phytosterols and Inflammation

The characteristic steroid skeleton, with its 4-ringed 17-carbon structure, is one of the most recognizable organic compounds in biochemistry. In the presence of a hydroxyl ion bound to the third carbon, this structure is defined as a "sterol" (chemical formula: C

Topics: Carbon; Cholesterol; Humans; Inflammation; Phytosterols; Sterols

Besides the well-characterized effect of foods and supplements enriched with plant sterols/stanols on serum LDL-C concentrations, evidence is now emerging that phytosterols exert beneficial effects on non-lipid variables such as inflammatory and oxidative stress markers, coagulation parameters and endothelial function. This makes sterols and stanols an attractive alternative for dietary interventions in cardiovascular disease prevention, particularly in populations at low or medium risk. This review aims to summarize the current knowledge derived from experimental studies and human data on the anti-inflammatory effects of phytosterols/stanols and their relevance in promoting atheroprotection and preventing cardiovascular disease. The anti-inflammatory effects induced by plant sterols/stanols have been demonstrated in in vitro studies and in experimental animal models. However, not all the beneficial effects seen at an experimental level have translated into clinical benefit. Indeed, clinical studies that evaluate the association between phytosterols consumption and inflammatory variables (CRP and cytokines) are inconsistent and have not yet provided a solid answer. Plant sterols have been proposed as useful adjuncts to statin therapy to further reduce the risk of cardiovascular disease. However, there is limited available data and more research needs to be done.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammation; Phytosterols

Under physiological conditions, neurons and glia are in a healthy, redox-balanced environment; when injury perturbs this equilibrium, a neuroinflammatory state is established by activated microglia that triggers pro-inflammatory responses and alters the oxidant/antioxidant balance, thus leading to neuronal loss and neurodegeneration. In neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyothrophic lateral sclerosis, and multiple sclerosis), the brain is in a constitutively self-sustaining cycle of inflammation and oxidative stress that prompts and amplifies brain damage. Recent Advances: Recently, an increasing amount of scientific data highlight the ability of specific nutrients to cross the blood-brain barrier, and to modulate inflammatory and oxidative pathways. Therefore, nutritional approaches may contribute to restore the lost equilibrium among factors accounting for neurodegeneration.. Herein, we critically examine how essential lipids (including fatty acids, liposoluble vitamins and phytosterols) might contribute to accelerate or prevent the onset and progression of such pathologies. In particular, we highlight that experimental and clinical findings, although promising, are still inadequate to draw definitive conclusions.. More research is warranted in order to establish the real impact of lipid intake on brain health, especially when redox balance and inflammatory responses have been already compromised. In the future, it would be hoped to gain a detailed knowledge of chemical modifications and dynamic properties of such nutrients, before planning to exploit them as potential therapeutics. Antioxid. Redox Signal. 29, 37-60.

Topics: Animals; Antioxidants; Dietary Fats; Fatty Acids; Humans; Inflammation; Neurodegenerative Diseases; Phytosterols; Vitamins

Non-cholesterol sterols are present in our body at very low concentrations as compared to cholesterol. Small changes in the structure of sterol molecules confer them highly distinct biological activities. The best-known example are steroid hormones derived from cholesterol. During the past decade, our knowledge of also other biomolecules related to or derived from cholesterol, particularly plant sterols, biosynthetic precursors of cholesterol, and oxysterols, has expanded rapidly. In this review article we recapitulate the latest insights into the properties and physiological activities of these non-cholesterol sterols, as well as their importance in disease processes and potential as diagnostic biomarkers.

Topics: Animals; Biomarkers; Cholesterol; Humans; Immune System; Inflammation; Lipid Metabolism; Oxidative Stress; Oxysterols; Phytosterols

Regular intake of phytosterols (PS) is proven to dose-dependently lower LDL-cholesterol (LDL-C). Whether PS consumption can also impact low-grade inflammation is unclear. Considering the low feasibility of outcomes studies involving PS consumption, investigation of surrogate markers of atherosclerosis represents a valuable approach. This study assessed the anti-inflammatory effect of PS consumption, according to inflammatory biomarkers, mainly C-reactive protein (CRP).. A systematic search of Medline, Cab Abstracts, and Food Science & Technology Abstracts was conducted through January 2015. Our study selection included randomized controlled trials (RCT), involving intake of PS-enriched foods as active treatment, and measurement of plasma inflammatory biomarkers. Random-effects meta-analyses were performed using average baseline and end-of-intervention concentrations and control-adjusted absolute changes in CRP and blood lipids. There were 20 eligible RCTs including a total of 1308 subjects. The absolute change of plasma CRP levels with PS consumption was -0.10 mg/L (95%CI -0.26; 0.05), a non-significant change, and heterogeneity had borderline significance (I(2) = 29.1; p-value = 0.073). The absolute reduction of LDL-C was -14.3 mg/dL (95%CI -17.3; -11.3). Meta-regression analyses showed that both the dose and duration of PS intake significantly influenced the absolute changes in plasma CRP (β = -0.35, p = 0.0255 and β = -0.03, p = 0.0209, respectively).. In this meta-analysis, regular intake of PS-enriched foods did not significantly change CRP, whilst LDL-C concentrations were significantly reduced. Further studies with higher PS doses may provide more definite conclusions on a potential anti-inflammatory effect of PS intake.

Topics: Anti-Inflammatory Agents; Biomarkers; Cholesterol; Cholesterol, LDL; Humans; Inflammation; Lipids; Phytosterols; Plants; Randomized Controlled Trials as Topic; Regression Analysis; Triglycerides

This EAS Consensus Panel critically appraised evidence relevant to the benefit to risk relationship of functional foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma low-density lipoprotein-cholesterol (LDL-C) levels, and thereby lower cardiovascular risk.. Plant sterols/stanols (when taken at 2 g/day) cause significant inhibition of cholesterol absorption and lower LDL-C levels by between 8 and 10%. The relative proportions of cholesterol versus sterol/stanol levels are similar in both plasma and tissue, with levels of sterols/stanols being 500-/10,000-fold lower than those of cholesterol, suggesting they are handled similarly to cholesterol in most cells. Despite possible atherogenicity of marked elevations in circulating levels of plant sterols/stanols, protective effects have been observed in some animal models of atherosclerosis. Higher plasma levels of plant sterols/stanols associated with intakes of 2 g/day in man have not been linked to adverse effects on health in long-term human studies. Importantly, at this dose, plant sterol/stanol-mediated LDL-C lowering is additive to that of statins in dyslipidaemic subjects, equivalent to doubling the dose of statin. The reported 6-9% lowering of plasma triglyceride by 2 g/day in hypertriglyceridaemic patients warrants further evaluation.. Based on LDL-C lowering and the absence of adverse signals, this EAS Consensus Panel concludes that functional foods with plant sterols/stanols may be considered 1) in individuals with high cholesterol levels at intermediate or low global cardiovascular risk who do not qualify for pharmacotherapy, 2) as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL-C targets on statins or are statin- intolerant, 3) and in adults and children (>6 years) with familial hypercholesterolaemia, in line with current guidance. However, it must be acknowledged that there are no randomised, controlled clinical trial data with hard end-points to establish clinical benefit from the use of plant sterols or plant stanols.

