol (MD: -0.34, 95% CI: -0.68 to 0, mmol/L, p = 0.05) and low-density lipoprotein cholesterol (MD: -0.31, 95% CI: -0.61 to 0, mmol/L, p = 0.05) was noticed. In comparison with cholesterol-lowering diet, the additional consumption of plant stanols decreased total cholesterol (MD: -0.62 mmol/L, 95% CI: -1.13 to -0.11, p = 0.02) and low-density lipoprotein cholesterol (MD: -0.58 mmol/L, 95% CI: -1.08 to -0.09, p = 0.02). The same was by plant sterols (MD: -0.46 mmol/L, 95% CI: -0.76 to -0.17, p < 0.01 for cholesterol and MD: -0.45 mmol/L, 95% CI: -0.74 to -0.16, p < 0.01 for low-density lipoprotein cholesterol). No heterogeneity was noticed among the studies included in these analyses. CONCLUSIONS: Available trials confirm that the addition of plant sterols or stanols has a cholesterol-lowering effect on such individuals. On the other hand, supplementation with omega-3 fatty acids effectively reduces triglycerides and might have a role in lowering the cholesterol of patients with familial hypercholesterolemia. Additional studies are needed to investigate the efficacy of cholesterol-lowering diet or the addition of soya protein and dietary fibers to a cholesterol-lowering diet in patients with familial hypercholesterolemia.

Plant Stanol Esters Reduce LDL (Low-Density Lipoprotein) Aggregation by Altering LDL Surface Lipids: The BLOOD FLOW Randomized Intervention Study.

OBJECTIVE: Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. Approach and Results: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm, P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index<25 kg/m2. Decreased LDL aggregation susceptibility was associated with decreased proportion of LDL-sphingomyelins and increased proportion of LDL-triacylglycerols. LDL binding to proteoglycans was decreased in the plant stanol ester group, the decrease depending on decreased serum LDL-cholesterol concentration. CONCLUSIONS: Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01315964.

Genetic basis for prediction of non-responders to dietary plant sterol intervention (GenePredict-PS): a study protocol for a double-blind, placebo-controlled, randomized two-period crossover study.

BACKGROUND: Functional food ingredients and natural health products have been demonstrated to reduce disease risk and thereby help to lower health care costs across populations at risk for chronic or degenerative diseases. However, typically a wide range of interindividual variability exists in response across individuals to nutritional and natural health product bioactives, such as plant sterols (PS). This study aims to determine and utilize information on the associations between genosets and the degree of responsiveness to dietary PS intervention, with a long-term objective of developing genetic tests to predict responses to PS. METHODS: This clinical trial is designed as a double-blind, placebo controlled, randomized two-period crossover study. Sixty-four eligible participants with the specific a priori-determined single nucleotide polymorphisms (SNPs) associated with a responsiveness to PS will consume PS or a placebo treatment for two 4-week periods. The PS treatment consists of two daily single portions of margarine, each providing 1 g PS during the PS period (2.0 g/day of PS in total). The placebo will be an identical margarine containing no added PS. Low-density lipoprotein cholesterol (LDL-C) responsiveness to the controlled administration of PS will be investigated as the primary outcome, and the associations between interindividual genoset variabilities and response to PS consumption will be determined. DISCUSSION: This research will provide further insight into whether the associations between previously identified SNPs and the response of LDL-C to PS consumption can be used in a predictive manner. It will also provide insight into the complexities of undertaking a nutrigenetic trial with prospective recruitment based on genotype. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT02765516. Registered on 6 May 2016.

Deciphering the Role of Polyphenols in Sports Performance: From Nutritional Genomics to the Gut Microbiota toward Phytonutritional Epigenomics.

The individual response to nutrients and non-nutrient molecules can be largely affected by three important biological layers. The gut microbiome can alter the bioavailability of nutrients and other substances, the genome can influence molecule kinetics and dynamics, while the epigenome can modulate or amplify the properties of the genome. Today the use of omic techniques and bioinformatics, allow the construction of individual multilayer networks and thus the identification of personalized strategies that have recently been considered in all medical fields, including sports medicine. The composition of each athlete's microbiome influences sports performance both directly by acting on energy metabolism and indirectly through the modulation of nutrient or non-nutrient molecule availability that ultimately affects the individual epigenome and the genome. Among non-nutrient molecules polyphenols can potentiate physical performances through different epigenetic mechanisms. Polyphenols interact with the gut microbiota, undergoing extensive metabolism to produce bioactive molecules, which act on transcription factors involved in mitochondrial biogenesis, antioxidant systems, glucose and lipid homeostasis, and DNA repair. This review focuses on polyphenols effects in sports performance considering the individual microbiota, epigenomic asset, and the genomic characteristics of athletes to understand how their supplementation could potentially help to modulate muscle inflammation and improve recovery.

Prophylactic Intra-Uterine ß-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep.

