Effects of phytosterol supplementation on lipoprotein subfractions and LDL particle quality.

Phytosterols are natural components of plant-based foods used as supplements because of their known cholesterol-lowering effect. However, their effects on lipoprotein subfractions and the quality of the LDL particle have not been studied in greater detail. We aimed to evaluate the effects of phytosterols supplements on lipids, lipoproteins subfractions, and on the quality of LDL. A prospective, pilot-type, open label, cross-over study, randomized 23 males in primary prevention of hypercholesterolemia to receive diet or diet plus phytosterol (2.6 g in 2 doses, with meals) for 12 weeks, when treatments were switched for another 12 weeks. Lipoprotein subfractions were analyzed by electrophoresis in polyacrylamide gel (Lipoprint System®). The Sampson equation estimated the small and dense (sd) and large and buoyant (lb) LDL subfractions from the lipid profile. Quality of LDL particle was analyzed by Z-scan and UV-vis spectroscopy. Primary outcome was the comparison of diet vs. diet plus phytosterols. Secondary outcomes assessed differences between baseline, diet and diet plus phytosterol. Non-parametric statistics were performed with p < 0.05. There was a trend to reduction on HDL-7 (p = 0.05) in diet plus phytosterol arm, with no effects on the quality of LDL particles. Heatmap showed strong correlations (ρ > 0.7) between particle size by different methods with both interventions. Diet plus phytosterol reduced TC, increased HDL-c, and reduced IDL-B, whereas diet increased HDL7, and reduced IDL-B vs. baseline (p < 0.05, for all). Phytosterol supplementation demonstrated small beneficial effects on HDL-7 subfraction, compared with diet alone, without effects on the quality of LDL particles.This trial is registered in Clinical Trials (NCT06127732) and can be accessed at https://clinicaltrials.gov .

Effects of dietary phytosterols or phytosterol esters supplementation on growth performance, biochemical blood indices and intestinal flora of C57BL/6 mice.

This study was conducted to evaluate the effects of phytosterols (PS) and phytosterol esters (PSE) on C57BL/6 mice. Three groups of 34 six-week-old C57BL/6 mice of specific pathogen free (SPF) grade, with an average initial body weight (IBW) of 17.7g, were fed for 24 days either natural-ingredient diets without supplements or diets supplemented with 89 mg/kg PS or diets supplemented with 400 mg/kg PSE. Growth performance, blood biochemistry, liver and colon morphology as well as intestinal flora status were evaluated. Both PS and PSE exhibited growth promotion and feed digestibility in mice. In blood biochemistry, the addition of both PS and PSE to the diet resulted in a significant decrease in Total Cholesterol (TC) and Triglyceride (TG) levels and an increase in Superoxide Dismutase (SOD) activity. No significant changes in liver and intestinal morphology were observed. Both increased the level of Akkermansia in the intestinal tract of mice. There was no significant difference between the effects of PS and PSE. It was concluded that dietary PS and PSE supplementation could improve growth performance, immune performance and gut microbiome structure in mice, providing insights into its application as a potential feed additive in animals production.

Dietary supplements: clinical cholesterol-lowering efficacy and potential mechanisms of action.

This review aims to analyse the efficacy of dietary supplements in reducing plasma cholesterol levels. Focusing on evidence from meta-analyses of randomised controlled clinical trials, with an emphasis on potential mechanisms of action as supported by human, animal, and cell studies. Certain dietary supplements including phytosterols, berberine, viscous soluble dietary fibres, garlic supplements, soy protein, specific probiotic strains, and certain polyphenol extracts could significantly reduce plasma total and low-density lipoprotein (LDL) cholesterol levels by 3-25% in hypercholesterolemic patients depending on the type of supplement. They tended to be more effective in reducing plasma LDL cholesterol level in hypercholesterolemic individuals than in normocholesterolemic individuals. These supplements worked by various mechanisms, such as enhancing the excretion of bile acids, inhibiting the absorption of cholesterol in the intestines, increasing the expression of hepatic LDL receptors, suppressing the activity of enzymes involved in cholesterol synthesis, and activating the adenosine monophosphate-activated protein kinase signalling pathway.