Topics: Animals; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Dyslipidemias; Humans; Inflammation; Lipids; Phytosterols; Sitosterols; Triglycerides

Phytosterols and their oxidation products have become increasingly investigated in recent years with respect to their roles in diet and nutrition. We present a comprehensive review of recent literature on Phytosterol Oxidation Products (POP) identifying critical areas for future investigation. It is evident that POP are formed on food storage/preparation; are absorbed and found in human serum; do not directly affect cholesterol absorption; have evidence of atherogenicity and inflammation; have distinct levels of cytotoxicity; are implicated with high levels of oxidative stress, glutathione depletion, mitochondrial dysfunction and elevated caspase activity.

Topics: Atherosclerosis; Caspases; Cholesterol; Food; Glutathione; Humans; Inflammation; Mitochondria; Oxidation-Reduction; Oxidative Stress; Phytosterols

High dietary intakes of cholesterol together with sedentary habits have been identified as major contributors to atherosclerosis. The latter has long been considered a cholesterol storage disease; however, today atherosclerosis is considered a more complex disease in which both innate and adaptive immune-inflammatory mechanisms as well as bacteria play a major role, in addition to interactions between the arterial wall and blood components. This scenario has promoted nutritional recommendations to enrich different type of foods with plant sterols (PS) because of their cholesterol-lowering effects. In addition to cholesterol, PS can also be oxidized during food processing or storage, and the oxidized derivatives, known as phytosterol oxidation products (POPs), can make an important contribution to the negative effects of both cholesterol and cholesterol oxidation oxides (COPs) in relation to inflammatory disease onset and the development of atherosclerosis. Most current research efforts have focused on COPs, and evaluations of the particular role and physiopathological implications of specific POPs have been only inferential. Appreciation of the inflammatory role described for both COPs and POPs derived from foods also provides additional reasons for safety studies after long-term consumption of PS. The balance and relevance for health of all these effects deserves further studies in humans. This review summarizes current knowledge about the presence of sterol oxidation products (SOPs) in foods and their potential role in inflammatory process and cardiovascular disease.

Topics: Atherosclerosis; Biological Availability; Cardiovascular Diseases; Cholesterol; Food; Food Handling; Humans; Inflammation; Phytosterols; Risk Factors

While many factors are involved in the etiology of cancer, it has been clearly established that diet significantly impacts one's risk for this disease. More recently, specific food components have been identified which are uniquely beneficial in mitigating the risk of specific cancer subtypes. Plant sterols are well known for their effects on blood cholesterol levels, however research into their potential role in mitigating cancer risk remains in its infancy. As outlined in this review, the cholesterol modulating actions of plant sterols may overlap with their anti-cancer actions. Breast cancer is the most common malignancy affecting women and there remains a need for effective adjuvant therapies for this disease, for which plant sterols may play a distinctive role.

Topics: Anticholesteremic Agents; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Membrane; Cholesterol; Estrogens; Female; Glucose; Humans; Immunity; Inflammation; Liver X Receptors; Orphan Nuclear Receptors; Oxidative Stress; Phytosterols; Receptors, Estrogen; Risk Factors; Signal Transduction; Sitosterols

Rice bran contains important bioactive phytochemicals. Among these phytochemicals, steryl ferulates including γ-oryzanol and its major components such as cycloartenyl ferulate (CAF), 24-methylenecycloartanyl ferulate (24-mCAF), β-sitosteryl ferulate (β-SF), and campesteryl ferulate have been intensively studied due to their crucial roles in pathological processes. On the basis of experimental studies published during the last decade in relation to antioxidant, anti-inflammatory, anti-ulcerogenic, hypolipidemic, anti-neoplastic, anti-diabetic, and anti-allergic phenomena, these bioactive phytochemicals are reviewed in this paper. Particularly, in vivo and in vitro studies have clarified that rice bran phytosteryl ferulates mediate anti-inflammatory effects by down-regulating the inflammatory transcription factor, nuclear factor κB (NF-κB), which in turn reduces expression of inflammatory enzymes such as COX-2 and iNOS, and proinflammatory cytokines such as IL-1β, IL-6 and TNF-α. Moreover, rice bran phytosteryl ferulates up-regulate blood adiponectin levels via indirect activation of peroxisomal proliferator-activated receptor γ (PPARγ) through NF-κB inhibition. In this review, we discuss potential pharmacological aspects of rice bran phytosteryl ferulates in the clinical setting.

Topics: Adiponectin; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Coumaric Acids; Cyclooxygenase 2; Humans; Hypersensitivity; Immunity; Inflammation; Interleukin-6; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Oryza; Oxidative Stress; Phenylpropionates; Phytosterols; Plant Extracts; PPAR gamma; Tumor Necrosis Factor-alpha; Up-Regulation

The proportion of elderly is growing worldwide. This trend is in parallel to an increase in diseases, such as cardiovascular disease (CVD). Plant sterols and stanols (PS) consumption is known to decrease low-density lipoprotein-cholesterol (LDL-C) levels by 5-15%, and thus lower CVD risk. Yet, the effect of PS on LDL-C levels differs between individuals. Furthermore, PS have recently been investigated for the prevention of other age-related diseases. The objective of this review is to examine the benefits of PS on CVD as well as ageing-associated diseases. PS have the ability to significantly lower LDL-C; yet, the large inter-individual variability in the lowering of LDL-C may be due to subject characteristics, food matrix of PS, dose of PS, dietary background, frequency of intake of PS, the additive effect of other foods or drugs, as well as genetic factors. Further, PS may also have other potential beneficial effects including anti-atherogenic, anti-inflammatory, antioxidant and anti-cancer activities. Overall, dietary intervention strategies, such as incorporating PS into a healthy diet, should be recommended and implemented in older adult populations in order to prevent ageing-associated diseases and hence promote healthy ageing.

Topics: Aged; Aging; Cardiovascular Diseases; Cognition Disorders; Eye Diseases; Food, Fortified; Humans; Inflammation; Meta-Analysis as Topic; Neoplasms; Oxidative Stress; Phytosterols; Randomized Controlled Trials as Topic

Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of ABC transporter loci. In Tangier disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis. Likewise, sitosterolemia is another inherited syndrome associated with premature atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting cholesterol and plant sterols, including sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes cholesterol and dietary sterols back into the gut, while ABCA1 functions to export excess cell cholesterol and phospholipid during the biogenesis of HDL. Interestingly, a third protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer cholesterol to mature HDL particles. Here we review the relationship between the lipid transport activities of these proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface cholesterol levels and inhibit its partitioning into lipid rafts. Given lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another HDL receptor, may directly act as anti-inflammatory receptors independent of their lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of lipids through the RCT pathway.