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in ß-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of ß-sitosterol and campesterol dissolved in ß-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + ß-cyclodextrin, or ß-cyclodextrin alone. In addition, IA administration of ß-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier ß-cyclodextrin did not have additional effects.

Combined effect of n-3 fatty acids and phytosterol esters on alleviating hepatic steatosis in non-alcoholic fatty liver disease subjects: a double-blind placebo-controlled clinical trial.

The aim of this study was to investigate the combined effect of n-3 fatty acids (EPA and DHA, at an EPA:DHA ratio of 150:500) and phytosterol esters (PS) on non-alcoholic fatty liver disease (NAFLD) patients. We conducted a randomised, double-blind, placebo-controlled trial. Ninety-six NAFLD subjects were randomly assigned to the following groups: the PS group (receiving 3·3 g/d PS); the FO group (receiving 450 mg EPA + 1500 mg DHA/d); the PS + FO combination group (receiving 3·3 g/d PS and 450 mg EPA + 1500 mg DHA/d) and the PO group (a placebo group). The baseline clinical characteristics of the four groups were similar. The primary outcome was liver:spleen attenuation ratio (L:S ratio). The percentage increase in liver-spleen attenuation (≤1) in the PS + FO group was 36 % (P = 0·083), higher than those in the other three groups (PS group, 11 %, P = 0·519; FO group, 18 %, P = 0·071; PO group, 15 %, P = 0·436). Compared with baseline, transforming growth factor-ß (TGF-ß) was significantly decreased in the three study groups at the end of the trial (PS, P = 0·000; FO, P = 0·002; PS + FO, P = 0·001) and TNF-α was significantly decreased in the FO group (P = 0·036), PS + FO group (P = 0·005) and PO group (P = 0·032) at the end of the intervention. Notably, TGF-ß was reduced significantly more in the PS + FO group than in the PO group (P = 0·032). The TAG and total cholesterol levels of the PS + FO group were reduced by 11·57 and 9·55 %, respectively. In conclusion, co-supplementation of PS and EPA + DHA could increase the effectiveness of treatment for hepatic steatosis.

Phytosterol-loaded CD44 receptor-targeted PEGylated nano-hybrid phyto-liposomes for synergistic chemotherapy.

Background: Phytosterols significantly reduce the risk of cancer by directly inhibiting tumor growth, inducing apoptosis, and inhibiting tumor metastasis. Stigmasterol (STS), a phytosterol, exhibits anticancer effects against various cancers, including breast cancer. Chemotherapeutics, including doxorubicin (DOX), might act synergistically with phytosterol against the proliferation and metastasis of breast cancer. Although such compounds can show potential anticancer activity, their combined effect with suitable formulation has not investigated yet.Methods: Hyaluronic acid (HA)-modified PEGylated DOX-STS loaded phyto-liposome was fabricated via a thin-film hydration method. The prepared phyto-liposome was optimized with regards to its physicochemical and other properties. Further, in vitro and in vivo study was carried out in breast cancer cells expressing a different level of CD44 receptors.Results: The particle size of prepared HA-DOX-STS-lipo was 173.9 ± 2.4 nm, and showed pH-depended DOX release, favoring the effective tumor targetability. The in vitro anticancer activity of HA-DOX-STS-lipo was significantly enhanced in MDA-MB-231, CD44-overexpressing cells relative to MCF-7 cells demonstrating HA-mediated targeting effect. HA-DOX-STS-lipo accumulated more and increased antitumor efficacy in the MDA-MB-231 xenograft tumor model expressing high levels of CD44, suggesting the potential of carrier system toward CD44-overexpressing tumors.

Effects of phytosterols supplementation on blood pressure: A systematic review and meta-analysis.

Several reports have indicated a positive effect of phytosterols on blood pressure (BP), nevertheless these findings have been controversial. Therefore, a systematic review and meta-analysis of randomized controlled trials (RCTs) was aimed to investigate the effects of phytosterol supplementation on BP. An online search was carried out in PubMed, Scopus, ISI Web of Science, Cochrane library and Google Scholar up to May 2019. Weighted Mean difference (WMD) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. The present meta-analysis of 19 RCTs showed that supplementation with phytosterols can decrease both systolic BP (WMD: -1.55 mmHg, 95% CI: -2.67 to -0.42, p = 0.007) and diastolic BP (WMD: -0.84 mmHg, 95% CI: -1.60 to -0.08, p = 0.03). Dose-response analysis revealed that phytosterol intake change SBP significantly based on treatment dose in nonlinear fashion. Subgroup analysis based on duration showed a significant effect of phytosterol on SBP and DBP in subsets of <12 weeks. In addition, a significant effect of phytosterol was observed in dosage of ≥2000 mg for SBP and <2000 mg for DBP. Based on current findings supplementation with phytosterol may be a beneficial adjuvant therapy in hypertensive patients as well as a complementary preventive option in prehypertensive and normotensive individuals. However, this issue is still open and requires further investigation in future studies.

Phytosterol Supplementation Could Improve Atherogenic and Anti-Atherogenic Apolipoproteins: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.