Combined supplementation with hesperidin, phytosterols and curcumin decreases adiposity and improves metabolic health in ovariectomized rats.

In recent years many women have looked for alternative therapies to address menopause. Hesperidin, phytosterols and curcumin are bioactive compounds that can ameliorate some cardiovascular risk factors associated with menopause, although there are no data concerning the effects of their combined supplementation. We used ovariectomized (OVX) rats, a postmenopausal model with oestrogen deficiency, to evaluate whether supplementation with a multi-ingredient (MI) including hesperidin, phytosterols and curcumin for 57 days would display beneficial effects against fat mass accretion and metabolic disturbances associated with menopause. Twenty OVX rats were orally supplemented with either MI (OVX-MI) or vehicle (OVX). Furthermore, 10 OVX rats orally received the vehicle along with subcutaneous injections of 17ß-oestradiol biweekly (OVX-E2), whereas 10 rats were sham operated and received oral and injected vehicles (control group; SH). MI supplementation partly counteracted the fat mass accretion observed in OVX animals, which was evidenced by decreased total fat mass, adiposity index, the weight of retroperitoneal, inguinal and mesenteric white adipose tissue (MWAT) depots and MWAT adipocyte hypertrophy. These effects were accompanied by a significant decrease in the circulating levels of leptin and the mRNA levels of the fatty acid uptake-related genes Lpl and Cd36 in MWAT. These results were very similar to those observed in OVX-E2 animals. OVX-MI rats also displayed a higher lean body mass, lean/fat mass ratio, adiponectin-to-leptin ratio and insulin sensitivity than their OVX counterparts. Our findings can pave the way for using this MI formulation as an alternative therapy to manage obesity and to improve the cardiometabolic health of menopausal women.

Phytosterol and phytostanol-mediated epigenetic changes in cancer and other non-communicable diseases: a systematic review.

Phytosterols/phytostanols are bioactive compounds found in vegetable oils, nuts and seeds and added to a range of commercial food products. Consumption of phytosterols/phytostanols reduces levels of circulating LDL-cholesterol, a causative biomarker of CVD, and is linked to a reduced risk of some cancers. Individuals who consume phytosterols/phytostanols in their diet may do so for many years as part of a non-pharmacological route to lower cholesterol or as part of a healthy diet. However, the impact of long term or high intakes of dietary phytosterols/phytostanols has not been on whole-body epigenetic changes before. The aim of this systematic review was to identify all publications that have evaluated changes to epigenetic mechanisms (post-translation modification of histones, DNA methylation and miRNA expression) in response to phytosterols/phytostanols. A systematic search was performed that returned 226 records, of which eleven were eligible for full-text analysis. Multiple phytosterols were found to inhibit expression of histone deacetylase (HDAC) enzymes and were also predicted to directly bind and impair HDAC activity. Phytosterols were found to inhibit the expression and activity of DNA methyl transferase enzyme 1 and reverse cancer-associated gene silencing. Finally, phytosterols have been shown to regulate over 200 miRNA, although only five of these were reported in multiple publications. Five tissue types (breast, prostate, macrophage, aortic epithelia and lung) were represented across the studies, and although phytosterols/phytostanols alter the molecular mechanisms of epigenetic inheritance in these mammalian cells, studies exploring meiotic or transgenerational inheritance were not found.

The effect of phytosterol supplementation on lipid profile: A critical umbrella review of interventional meta-analyses.