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Cholesterol; Coronary Vessels; Hepatocytes; Humans; Hypercholesterolemia; Inflammation; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Models, Biological; Myocardial Infarction; Phenotype; Phytosterols; Tangier Disease

Consumption of foods and supplements enriched with plant sterols/stanols (PS) may help reduce low-density lipoprotein cholesterol (LDL-C) levels. In this review, we consider the effects of PS beyond LDL-C lowering. Plant sterols/stanols exert beneficial effects on other lipid variables, such as apolipoprotein (apo) B/apoAI ratio and, in some studies, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Plant sterols/stanols may also affect inflammatory markers, coagulation parameters, as well as platelet and endothelial function. Evidence also exists about a beneficial effect on oxidative stress, but this does not seem to be of greater degree than that expected from the LDL-C lowering. Many of these effects have been demonstrated in vitro and animal models. Some in vitro effects cannot be seen in vivo or in humans at usual doses. The epidemiological studies that evaluated the association of plasma PS concentration with cardiovascular disease (CVD) risk do not provide a definitive answer. Long-term randomized placebo-controlled studies are required to clarify the effects of supplementation with PS on CVD risk and progression of atherosclerosis.

Topics: Animals; Apolipoprotein A-I; Apolipoproteins B; Atherosclerosis; Biomarkers; Blood Coagulation; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Endothelium, Vascular; Humans; Inflammation; Oxidative Stress; Phytosterols; Platelet Aggregation; Triglycerides

Experimental and clinical studies have demonstrated the effect of phytosterols (PS) on reducing plasma levels of cholesterol and LDL-c, but the effects of plant sterols beyond cholesterol-lowering are still questionable. Since inflammation and endothelial dysfunction are involved in the pathogenesis of atherosclerosis, this study aims to evaluate the effect of PS on biomarkers involved in atherosclerosis progression and whether these effects are independent of alterations in plasma LDL-c levels. Thirty-eight moderately hypercholesterolemic volunteers (58 ± 12 years; LDL-c ≥ 130 mg/dL) were randomly assigned to consume 400 mL/day of soy milk or soy milk + PS (1.6 g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and lipid profiles and biomarkers for inflammation and endothelial dysfunction determined. The results showed that PS treatment reduced endothelin-1 plasma concentration by 11% (

Topics: Adult; Aged; Apolipoproteins B; Atherosclerosis; Biomarkers; Brazil; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Endothelin-1; Female; Humans; Hypercholesterolemia; Inflammation; Lipids; Male; Middle Aged; Phytosterols; Plasma; Soy Milk; Sterols; Triglycerides

Cardiovascular disease (CVD) remains one of the major causes of death and disability worldwide. In addition to drug treatment, nutritional interventions or supplementations are becoming a health strategy for CVD prevention. Phytosterols (PhyS) are natural components that have been shown to reduce cholesterol levels; while poly-unsaturated fatty acids (PUFA), mainly omega-3 (ω3) fatty acids, have shown to reduce triglyceride levels. Here we aimed to investigate whether the proteins in the main lipoproteins (low density lipoproteins (LDL) and high density lipoproteins (HDL)) as well as proteins in the lipid free plasma fraction (LPDP) were regulated by the intake of PhyS-milk or ω3-milk, in overweight healthy volunteers by a proteomic based systems biology approach. The study was a longitudinal crossover trial, including thirty-two healthy volunteers with body mass index (BMI) 25-35 kg/m² (Clinical Trial: ISRCTN78753338). Basal samples before any intervention and after 4 weeks of intake of PhyS or ω3-milk were analyzed. Proteomic profiling by two dimensional electrophoresis (2-DE) followed by mass spectrometry-(MALDI/TOF), ELISA, Western blot, conventional biochemical analysis, and in-silico bioinformatics were performed. The intake of PhyS-milk did not induce changes in the lipid associated plasma protein fraction, whereas ω3-milk significantly increased apolipoprotein (Apo)- E LDL content (

Topics: Animals; Cross-Over Studies; Dietary Fats; Double-Blind Method; Fatty Acids, Omega-3; Female; Gene Expression Regulation; Humans; Inflammation; Male; Middle Aged; Milk; Phytosterols; Signal Transduction

The sterol profile of rapeseed oil differs from that of tall oil with higher contents of campesterol and brassicasterol. We previously found that margarines providing 2 g/day of sterols from rapeseed or tall oil resulted in similar reductions in LDL cholesterol of 8-9%. The aim of the present study was to investigate whether the consumption of these margarines affected markers of endothelial function, inflammation and hemostasis.. Blood samples were collected from 58 hypercholesterolemic volunteers who completed a double-blinded, randomized, crossover trial. Subjects consumed each of the two sterol margarines and a control non-sterol margarine for 4 weeks separated by one-week washout periods. All the margarines had the same fatty acid composition. Concentrations of vascular cell adhesion molecule-l (VCAM-1), E-selection, circulating tumor necrosis factor α (TNFα) and plasminogen activator inhibitor-1 (total, tPAI-1; active, PAI-1) were quantified.. Rapeseed-sterol margarine reduced E-selection concentrations compared to the control margarine (p = 0.012) while tall-sterol margarine had no effect. The rapeseed-sterol margarine also reduced tPAI-1 (p = 0.008) compared to the tall-sterol margarine. No significant changes were observed in TNFα and VCAM-1. No association was found between LDL reduction and changes in E-selection and tPAI-1.. Rapeseed-sterol margarine demonstrated favorable effects on vascular risk markers.

Topics: Adult; Aged; Biomarkers; Brassica rapa; Cholestadienols; Cholesterol, LDL; Cytokines; E-Selectin; Endothelium, Vascular; Female; Hemostasis; Humans; Hypercholesterolemia; Inflammation; Male; Margarine; Middle Aged; Phytosterols; Plant Oils; Vascular Cell Adhesion Molecule-1

High-risk subjects with elevated C-reactive protein (CRP) are at high risk for cardiovascular events and frequently require potent statins or combined lipid-lowering therapy to achieve lipid targets and decrease inflammation. Our study aimed at evaluating the effects of three lipid-modifying therapies on LDL-cholesterol, CRP levels and markers of cholesterol absorption and synthesis.. A prospective intervention study was performed in high cardiovascular risk individuals receiving atorvastatin 10mg daily for four weeks. Those with CRP≥2.0mg/L were randomized to another four-week treatment period with atorvastatin 40mg, ezetimibe 10mg or the combination of atorvastatin 40mg / ezetimibe 10mg. Lipids, markers of cholesterol absorption (campesterol and β-sitosterol), and synthesis (desmosterol), as well as CRP were quantified at baseline and end of study.. One hundred and twenty two individuals were included. Atorvastatin alone or combined with ezetimibe reduced both LDL-cholesterol and CRP (P<0.002 vs. baseline; Wilcoxon); ezetimibe did not modify CRP. Ezetimibe-based therapies reduced absorption markers and their ratios to cholesterol (P<0.0001 vs. baseline, for all; Wilcoxon), whereas atorvastatin alone increased campesterol/cholesterol and β-sitosterol/cholesterol ratios (P<0.05 vs. baseline; Wilcoxon). In addition, ezetimibe also increased desmosterol and desmosterol/cholesterol ratio (P<0.0001 vs. baseline; Wilcoxon).. These results contribute to understanding the link between cellular cholesterol homeostasis, inflammation and lipid-modifying therapies. Our findings highlight the broader benefit of combined therapy with a potent statin and ezetimibe decreasing inflammation, and preventing increase in cholesterol biosynthesis, an effect not observed with ezetimibe alone.