Phytosterol and phytostanol (PS) supplementation is reported to improve atherogenic and anti-atherogenic apolipoproteins (Apo). The purpose of the present study is to critically investigate the effectiveness of PS supplementation on Apo in adults.A comprehensive search was conducted of all randomized controlled trials (RCTs) conducted up to September 2018 in the following databases: PubMed, Web of Science, Cochrane Library, and Scopus. Mean difference with 95% confidence intervals (CIs) were pooled using a random-effects model (DerSimonian-Laird method).Fifty-one arms from 37 RCTs were included in the present meta-analysis. Findings showed that PS supplementation and fortification increased Apo-AI (weighted mean difference [WMD]: 0.014 mg/dl, 95% CI: 0.001, 0.028, p = 0.042) and Apo-CII (WMD: 0.303 mg/dl, 95% CI: 0.084, 0.523, p = 0.007) and lowered Apo-B (WMD: -0.063 mg/dl, 95% CI: -0.075, -0.051, p < 0.001), Apo-B/Apo-A-I ratio (WMD: -0.044 mg/dl, 95% CI: -0.062, -0.025, p < 0.001), and Apo-E (WMD: -0.255 mg/dl, 95% CI: -0.474, -0.036, p = 0.023). However, PS supplementation did not have significant effects on Apo-AII and Apo-CIII. PS supplementation or fortification significantly changes Apo-E (r = -0.137, p nonlinearity = 0.006) and Apo-CIII (r = 1.26, p nonlinearity = 0.028) based on PS dosage (mg/d) and Apo-CIII (r = 3.34, p nonlinearity = 0.013) and Apo-CII (r = 1.09, p nonlinearity = 0.017) based on trial duration (weeks) in a nonlinear fashion.Based on our findings, supplements or fortified foods containing PS might have a considerable favorite effect in achieving Apo profile target; however, due to high heterogeneity among included studies, results must be interpreted with caution.KEY TEACHING POINTSCardiovascular diseases (CVDs) recognized as main public health concern worldwide with considerable mortality of all global deaths.Apo-lipoproteins are amphipathic molecules involved in the lipoprotein metabolism which introduced as biomarkers in the evaluation of CVD risk.Phytosterols bioactive components of plants have important biological functions in cholesterol metabolism in humans.Here we showed that phytosterols and phytostanols improve apo-lipoproteins profile of humans; finding from meta-analysis of randomized controlled trials.Phytosterols supplementation lowered atherogenic apo-lipoproteins (Apo-B and Apo-E) and increased anti-atherogenic apo-lipoproteins (Apo-AI, Apo-CII).

Combined Effects of Plant Sterols with Low Ratio of n-6/n-3 Polyunsaturated Fatty Acids against Atherosclerosis in ApoE-/- Mice.

The effects of low ratio of n-6/n-3 polyunsaturated fatty acids (PUFA) have been clarified against atherosclerosis. Increasing evidence indicated that plant sterols (PS) have a significant cholesterol-lowering effect. This study explored the effects of PS combined with n-6/n-3 (2:1) PUFA on atherosclerosis and investigated the possible mechanism. In ApoE-/- mice, the milk fat in high fat diets was replaced with n-6/n-3 (2:1) PUFA alone or supplemented with 6% PS for 16 weeks. Results demonstrated that PS combined with PUFA exerted commentary and synergistic effects on ameliorating atherosclerosis, improving lipid metabolism and lipid deposition in liver, and alleviating inflammatory response. These changes were accompanied with decreased serum TC, TG, LDL-C and increased fecal cholesterol efflux, as well as the lower inflammatory cytokine CRP, IL-6, TNF-α. It is suggested that the underlying mechanism of PS combined with n-6/n-3 (2:1) PUFA promoting the fecal cholesterol efflux may be mediated by liver X receptor α/ATP-binding cassette transporter A1 pathway.

Phytoecdisteroids from Serratula coronata when growing ducklings.

This article presents the results of comprehensive studies to analyze the effect of a mixture of phytoecdysteroids extracted from the juice of Serratula coronata L. on the productivity and vitality of ducklings when grown for meat, and the optimal doses of its inclusion in the diet of the bird are revealed. The methodological basis of this study was the earlier works of domestic and foreign scientists on the topic under study. In the studies, a mixture of ecdysteroids extracted from the juice of the Serratula coronata L. was used according to the method developed by a team of scientists of the Ufa Federal Research Center of the Russian Academy of Sciences (Patent RU 2151598). The object of the study was the young ducks of the cross breed "Agidel 34" of the Beijing breed. It was established that the use of phytoecdysteroids in the diets of ducklings at a dose of 1.0 mg/l of drinking water allowed to increase the safety of the livestock by 4.0%, live weight by 4.5% (p <  0.01), average daily live weight gain by 3.0-3.5%, gutted carcass weight - 7.1%. At the same time, feed costs per unit of production decreased by 2.0%, and the profitability of duck meat production increased by 5.2%.