Despite multiple investigations assessing the impact of phytosterol supplementation on serum lipid levels, there is still a great deal of debate regarding the benefits of this intervention in the management of dyslipidemia. Therefore, we aimed at clarifying this dilemma by conducting the present umbrella review of interventional meta-analyses. Scopus, PubMed, Web of Science, and EMBASE were used to search for pertinent publications on the effect of phytosterol supplementation on the lipid profile in humans up to June 2023. To compute the overall effect size (ES) and confidence intervals (CI), the random-effects model was used. The I2 statistic and Cochrane's Q-test were applied to estimate the heterogeneity among the studies. Seventeen meta-analyses with 23 study arms were included in the umbrella meta-analysis. Data pooled from the 23 eligible arms revealed that phytosterol supplementation reduces low-density lipoprotein cholesterol (LDL-C) (ES = -11.47 mg/dL; 95% CI: -12.76, -10.17, p < 0.001), total cholesterol (TC) (ES = -13.02 mg/dL; 95% CI: -15.68, -10.37, p < 0.001), and triglyceride (TG) (ES = -3.77 mg/dL; 95% CI: -6.04, -1.51, p = 0.001). Subgroup analyses showed that phytosterol administration with dosage ≥2 g/day and duration over 8 weeks and in hypercholesterolemic subjects was more likely to decrease LDL-C, TC, and TG. Phytosterol administration did not significantly modify HDL-C (ES = 0.18 mg/dL; 95% CI: -0.13, -0.51, p = 258) levels when compared to controls. The present umbrella meta-analysis confirms that phytosterol administration significantly reduces LDL-C, TC, and TG, with a greater effect with doses of ≥2 g/day and treatment duration >8 weeks, suggesting its possible application as a complementary therapy for cardiovascular risk reduction. Further studies are needed to determine the efficacy of phytosterols in patients with specific health conditions, as well as to ascertain the adverse effects, the maximum tolerable dose, and the maximum recommended duration of phytosterol administration.

Phytosterol intake and risk of coronary artery disease: Results from 3 prospective cohort studies.

BACKGROUND: Phytosterols are structurally similar to cholesterol and partially inhibit intestinal absorption of cholesterol, although their impact on coronary artery disease (CAD) risk remains to be elucidated. OBJECTIVES: This study aimed to prospectively assess the associations between total and individual phytosterol intake and CAD risk in United States health professionals. METHODS: The analysis included 213,992 participants from 3 prospective cohorts-the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study-without cardiovascular disease or cancer at baseline. Diet was assessed using a validated food frequency questionnaire every 2-4 y since baseline. Associations between phytosterol intake and the risk of CAD, such as nonfatal myocardial infarction and fatal CAD, were evaluated using Cox proportional hazards regression models. RESULTS: More than 5,517,993 person-years, 8725 cases with CAD were documented. Comparing extreme quintiles, pooled hazard ratios (95% CIs) of CAD were 0.93 (0.86, 1.01; P-trend = 0.16) for total phytosterols, 0.89 (0.82, 0.96; P-trend = 0.05) for campesterol, 0.95 (0.88, 1.02; P-trend = 0.10) for stigmasterol, and 0.92 (0.85, 1.00; P-trend = 0.09) for ß-sitosterol. Nonlinear associations were observed for total phytosterols, campesterol, and ß-sitosterol: the risk reduction plateaued at intakes above ∼180, 30, and 130 mg/d, respectively (P-nonlinearity < 0.001). In a subset of participants (N range between 11,983 and 22,039), phytosterol intake was inversely associated with plasma concentrations of total cholesterol, triglycerides, high-density lipoprotein cholesterol, and IL-6 and positively associated with adiponectin, whereas no significant associations were observed for low-density lipoprotein cholesterol or C-reactive protein concentrations. CONCLUSIONS: Higher long-term intake of total and major subtypes of phytosterols may be associated with a modest reduction in CAD risk, displaying a nonlinear relationship that plateau at moderate intake levels. The role of phytosterols in preventing CAD warrants further investigation.

Ethylcoprostanol modulates colorectal cancer cell proliferation and mitigates cytotoxicity of cholesterol metabolites in non-tumor colon cells.