Topics: Aged; Anticholesteremic Agents; Atorvastatin; Azetidines; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Desmosterol; Ezetimibe; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Phytosterols; Prospective Studies; Pyrroles; Risk Factors; Sitosterols; Statistics, Nonparametric

Consumption of plant sterol (PS) esters lower low-density lipoprotein (LDL)-cholesterol levels by suppressing intestinal absorption of cholesterol. Commercially available PS are mainly esterified to omega-6 fatty acid (FA), such as sunflower oil (SO) FA. Emerging trends include using other sources such as olive oil (OO) or omega-3 FA from fish oil (FO), known to exert potent hypotriglyceridemic effects. Our objective was to compare the actions of different FA esterified to PS on blood lipids, carotenoid bioavailability as well as inflammatory and coagulation markers.. Twenty-one moderately overweight, hypercholesterolemic subjects consumed experimental isoenergetic diets enriched with OO (70% of fat), each lasting 28-day and separated by 4-week washout periods, using a randomized crossover design. Diets were supplemented with three PS esters preparations, PS-FO, PS-SO, or PS-OO. All PS treatments contained an equivalent of 1.7 PS g/d, and the PS-FO provided a total of 5.4 g/d FO FA (eicosapentaenoic and docosahexaenoic acids).. There were no differences between PS-containing diet effects on total cholesterol, LDL-cholesterol, or high-density lipoprotein (HDL)-cholesterol levels. However, PS-FO consumption resulted in markedly lower (P < 0.0001) fasting and postprandial triglyceride concentrations compared with PS-SO and PS-OO. These treatments affected plasma beta-carotene (P = 0.0169) and retinol (P = 0.0244), but not tocopherol (P = 0.2108) concentrations. Consumption of PS-FO resulted in higher beta-carotene (P = 0.0139) and retinol (P = 0.0425) levels than PS-SO and PS-OO, respectively. Plasma TNF-alpha, IL-6, C-reactive protein, prostate specific antigen, and fibrinogen concentrations were unaffected by the PS-interventions. In contrast, plasminogen activator inhibitor 1 (PAI-1) concentrations were lower (P = 0.0282) in the PS-FO-fed than the PS-SO, but not the PS-OO (P = 0.7487) groups.. Our findings suggest that, in hypercholesterolemic subjects consuming an OO-based diet, PS-FO results in lowered blood triglyceride and PAI-1 concentrations, and higher fat-soluble vitamin levels in comparison to the vegetable oil FA esters of PS (PS-SO and PS-OO). Thus, PS-FO may offer hyperlipidemic subjects a more comprehensive lipid lowering approach while reducing the potential risk of decreased plasma carotenoid concentrations.

Topics: Adipose Tissue; Adult; Aged; Biological Availability; Biomarkers; Blood Coagulation; Carotenoids; Esters; Fasting; Female; Fish Oils; Humans; Hypercholesterolemia; Inflammation; Male; Middle Aged; Phytosterols; Plant Oils; Plasminogen Activator Inhibitor 1; Solubility; Triglycerides; Vitamins

A pilot study was undertaken to investigate the effects of the intake of capsules containing the plant sterols and sterolins (BSS:BSSG mixture) on selected immune parameters of volunteers participating in an ultra-marathon in Cape Town, South Africa. Those runners having received active capsules (n=9) showed less neutrophilia, lymphopenia and leukocytosis when compared to their counterparts having received placebo capsules (n=8): the placebo treated individuals showed significant increases in their total white blood cell numbers as well as in their neutrophils (p=0.03 and 0.03 respectively). Furthermore, statistically significant increases within lymphocyte subsets were observed in the runners having received the active capsules: CD3+ cells increased (p=0.02) as did CD4+ cells (p=0.03). In parallel, the BSS:BSSG capsules decreased the plasma level of IL6 in the runners using the active capsules (p=0.08) and significantly decreased the cortisol: DHEAs ratio (p=0.03), suggesting that these volunteers had less of an inflammatory response and were less immune suppressed during the post-marathon recovery period. These findings justify further investigations into the use of the phytosterols to prevent the subtle immunosuppression associated with excessive physical stress.

Topics: Adult; Blood Cell Count; Dietary Supplements; Exercise; Female; Humans; Immunosuppression Therapy; Inflammation; Leukocytosis; Lymphocyte Subsets; Lymphopenia; Male; Middle Aged; Neutrophils; Phytosterols; Sitosterols

Topics: Animals; Inflammation; Mice; Molecular Docking Simulation; Phytosterols; Psoriasis; Sitosterols; Stigmasterol; Swine

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.

Topics: alpha-Linolenic Acid; Animals; Cholesterol; Esters; Inflammation; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Phytosterols; Pyroptosis; Sirtuin 1

Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.

Topics: Animals; Arrhythmias, Cardiac; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cytokines; Death, Sudden, Cardiac; Fibrosis; Heart Failure; Hypercholesterolemia; Inflammation; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phytosterols

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytokines; Gynostemma; Humans; Inflammation; Lipopolysaccharides; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Motor Activity; Phytosterols; Phytotherapy; Plant Extracts; Polyphenols; Saponins

Ganoderma lucidum exhibits pronounced anti-inflammatory effects, polysaccharides and triterpenoids are regarded as major constituents displaying the anti-inflammatory activities, whether sterols contribute to this activity remains unclear. Herein Ganoderma lucidum sterols (GLS) were innovatively isolated by a single-step procedure, the profile of GLS was characterized by HPLC-ELSD and shown similar to that of sterols separated by a traditional method, but much higher in content. Furthermore, GLS inhibited inflammation in macrophages by significantly attenuating LPS-induced cell polarization as well as releases and mRNA expressions of pro-inflammatory mediators NO, TNF-α, IL-1β and IL-6. Moreover, the anti-inflammatory activity of GLS was mediated by MAPK and NF-κB pathways, GLS suppressed MAPK pathways by blocking phosphorylation of p38 but not ERK and JNK, which is complementary with inhibitory effects of Ganoderma polysaccharides and triterpenes on JNK and ERK, indicating Ganoderma sterols may exert synergistic anti-inflammatory effect with polysaccharides and triterpenes. GLS also inhibited NF-κB pathways by restraining phosphorylation and degradation of IκB-α and blocking phosphorylation of NF-κB p65. Molecular docking confirmed that sterols of GLS were directly bound to active sites of p38 and p65 to suppress their activation. Therefore, our findings suggest GLS as natural and safe anti-inflammatory agents to prevent and treat inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Survival; Gene Expression Regulation, Enzymologic; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Phytosterols; Phytotherapy; Plant Extracts; RAW 264.7 Cells; Reishi; RNA, Messenger

As part of our continuous effort to find potential anti-inflammatory agents from endophytic fungi, a

Topics: Animals; Anti-Inflammatory Agents; Cell Survival; Dinoprostone; Fusarium; Heme Oxygenase-1; Inflammation; Magnoliopsida; MAP Kinase Signaling System; Membrane Proteins; Mice; Molecular Docking Simulation; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide; Phosphorylation; Phytosterols; RAW 264.7 Cells; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Transcription Factor AP-1

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)

Topics: Animals; beta-Cyclodextrins; Cholesterol; Chorioamnionitis; Disease Models, Animal; Drug Carriers; Enterocolitis, Necrotizing; Enterohepatic Circulation; Female; Fetus; Inflammation; Injections, Intralesional; Liver; Phytosterols; Phytotherapy; Post-Exposure Prophylaxis; Pregnancy; Sheep; Sitosterols; Ureaplasma; Ureaplasma Infections

Chorioamnionitis, clinically most frequently associated with

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Chorioamnionitis; Diet; Drug Administration Routes; Female; Fetus; Gastrointestinal Diseases; Inflammation; Phytosterols; Pregnancy; Random Allocation; Sheep; Sheep Diseases; Ureaplasma; Ureaplasma Infections

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both

Topics: Animals; Anti-Inflammatory Agents; Croton Oil; Diosgenin; Ear Diseases; Edema; Enzyme-Linked Immunosorbent Assay; Glycyrrhetinic Acid; Inflammation; Interleukin-6; Mice; Molecular Docking Simulation; Phytosterols; Pregnenediones; Rats; Receptors, Glucocorticoid; Software; Thymus Gland; Triterpenes; Tumor Necrosis Factor-alpha; Withanolides

Phytosterols are implicated in the development of parenteral nutrition-associated liver disease. A newly proposed mechanism for phytosterol-mediated parenteral nutrition-associated liver disease is through phytosterol-facilitated hepatic proinflammatory cytokine release following exposure to intestinally derived bacteria. Whether the proinflammatory effects are liver cell specific is not known.. To determine if phytosterols cause inflammation in hepatocytes or Kupffer cells independently or require costimulation by lipopolysaccharide (LPS).. In an in vivo study, neonatal piglets on parenteral nutrition for 11 days received an 8-hour infusion of LPS. In the in vitro studies, neonatal piglet Kupffer cells and hepatocytes were treated with media, media + 1% soy oil, or media + 1% soy oil + 100µM phytosterols. After 24-hour incubation, cells were treated with farnesoid X receptor (FXR) agonist obeticholic acid or liver X receptor (LXR) agonist GW3965 and challenged with LPS or interleukin 1β.. LPS administration in piglets led to transient increases in proinflammatory cytokines and suppression of the transporters bile salt export pump and ATP-binding cassette transporter G5. In hepatocytes, phytosterols did not activate inflammation. Phytosterol treatment alone did not activate inflammation in Kupffer cells but, combined with LPS, synergistically increased interleukin 1β production. FXR and LXR agonists increased transporter expression in hepatocytes. GW3965 suppressed proinflammatory cytokine production in Kupffer cells, but obeticholic acid did not.. LPS suppresses transporters that control bile acid and phytosterol clearance. Phytosterols alone do not cause inflammatory response. However, with costimulation by LPS, phytosterols synergistically maximize the inflammatory response in Kupffer cells.

Topics: Animals; Animals, Newborn; Cells, Cultured; Disease Models, Animal; Endotoxins; Hepatocytes; Inflammation; Kupffer Cells; Lipopolysaccharides; Phytosterols; Soybean Oil; Swine

Although phytosterols, plant-derived sterol-like components, are well known for their cholesterol-lowering properties, their atherogenic potential is still under debate. Although they are known to share structural similarities with cholesterol, it is unclear whether their oxidized forms (oxyphytosterols) have the capacity to mediate proinflammatory responses in macrophages. In the present study, bone marrow-derived macrophages were treated with oxidized low-density lipoproteins, oxyphytosterols (7keto-sito/campesterol [7keto-sit/camp] or 7-beta-hydroxy-sito/campesterol [7βOH-sit/camp]), nonoxidized phytosterol (β-sitosterol), or carrier-control (cyclodextrin) in a dose- and time-dependent manner. Inflammatory cytokine release, activity, and the corresponding mRNA expression levels were analyzed. 7βOH-sit/camp, rather than 7keto-sit/camp, induced a modest proinflammatory response in wild-type cells derived from C57Bl/6 mice. The observed mild inflammatory effects are independent of the low-density lipoprotein receptor and Cluster of differentiation 36/Scavenger receptor-a. These data suggest that exogenously added oxyphytosterols do not affect macrophage-mediated inflammatory responses, at least in vitro.

Topics: Animals; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Phytosterols

Rice bran is a by-product of rice milling and is rich in bioactive molecules such as γ-oryzanol, phytosterols, and tocotrienols. The rice bran enzymatic extract (RBEE) previously showed vessel remodeling prevention and lipid-lowering, antioxidant, anti-inflammatory, and antiapoptotic activities. The aim of this study was to identify RBEE hypolipidemic mechanisms and to study the effects of RBEE on the progression of atherosclerosis disease and linked vascular dysfunction and liver steatosis in apolipoprotein E-knockout (ApoE-/-) mice fed low- or high-fat (LFD, HFD, respectively) and cholesterol diets.. ApoE-/- mice were fed LFD (13% kcal) or HFD (42% kcal) supplemented or not supplemented with 1 or 5% RBEE (w/w) for 23 wk. Then, serum, aorta, liver, and feces were collected and flash frozen for further analysis.. RBEE supplementation of HFD improved serum values by augmenting high-density lipoprotein cholesterol and preventing total cholesterol and aspartate aminotransferase increase. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was attenuated (1 and 5% RBEE) and cholesterol excretion increased (5% RBEE). Diet supplementation with 5% RBEE reduced plaque development regardless of the diet. In HFD-fed mice, both doses of RBEE reduced lipid deposition and macrophage infiltration in the aortic sinus and downregulated intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. None of these effects was observed in mice fed LFD. Liver steatosis was reduced by RBEE supplementation of LFD (1% RBEE) and HFD (1 and 5% RBEE) and nuclear peroxisome proliferator-activated receptor-α expression upregulated in the HDF 5% RBEE group.. Regular consumption of RBEE-supplemented HFD reduced plaque development and liver steatosis by decreasing inflammation and hyperlipidemia through an HMG-CoA reductase activity and lipid excretion-related mechanism.