Sterols can be metabolized by gut microbiota. The cholesterol metabolites have been proposed as promoters of colorectal cancer (CRC), while the effect of plant sterol metabolites is unknown. This study aimed to evaluate the cytotoxicity of metabolites from cholesterol (coprostanol, cholestanol, coprostanone and cholestenone) and ß-sitosterol (ethylcoprostanol) on human colon tumor (Caco-2) and non-tumor (CCD-18Co) cells at physiological concentrations (9-300 µM) and exposure time (24 h). Ethylcoprostanol reduced the tumor cell proliferation (MTT), showing in flow cytometry assays induction of apoptosis via production of reactive oxygen species (ROS) and ceramide. Transcriptomic analysis (qPCR) showed activation of the intrinsic apoptosis pathway (BAX/BCL2 ratio and CASP9 increased), accompanied by downregulation of the p21 gene. Cholesterol metabolites, mainly the most hydrophobic, induced apoptosis and G0/G1 phase arrest in non-tumor cells through overproduction of ROS. Both the intrinsic and extrinsic (CASP8 increased) apoptosis pathways occurred. In turn, a reduction in the expression of the cyclin E1 gene confirmed the cell cycle arrest. In addition, ethylcoprostanol protected non-tumor cells from the most cytotoxic cholesterol metabolite (cholestenone). In conclusion, ethylcoprostanol is a promising candidate as a therapeutic adjuvant in CRC, while cholesterol metabolites could act as CRC promoters through their cytotoxicity.

Concentrated Grape Powder Consumption Modulates Cholesterol Metabolism and Homeostasis in Healthy Subjects.

SCOPE: Four weeks' of concentrated grape powder (GP) consumption reduces circulating cholesterol in healthy free-living subjects consuming a low-fiber/low-polyphenol diet. Here, the study aims to investigate the underlying mechanisms for cholesterol reduction by evaluating biomarkers of cholesterol de novo biosynthesis, intestinal absorption, miRNA involved in transcriptional regulation of cholesterol metabolism, as well as cholesterol oxidation. METHODS AND RESULTS: Fasting plasma samples collected from 19 healthy free-living subjects at baseline and week 4 of GP consumption are used in this study. Gas chromatography-mass (GC-MS) analysis of plasma samples shows that lathosterol, a precursor of cholesterol synthesis, is significantly decreased after GP consumption indicating reduced cholesterol de novo biosynthesis. Markers of intestinal absorption, campesterol, and ß-sitosterol are not changed. Realtime PCR shows that plasma exosomal miRNA-1 is increased after GP consumption. GC-MS also shows that GP consumption reduces the plasma cholesterol oxidation product 27-hydroxycholesterol (27-HC). CONCLUSIONS: This study enhances the understanding of the mechanisms of the cholesterol lowering effects of GP, and provides new insights into the potential health benefits of grape consumption.

Dietary ω3 Fatty Acids and Phytosterols in the Modulation of the HDL Lipidome: A Longitudinal Crossover Clinical Study.

High-density lipoproteins (HDLs) are complex particles composed of a wide range of lipids, proteins, hormones and vitamins that confer to the HDL particles multiple cardiovascular protective properties, mainly against the development of atherosclerosis. Among other factors, the HDL lipidome is affected by diet. We hypothesized that diet supplementation with ω3 (docosahexaenoic acid: DHA and eicosapentaenoic acid: EPA) and phytosterols (PhyS) would improve the HDL lipid profile. Overweight subjects (n = 20) were enrolled in a two-arm longitudinal crossover study. Milk (250 mL/day), supplemented with either ω3 (EPA + DHA, 375 mg) or PhyS (1.6 g), was administered to the volunteers over two consecutive 28-day intervention periods, followed by HDL lipidomic analysis. The comprehensive lipid pattern revealed that the HDL lipidome is diet-dependent. ω3-milk supplementation produced more changes than PhyS, mainly in cholesteryl esters (CEs). After ω3-milk intake, levels of DHA and EPA within phosphatylcholines, triglycerides and CE lipids in HDLs increased (p < 0.05). The correlation between lipid species showed that lipid changes occur in a coordinated manner. Finally, our analysis revealed that the HDL lipidome is also sex-dependent. The HDL lipidome is affected by diet and sex, and the 4 weeks of ω3 supplementation induced HDL enrichment with EPA and DHA.

Steroidal constituents from Solanum nigrum.

Three previously undescribed steroidal constituents including two sterols (1-2) and one pregnane-type steroidal glycoside (6), along with nineteen known ones (3-5, 7-22), were isolated from the 80% alcohol extraction of Solanum nigrum L. Their structures and the absolute configurations were established by analysis of the extensive spectroscopic data (1H/13 NMR, 1H1H COSY, HSQC, HMBC, and NOESY), and/or by comparisons of the experimental electronic circular dichroism (ECD) spectra with those calculated ones by TDDFT method. Further, a MTT assay was applied to demonstrate that compounds 1-4, 6-12, 18, and 22 exhibited significant cytotoxic activities against SW480 cells, and compounds 1-4, 6-14, and 16-22 showed significant cytotoxic activities against Hep3B cells.

Phytosterol-mediated glycerosomes combined with peppermint oil enhance transdermal delivery of lappaconitine by modulating the lipid composition of the stratum corneum.

Although the introduction of glycerosomes has enriched strategies for efficient transdermal drug delivery, the inclusion of cholesterol as a membrane stabilizer has limited their clinical application. The current study describes the development and optimization of a new type of glycerosome (S-glycerosome) that is formed in glycerol solution with ß-sitosterol as the stabilizer. Moreover, the transdermal permeation properties of lappaconitine (LA)-loaded S-glycerosomes and peppermint oil (PO)-mediated S-glycerosomes (PO-S-glycerosomes) are evaluated, and the lipid alterations in the stratum corneum are analyzed via lipidomics. The LA-loaded S-glycerosomes prepared by the preferred formulation from the uniform design have a mean size of 145.3 ± 7.81 nm and an encapsulation efficiency of 73.14 ± 0.35%. Moreover, the addition of PO positively impacts transdermal flux, peaking at 0.4% (w/v) PO. Tracing of the fluorescent probe P4 further revealed that PO-S-glycerosomes penetrate deeper into the skin than S-glycerosomes and conventional liposomes. Additionally, treatment with PO-S-glycerosomes alters the isoform type, number, and composition of sphingolipids, glycerophospholipids, glycerolipids, and fatty acids in the stratum corneum, with the most notable effect observed for ceramides, the main component of sphingolipids. Furthermore, the transdermal administration of LA-loaded PO-S-glycerosomes improved the treatment efficacy of xylene-induced inflammation in mice without skin irritation. Collectively, these findings demonstrate the feasibility of ß-sitosterol as a stabilizer in glycerosomes. Additionally, the inclusion of PO improves the transdermal permeation of S-glycerosomes, potentially by altering the stratum corneum lipids.

Liposomal Phytosterols as LDL-Cholesterol-Lowering Agents in Diet-Induced Hyperlipidemia.

The high blood level of low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for cardiovascular disease. Plant sterols, known as phytosterols (PSs), can reduce LDL-C in a range of 8-14%. The extent of LDL-C reduction depends on its formulation. Encapsulation into liposomes is one formulation strategy to enhance the efficiency of PSs. PSs (campesterol, stigmasterol, and ß-sitosterol) have frequently been assessed alone or in combination for their LDL-C-lowering ability. However, one naturally abundant PS, brassicasterol, has not yet been tested for its efficacy. We have previously developed a novel liposomal formulation containing the PS mixture present naturally in canola that is composed of brassicasterol, campesterol, and ß-sitosterol. In this work, the efficacy of our novel liposomal PS formulation that includes brassicasterol was assessed in a hamster model. Animals were divided into five groups: (i) liposomal PS in orange juice, (ii) liposomal PS in water, (iii) marketed PS in orange juice, (iv) control orange juice, and (v) control water. The animals were fed a high-fat, cholesterol-supplemented (0.5%) diet to induce hypercholesterolemia. The treatment was administered orally once daily for 4 weeks. Fasting blood samples were collected at baseline, week 2, and week 4. The extent of the reduction of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides was compared among the groups. Liposomal PSs in both orange juice and water significantly reduced LDL-C compared to their controls. Furthermore, the liposomal PS was as effective as a marketed PS-containing product in reducing LDL-C. Liposomal PSs in both orange juice and water showed similar efficacy in LDL-C reduction, highlighting that these vehicles/food matrices do not affect the efficacy of PSs. The liposomal formulation of a natural PS mixture extracted from canola oil, with brassicasterol as a major component, exhibited a significant LDL-C reduction in a hamster model.