Topics: Acyl Coenzyme A; Animals; Antioxidants; Aspartate Aminotransferases; Cholesterol, Dietary; Diet, High-Fat; Dietary Fiber; Dietary Supplements; Dose-Response Relationship, Drug; Fatty Liver; Inflammation; Intercellular Adhesion Molecule-1; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylpropionates; Phytosterols; Plant Extracts; Plaque, Atherosclerotic; PPAR alpha; Tocotrienols; Vascular Cell Adhesion Molecule-1

Parenteral plant sterols (PSs) are considered hepatotoxic; however, liver PSs and their associations with liver injury in patients with intestinal failure (IF) have not been reported.. We analyzed liver and serum PS (avenasterol, campesterol, sitosterol, and stigmasterol) concentrations and ratios to cholesterol and their associations with biochemical and histologic liver damage in children with IF during (n = 7) parenteral nutrition (PN) and after weaning off it (n = 9), including vegetable oil-based lipid emulsions.. Liver avenasterol, sitosterol, and total PS concentrations and cholesterol ratios were 2.4-fold to 5.6-fold higher in PN-dependent patients ( P < .05). Parenteral PS delivery reflected liver avenasterol and sitosterol ratios to cholesterol ( r = 0.83-0.89, P = .02-.04), while serum and liver total PS levels were positively interrelated ( r = 0.98, P < .01). Any liver histopathology was equally common while portal inflammation more frequent (57 vs 0%, P = .02) in PN-dependent patients. All liver PS fractions correlated positively with histologic portal inflammation ( r = 0.53-0.66, P < .05), and their total concentration was significantly ( P = .01) higher among patients with versus without portal inflammation. In PN-dependent patients, liver fibrosis and any histopathology correlated with liver campesterol and stigmasterol levels ( r = 0.79-0.87, P ≤ .03).. Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cholesterol; Female; gamma-Glutamyltransferase; Humans; Infant; Inflammation; Intestinal Diseases; Liver; Male; Parenteral Nutrition; Phytosterols; Plant Oils; Portal Vein; Sitosterols; Stigmasterol; Triglycerides

To assess whether an abnormality in cholesterol absorption or synthesis may be associated with hypocholesterolemia in patients with single ventricle anatomy following Fontan palliation.. This is a cross-sectional study of 21 patients with hypocholesterolemia following Fontan procedure and age/sex-matched healthy controls, with median age of 13.4 (IQR 10.6-16.1) years. Laboratory values of several biomarkers, including phytosterols and 5-α-cholestanol (for cholesterol absorption) and lathosterol (for cholesterol biosynthesis), as well as cholesterol levels, inflammatory markers, and indices of liver function were compared between patients following Fontan procedure and controls.. The Fontan cohort had significantly lower total cholesterol (mean 117 ± SD 13.9, vs 128 ± 19.2 mg/dL, P = .03) and free cholesterol (35.5 ± 4.5 vs 39.2 ± 5.4 mg/dL, P = .02) compared with control patients. There was an increase in normalized 5-α-cholestanol (1.51 ± 0.6 vs 1.14 ± 0.37 μg/mL, P = .02), and a significantly lower lathosterol/5-α-cholestanol ratio (0.70 ± 0.38 vs 1.11 ± 0.76, P = .04). There was a strong correlation (r = 0.78, P < .0001) between lathosterol and cholesterol levels in the Fontan cohort, not seen in controls (r = 0.47, P = .04). The Fontan cohort also had significantly higher C-reactive protein, transaminases, total bilirubin, and gamma-glutamyl transferase levels.. Patients with hypocholesterolemia following Fontan procedure have evidence of increased cholesterol absorption and decreased cholesterol synthesis. As cholesterol absorption efficiency is a regulated process, this finding suggests an upregulation of cholesterol absorption as a result of decreased cholesterol production. In the setting of elevated liver indices and possible inflammation, this finding supports a growing body of data suggesting development of liver disease in patients receiving Fontan.

Topics: Adolescent; Biomarkers; C-Reactive Protein; Child; Cholestanol; Cholesterol; Cholesterol, HDL; Cross-Sectional Studies; Female; Fontan Procedure; Humans; Hypolipoproteinemias; Inflammation; Liver; Liver Function Tests; Male; Phytosterols; Up-Regulation; Young Adult

Patients with cardiac sarcoidosis (CS) suffer from myocardial inflammation, but atherosclerosis is not infrequent in these patients. However, the classical atherosclerotic risk factors, such as perturbed serum lipids and whole-body cholesterol metabolism, remain unravelled in CS.. We assessed serum non-cholesterol sterols, biomarkers of whole-body cholesterol synthesis and cholesterol absorption efficiency, with gas-liquid chromatography in 39 patients with histologically verified CS and in an age-adjusted random population sample (n = 124).. CS was inactive or responding to treatment in all patients. Concentrations of serum, LDL, and HDL cholesterol and serum triglycerides were similar in CS patients and in control subjects. Cholesterol absorption markers were higher in CS patients than in controls (eg serum campesterol to cholesterol ratio in CS 246 ± 18 vs in controls 190 ± 8 10(2) x μmol/mmol of cholesterol, p = 0.001). Cholesterol synthesis markers were lower in CS patients than in controls (eg serum lathosterol to cholesterol ratio in CS 102 ± 8 vs in controls 195 ± 5 10(2) x μmol/mmol of cholesterol, p = 0.000). In CS patients, cholesterol absorption markers significantly correlated with plasma prohormone brain natriuretic peptide (proBNP), a marker of hemodynamic load.. High cholesterol absorption efficiency, which is suggested to be atherogenic, characterized the metabolic profile of cholesterol in CS patients. The association between cholesterol absorption efficiency and plasma proBNP concentration, which suggests a link between inflammation, cholesterol homeostasis, and hemodynamic load, warrants further studies in order to confirm this finding and to reveal the underlying mechanisms.

Topics: Adult; Aged; Atherosclerosis; Body Mass Index; Cardiomyopathies; Case-Control Studies; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet; Down-Regulation; Female; Finland; Heart Diseases; Hemodynamics; Homeostasis; Humans; Inflammation; Lipoproteins; Male; Middle Aged; Phytosterols; Risk Factors; Sarcoidosis; Sitosterols

In this study, we evaluated the effects of dietary plant sterols and stanols as their fatty acid esters on the development of experimental colitis. The effects were studied both in high- and low-fat diet conditions in two models, one acute and another chronic model of experimental colitis that resembles gene expression in human inflammatory bowel disease (IBD). In the first experiments in the high fat diet (HFD), we did not observe a beneficial effect of the addition of plant sterols and stanols on the development of acute dextran sulphate sodium (DSS) colitis. In the chronic CD4CD45RB T cell transfer colitis model, we mainly observed an effect of the presence of high fat on the development of colitis. In this HFD condition, the presence of plant sterol or stanol did not result in any additional effect. In the second experiments with low fat, we could clearly observe a beneficial effect of the addition of plant sterols on colitis parameters in the T cell transfer model, but not in the DSS model. This positive effect was related to the gender of the mice and on Treg presence in the colon. This suggests that especially dietary plant sterol esters may improve intestinal inflammation in a T cell dependent manner.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antigens, CD; Brassica rapa; Chronic Disease; Colitis; Colon; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Esters; Fatty Acids; Fatty Acids, Monounsaturated; Female; Inflammation; Inflammatory Bowel Diseases; Male; Mice, Inbred C57BL; Phytosterols; Phytotherapy; Plant Oils; Rapeseed Oil; Sitosterols; T-Lymphocytes