Through regulation of the SIRT1 pathway plant sterol ester of α-linolenic acid inhibits pyroptosis thereby attenuating the development of NASH in mice.

Increasing evidence demonstrated that pyroptosis and subsequent inflammation played an important role in the pathological process of non-alcoholic steatohepatitis (NASH). Plant sterol ester of α-linolenic acid (PS-ALA) was beneficial for non-alcoholic fatty liver disease, but the underlying mechanisms are still not fully understood. This study aims to investigate whether PS-ALA can protect against proptosis via regulating SIRT1. Thirty male C57BL/6J mice were fed a normal diet, a high-fat and high-cholesterol diet (HFCD), or a HFCD supplemented with either 1.3%ALA, 2%PS, or 3.3% PS-ALA for 24 weeks. Hepatocytes were treated with oleic acid and cholesterol (OA/Cho) with or without PS-ALA. We found that PS-ALA ameliorated NASH in HFCD-fed mice. In addition, PS-ALA decreased the expression of NLRP3 and ASC and reduced the co-localization of NLRP3 and cleave-Caspase-1. Also, PS-ALA protected against pyroptosis as evidenced by decreased co-localization of GSDMD and propidium iodide (PI) positive cells. Mechanistically, we revealed that the inhibitory action of PS-ALA on the pyroptosis was mediated by SIRT1. This was demonstrated by the fact that silencing SIRT1 with small interfering RNA or inhibition of SIRT1 with its inhibitor abolished the inhibition effect of PS-ALA on the expression of NLRP3 and GSDMD cleavage. Collectively, the data from the present study reveals a novel mechanism that PS-ALA inhibits pyroptosis and it triggered inflammation via stimulating SIRT1, which provides new insights into the beneficial effect of PS-ALA on NASH.

Regulating effects of phytosterol esters-loaded emulsions stabilized with green tea polysaccharide conjugates and Tween on lipids in KKAy mice.

Phytosterol esters (PSE) have been shown to have cholesterol-lowering effects, but their insolubility in water limits their applications. Green tea polysaccharide conjugates (gTPC) have hypoglycemic and emulsifying effects. To address lipid dysregulation in diabetic patients, we developed PSE-loaded emulsions stabilized with gTPC and Tween-20 (gTPC-PSE emulsions) and evaluated their physicochemical properties. We subsequently investigated the lipid-regulating potential of these emulsions to in KKAy mice. The KKAy mice were randomly assigned to eight groups: the model group, the Lipitor (10 mg·kg-1)-acarbose (30 mg·kg-1) combination group, two gTPC groups, two PSE groups, and two gTPC-PSE groups with a 1:2 mass ratio of gTPC to PSE. The administered doses were 90 and 270 mg kg-1, respectively. Administration of a 270 mg·kg-1 dose of gTPC-PSE emulsions led to the most significant effects including increased levels of liver and serum high-density lipoprotein cholesterol (HDL-CH), reduced serum leptin and insulin, and improved liver superoxide dismutase (SOD) and reduced malondialdehyde (MDA). In general, gTPC and PSE demonstrated a synergistic effect on lipid regulation in mice. Our results indicate that gTPC-PSE emulsions hold potential as a nutritional intervention for diabetes by modulating lipid levels.

Phytosterols Alleviate Hyperlipidemia by Regulating Gut Microbiota and Cholesterol Metabolism in Mice.

Phytosterols (PS) have been shown to regulate cholesterol metabolism and alleviate hyperlipidemia (HLP), but the mechanism is still unclear. In this study, we investigated the mechanism by which PS regulates cholesterol metabolism in high-fat diet (HFD) mice. The results showed that PS treatment reduced the accumulation of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in the serum of HFD mice, while increasing the serum levels of high-density lipoprotein cholesterol (HDL-C). Compared with HFD mice, PS not only increased the antioxidant activity of the liver but also regulated the mRNA expression levels of enzymes and receptors related to cholesterol metabolism. The hypolipidemic effect of PS was abolished by antibiotic (Abx) intervention and reproduced by fecal transplantation (FMT) intervention. The results of 16S rRNA sequencing analysis showed that PS modulated the gut microbiota of mice. PS reduced the relative abundance of Lactobacillus and other bile salt hydrolase- (BSH-) producing gut microbiota in HFD mice, which are potentially related to cholesterol metabolism. These findings partially explain the mechanisms by which PS regulates cholesterol metabolism. This implies that regulation of the gut microbiota would be a potential target for the treatment of HLP.

Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases-A German Expert Panel Statement.

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20-40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies.

The critical role of the phytosterols in modulating tumor microenvironment via multiple signaling: A comprehensive molecular approach.

Cancer is the leading cause of mortality and morbidity worldwide, and its cases are rapidly increasing every year. Several factors contribute to the development of tumorigenesis. including radiation, dietary lifestyle, smoking, environmental, and genetic factors. The cell cycle is regulated by a variety of molecular signaling proteins. However, when the proteins involved in the cell cycle regulation are altered, cellular growth and proliferation are significantly affected. Natural products provide an important source of new drug development for a variety of ailments. including cancer. Phytosterols (PSs) are an important class of natural compounds reported for numerous pharmacological activities, including cancer. Various PSs, such as ergosterol, stigmasterol, sitosterol, withaferin A, etc., have been reported for their anti-cancer activities against a variety of cancer by modulating the tumor microenvironment via molecular signaling pathways discussed within the article. These signaling pathways are associated with the production of pro-inflammatory mediators, growth factors, chemokines, and pro-apoptotic and anti-apoptotic genes. These mediators and their upstream signaling are very active within the variety of tumors and by modulating these signalings, thus PS exhibits promising anti-cancer activities. However, further high-quality studies are needed to firmly establish the clinical efficacy as well the safety of the phytosterols.

A Mixture of Dietary Plant Sterols at Nutritional Relevant Serum Concentration Inhibits Extrinsic Pathway of Eryptosis Induced by Cigarette Smoke Extract.

Cell death program of red blood cells (RBCs), called eryptosis, is characterized by activation of caspases and scrambling of membrane phospholipids with externalization of phosphatidylserine (PS). Excessive eryptosis confers a procoagulant phenotype and is implicated in impairment of microcirculation and increased prothrombotic risk. It has recently been reported that cigarette smokers have high levels of circulating eryptotic erythrocytes, and a possible contribution of eryptosis to the vaso-occlusive complications associated to cigarette smoke has been postulated. In this study, we demonstrate how a mixture of plant sterols (MPtS) consisting of ß-sitosterol, campesterol and stigmasterol, at serum concentration reached after ingestion of a drink enriched with plant sterols, inhibits eryptosis induced by cigarette smoke extract (CSE). Isolated RBCs were exposed for 4 h to CSE (10-20% v/v). When RBCs were co-treated with CSE in the presence of 22 µM MPtS, a significant reduction of the measured hallmarks of apoptotic death like assembly of the death-inducing signaling complex (DISC), PS outsourced, ceramide production, cleaved forms of caspase 8/caspase 3, and phosphorylated p38 MAPK, was evident. The new beneficial properties of plant sterols on CSE-induced eryptosis presented in this work open new perspectives to prevent the negative physio-pathological events caused by the eryptotic red blood cells circulating in smokers.

Phytosterols as bioactive food components against nonalcoholic fatty liver disease.

Phytosterols are bioactive food components widely present in cell membranes of plants, especially in nuts and oilseeds. In recent years, many studies have shown that phytosterols possess therapeutic potentials for nonalcoholic fatty liver disease (NAFLD). This review summarizes the effects of phytosterols from in vitro and in vivo studies to lower the levels of total cholesterol (TC) and triglycerides (TG), and the evidence supporting the potential of phytosterols against NAFLD. The potential mechanisms by which phytosterols improve NAFLD may include (i) competition with cholesterol; (ii) regulation of key factors involved in cholesterol and TG metabolism; and (iii) inhibition of liver inflammation and (iv) regulation of liver fatty acid composition. In summary, phytosterols are potential natural ingredients with good safety profile against NAFLD, which deserve more future studies.