Lopezia racemosa Cav. is a plant used in Mexican traditional medicine to heal inflammatory diseases. From this plant we isolated the novel compound 6-O-palmitoyl- 3-O-β-D-glucopyranosylcampesterol (1) and 6-O-palmitoyl-3-O-β-D-glucopyranosyl-β-sitosterol (2), previously reported to have cytotoxic activity on several cancer cell lines. We evaluated the anti-inflammatory activity of 1 in vivo by mouse ear edema induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and 57.14% inhibition was observed. The aim of our study was to obtain callus cultures derived from this plant species with the ability to produce the compounds of interest. Callus cultures were initiated on MS basal medium amended with variable amounts of naphthaleneacetic acid (NAA), or 2,4-dichlorophenoxyacetic acid (2,4-D), combined or not with 6-benzylaminopurine (BAP). Ten treatments with these growth regulators were carried out, using in vitro germinated seedlings as source of three different explants: hypocotyl, stem node, and leaf. Highest yield of 1 was observed on callus derived from leaf explants growing in medium containing 1.0 mg/L 2,4-D and 0.5 mg/L BAP. Selected callus lines produced less 1 than wild plants but the in vitro cultured seedlings showed higher production. So we conclude that it could be attractive to further investigate their metabolic potential.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cholesterol; Ear; Edema; Germination; Inflammation; Male; Mice; Onagraceae; Phytochemicals; Phytosterols; Plant Extracts; Seeds; Tetradecanoylphorbol Acetate

The inflammatory component of non-alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.

Topics: Animals; Cholesterol; Desmosterol; Dietary Fats; Female; Humans; Inflammation; Liver; Macrophages; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Phytosterols

Four new compounds, including three new steroids (1-3) and one new sesquiterpene (6), and two new natural products (4-5), as well as three known steroids (7-9) were isolated from the twigs of Turraea pubescens. Compounds 3-5 are C₂₂ steroids isolated from the Meliaceae family for the first time. Their structures were elucidated by extensive NMR and MS analyses. Compound 1 exhibited inhibitory activity against lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW264.7 cells with an IC₅₀ value of 11.5 μM.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Inflammation; Inhibitory Concentration 50; Lipopolysaccharides; Meliaceae; Mice; Molecular Structure; Nitric Oxide; Phytosterols; Plant Extracts; Plant Stems; Sesquiterpenes

Dilated cardiomyopathy (DCM) in A/J mice homozygous for the spontaneous thrombocytopenia and cardiomyopathy (trac) mutation results from a single base pair change in the Abcg5 gene. A similar mutation in humans causes sitosterolemia with high plant sterol levels, hypercholesterolemia, and early onset atherosclerosis. Analyses of CD3+ and Mac-3+ cells and stainable collagen in hearts showed inflammation and myocyte degeneration in A/J-trac/trac mice beginning postweaning and progressed to marked dilative and fibrosing cardiomyopathy by 140 days. Transmission electron microscopy (TEM) demonstrated myocyte vacuoles consistent with swollen endoplasmic reticulum (ER). Myocytes with cytoplasmic glycogen and irregular actinomyosin filament bundles formed mature intercalated disks with normal myocytes suggesting myocyte repair. A/J-trac/trac mice fed lifelong phytosterol-free diets did not develop cardiomyopathy. BALB/cByJ-trac/trac mice had lesser inflammatory infiltrates and later onset DCM. BALB/cByJ-trac/trac mice changed from normal to phytosterol-free diets had lesser T cell infiltrates but persistent monocyte infiltrates and equivalent fibrosis to mice on normal diets. B- and T-cell-deficient BALB/cBy-Rag1(null) trac/trac mice fed normal diets did not develop inflammatory infiltrates or DCM. We conclude that the trac/trac mouse has many features of inflammatory DCM and that the reversibility of myocardial T cell infiltration provides a novel model for investigating the progression of myocardial fibrosis.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Cardiomyopathy, Dilated; Disease Models, Animal; Echocardiography; Female; Fibrosis; Histocytochemistry; Inflammation; Lipoproteins; Male; Mice; Mice, Transgenic; Microscopy, Electron; Monocytes; Myocardium; Myofibrils; Phytosterols; T-Lymphocytes

Evening Primrose oil is a natural product extracted by cold-pressed from Oenothera biennis L. seeds. The unsaponifiable matter of this oil is an important source of interesting minor compounds, like long-chain fatty alcohols, sterols and tocopherols. In the present study, sterols were isolated from the unsaponifiable matter of Evening Primrose oil, and the composition was identified and quantified by GC and GC-MS. The major components of sterols fraction were β-Sitosterol and campesterol. We investigated the ability of sterols from Evening Primrose oil to inhibit the release of different proinflammatory mediators in vitro by murine peritoneal macrophages stimulated with lipopolysaccharide. Sterols significantly and dose-dependently decreased nitric oxide production. Western blot analysis showed that nitric oxide reduction was a consequence of the inhibition of inducible nitric oxide synthetase expression. Sterols also reduced tumor necrosis factor-α, interleukine 1β and tromboxane B₂. However, sterols did not reduce prostaglandin E₂. The reduction of eicosanoid release was related to the inhibition of cyclooxygenase-2 expression. These results showed that sterols may have a protective effect on some mediators involved in inflammatory damage development, suggesting its potential value as a putative functional component of Evening Primrose oil.

Topics: Animals; Cholesterol; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Inflammation; Inflammation Mediators; Lipopolysaccharides; Macrophages; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Oenothera biennis; Phytosterols; Phytotherapy; Plant Oils; Seeds; Sitosterols

The aim of this study was to investigate the immunomodulatory and anti-inflammatory role of a mixture of phytosterols extracted from the microalga Dunaliella tertiolecta on peripheral blood mononuclear cells (PBMC) isolated from sheep. PBMC were treated to determine cell proliferation and cytokine production with different sterols: ergosterol (E), a mixture of eleven Algae sterols extracted and purified from D. tertiolecta (Algae Extract, AE), a mixture of ergosterol and 7-dehydroporiferasterol extracted and purified from D. tertiolecta (Purified Extract, PE). Cytokine production (TNF-α, IL-6, IL-1β, and IL-10) was evaluated after cell treatment with Concanavalin A (Con A) and lipopolysaccharide (LPS). The mixture of ergosterol and 7-dehydroporiferasterol extracted and purified from D. tertiolecta showed a suppressive effect on cell proliferation, and a reduction of pro-inflammatory cytokines production. Furthermore, a stimulatory effect on the production of the regulatory cytokine IL-10 was found. The immunosuppressive effect exerted by the mixture of ergosterol and 7-dehydroporiferasterol from D. tertiolecta was dose-dependent both in suppressing cell proliferation and in stimulating IL-10 production. Present results showed that the immunomodulatory and anti-inflammatory activities were more apparent in the purified extract characterized by the mixture of ergosterol and 7-dehydroporiferasterol, and might depend on the existence of a synergic effect of the structures of the two phytosterols. Furthermore, findings from our study suggest that the purified extract characterized by the mixture of ergosterol and 7-dehydroporiferasterol from D. tertiolecta could be used to reduce immune reactions resulting from inflammatory diseases in sheep production systems, and could have innovative implications on the modulation of sheep immune system when used as feed supplements.

Topics: Animals; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gas Chromatography-Mass Spectrometry; Inflammation; Leukocytes, Mononuclear; Microalgae; Phytosterols; Sheep

Using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), the objective of this study was to examine the effect of phytosterol (PS) administration on inflammation-based EAE development.. Female SJL mice were orally administered PS prior to disease induction and maintained throughout the experiment. EAE was induced with antigenic peptide (PLP(131-155)). Mice were clinically scored for disease and euthanized for biochemical and histological analysis of inflammation.. PS delayed onset of EAE development by 2 days and decreased disease severity by 55%. Brain histological analysis revealed an 82% decrease in central nervous system (CNS) inflammatory infiltration and a 48% decrease in demyelination in PS-treated mice versus control. Immunohistochemistry (IHC) showed a 35% reduction in macrophages entering brains of PS-treated mice. Anti-inflammatory interleukin (IL)-10 was up-regulated by 10%, while pro-inflammatory CCL2 was inhibited by 50% with PS treatment. Additionally, PS slightly decreased other pro-inflammatory factors, such as tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ.. PS protects against development of EAE by reducing infiltration and inflammatory activity of immune cells into CNS of treated mice, thereby decreasing demyelination associated with EAE. These results provide evidence to support PS as a preventative agent that helps to protect against the development of inflammation-driven disease, such as MS.

Topics: Animal Feed; Animals; Brain; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Female; Immunohistochemistry; Inflammation; Lymphocytes; Macrophages; Mice; Multiple Sclerosis; Peptides; Phytosterols; Time Factors

Although most studies have focused on the cholesterol-lowering activity of phytosterols, other biological actions have been ascribed to these plant sterol compounds, one of which is a potential immune modulatory effect. To gain insight into this issue, we used a mouse model of acute, aseptic inflammation induced by a single subcutaneous turpentine injection. Hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) mice, fed with or without a 2% phytosterol supplement, were treated with turpentine or saline and euthanized 48 h later. No differences were observed in spleen lymphocyte subsets between phytosterol- and control-fed apoE(-/-) mice. However, cultured spleen lymphocytes of apoE(-/-) mice fed with phytosterols and treated with turpentine showed increased IL-2 and IFN-gamma secretion (T-helper type1, Th1 lymphocyte cytokines) compared with turpentine-treated, control-fed animals. In contrast, there was no change in Th2 cytokines IL-4 and IL-10. Phytosterols also inhibit intestinal cholesterol absorption in wild-type C57BL/6J mice but, in this case, without decreasing plasma cholesterol. Spleen lymphocytes of turpentine-treated C57BL/6J mice fed with phytosterols also showed increased IL-2 production, but IFN-gamma, IL-4 and IL-10 production was unchanged. The Th1/Th2 ratio was significantly increased both in phytosterol-fed apoE(-/-) and C57BL/6J mice. We conclude that phytosterols modulate the T-helper immune response in vivo, in part independently of their hypocholesterolemic effect in a setting of acute, aseptic inflammation. Further study of phytosterol effects on immune-based diseases characterized by an exacerbated Th2 response is thus of interest.

Topics: Analysis of Variance; Animals; Apolipoproteins E; Cholesterol; Dietary Supplements; Flow Cytometry; Fluorescent Antibody Technique; Immunity, Cellular; Inflammation; Interferon-gamma; Interleukin-2; Mice; Mice, Inbred C57BL; Mice, Knockout; Phytosterols; Th1 Cells; Turpentine

Eryngium foetidum L. (Apiaceae) is a Caribbean endemic plant, used in folk medicine for the treatment of several antiinflammatory disorders. A preliminary phytochemical study showed that the hexane extract is rich in terpenic compounds. Chromatographic fractionation of this extract yielded: alpha-cholesterol, brassicasterol, campesterol, stigmasterol (as the main component, 95%) clerosterol, beta-sitosterol, delta 5-avenasterol, delta (5)24-stigmastadienol and delta 7-avenasterol. The topical antiinflammatory activity of the hexane extract and of stigmasterol was evaluated by auricular oedema, induced by 12-0-tetradecanoylphorbol acetate (TPA), in the mouse, using single and multiple applications of the phlogistic agent. Both reduced the oedema in a similar proportion in the two model assays (acute and chronic). Meloperoxidase activity was strongly reduced by both the extract and the compound, in the acute but not the chronic model. These results indicate that the leaves of Eryngium foetidum L may be effective against topical inflammation processes. Stigmasterol also exerts a significant topical antiinflammatory activity although it cannot be considered to be a major antiinflammatory agent, therefore other bioactive components are probably involved in the activity of the hexane extract.

Topics: Acute Disease; Administration, Topical; Animals; Anti-Inflammatory Agents; Caribbean Region; Chronic Disease; Edema; Female; Inflammation; Mice; Peroxidase; Phytosterols; Plants, Medicinal; Tetradecanoylphorbol Acetate

The oxygenated stigmastane-type sterols stigmastane-3 beta, 6 alpha-diol, stigmastane-3 beta, 6 beta-diol, 7 alpha-hydroxysitosterol and its diacetyl derivative, 7 beta-hydroxysitosterol and its diacetyl derivative, 7-oxositosterol, 4 beta-hydroxysitosterol, and stigmast-4-ene-3 beta, 6 beta-diol were evaluated with respect to their anti-inflammatory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice. All of the sterols, with the exception of 7 alpha-hydroxysitosterol and its diacetyl derivative, were found to possess marked inhibitory activity. The 50% inhibitory dose of these compounds for TPA-inflammation (1 microgram) was 0.5--1.0 mg/ear.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Ear, External; Edema; Female; Inflammation; Mice; Mice, Inbred ICR; Phytosterols; Tetradecanoylphorbol Acetate

Topics: Administration, Oral; Adolescent; Adult; Capsules; Drug Combinations; Drug Evaluation; Female; Humans; Inflammation; Male; Middle Aged; Periodontal Diseases; Periodontal Index; Phytosterols; Plant Extracts; Vitamin E