Role of Phytosterols in Cancer Prevention and Treatment.

Plant sterols or phytosterols have been shown to be effective in improving blood lipid profile and thereby protective against cardiovascular disease. In addition to their cardioprotective effects, phytosterols have gained more insight for their protective effect against various forms of cancer. Phytosterols have been reported to alleviate cancers of breast, prostate, lung, liver, stomach and ovary. Reductions in growth of various cancer cells including liver, prostate and breast by phytosterols treatment have been demonstrated. Although exact mechanisms of phytosterols for their anticancer effects are not very well delineated, there have been several mechanisms proposed such as inhibition of carcinogen production, cancer cell growth and multiplication, invasion and metastasis and induction of cell cycle arrest and apoptosis. Other mechanisms including reduction of angiogenesis, invasion and adhesion of cancer cells and production of reactive oxygen species have also been suggested. However, cancer therapy using phytosterol formulations have yet to be designed, largely due to the gap in the literature with regards to mode of action. Furthermore, most of the studies on anticancer effects of phytosterols were conducted in vitro and animal studies and need to be confirmed in humans.

L-arginine and nitric oxide in CNS function and neurodegenerative diseases.

One of the main functions of L-arginine (ARG) is the synthesis of nitric oxide (NO). NO is an important regulator of physiological processes in the central nervous system (CNS). NO promotes optimal cerebral blood flow, consolidates memory processes, facilitates long-term potentiation, maintains sleep-wake cycles, and assists in normal olfaction. However, at pathological levels, NO adversely affects brain function producing nitroxidative stress and promoting development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and other disorders of the CNS. This review summarizes current knowledge of the role of NO in the CNS and the role of diet in regulating the levels of NO.

Vitamin D and multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system and characterized by neurological and cognitive manifestations. The disease is more common in populations living in high altitudes with low sun exposure, women more than men, and certain ethnic backgrounds more than others. The etiology of MS is yet unknown, although several factors have been implicated in its development. These include genetic factors and environmental factors as well as dietary components and their interactions. Among the dietary components that have recently attracted the attention is vitamin D. This mini-review summarizes current knowledge on the potential use of vitamin D in the protection and treatment of MS. In addition, the mechanism(s) by which vitamin D plays a role in the development and/or protection from MS are discussed.

Statin therapy depresses fat metabolism in older individuals.

OBJECTIVE: Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase inhibitors) reduce blood lipoproteins and reduce the risk of cardiovascular events. However, they may reduce fat metabolism. This study tested the hypothesis that total body fat oxidation is reduced by statins in older subjects and the reduction is not due to substrate availability. METHODS: A total of 14 elderly patients (71 ± 6 years) on statin therapy were compared with 14 matched elderly controls (75 ± 7 years). Subjects were tested for respiratory exchange ratio (RER) during both maximal and submaximal sustained (70% Vo(2max)) exercise to voluntary exhaustion. Blood samples were drawn for lipoprotein analysis and substrate availability. RESULTS: RER was significantly higher in subjects taking statins during both the max and submax tests, indicating reduced fat oxidation. Blood lipoprotein levels after a fast were not different between the statin and control groups. Levels of glucose, lactate, or triglyceride were not different between groups; however, free fatty acid levels were elevated by exercise in the statin group. Fat oxidation was significantly reduced in older subjects taking statin drugs that were not associated with diet, exercise, and fitness, which were matched between groups, nor availability of fat from the blood, which was higher in the statin group. CONCLUSION: Although statin therapy normalizes blood lipoproteins, it reduced fat metabolism in older individuals, which cannot be a result of lower availability from blood.

Regulatory approval of plant sterols in Canada: implications for health care and clinical practice.

Health Canada's recent approval of plant sterols as food ingredients to decrease low-density lipoprotein cholesterol (LDL-C) is believed to be a significant step toward improving Canadians' cardiovascular health and reducing the economic burden of heart disease. When dyslipidemic patients consume plant sterols at a recommended daily dose of 2 g, they can reduce LDL-C by 10% to 15%, with no deleterious effects on high-density lipoprotein cholesterol. A 10% LDL-C reduction in response to plant sterol consumption is projected to reduce heart disease risk by 25%. Because they are available without a prescription, plant sterols are an option for dietitians who wish to provide cholesterol-lowering guidance beyond traditional dietary advice (i.e., lowering saturated fat intake and restricting dietary cholesterol). In addition, plant sterols can be used in combination with a statin or when statin use is contraindicated, and they have recently emerged as a potentially valuable triglyceride-lowering option. However, the projected improvement in public health and health care savings will be realized only if impediments to daily use are removed. One such impediment is the higher cost of fortified food products, such as yogurt and margarine. If the cost of plant sterol food products is to decline, cost-effective sources must be investigated and a larger range of foods containing plant sterols must be made available.

Vitamin d and metabolic syndrome risk factors: evidence and mechanisms.

The metabolic syndrome develops in an individual with any three of the following risk factors: obesity, diabetes, inflammation, hypertension, dyslipidemia, and thrombosis. Recent evidence suggests that vitamin D may play a role in the development of some of these risk factors. The metabolic syndrome is more common in western societies than the underdeveloped countries. Individuals in western societies usually consume a high calorie diet that lacks essential nutrients and, by virtue of being located in the northern hemisphere, they have limited sun exposures which restrict their vitamin D synthesis. Moreover, the lifestyle of these societies is considered sedentary. These dietary and environmental factors coupled with the sedentary lifestyle predispose them to metabolic syndrome risk factors. Active research revealed the role of vitamin D in the development of obesity, diabetes, inflammation, and hypertension. On the other hand, limited research has been done on the role of vitamin D in other risk factors such as dyslipidemia and thrombosis. The scientific community proposes to increase the current vitamin D fortification level in foods to reduce the risk factors of the metabolic syndrome.

ß-Sitosterol down-regulates some pro-inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase SHP-1 in J774A.1 murine macrophages.

The objective of the present study was to examine the anti-inflammatory effects of ß-sitosterol (SIT), the most common phytosterol in the diet, and to investigate its involvement in NF-κB and STAT1 pathways as potential mechanisms. In addition, the activity of the phosphatase SHP-1 as a negative modulator to these pathways, was investigated. Utilizing murine J774A.1 macrophages, cells were treated with various physiological concentrations of SIT and stimulated with LPS (100 ng/ml) for 6h. Results indicate that 1 and 16 µM SITs increased SHP-1 activity by 300% and 200%, respectively. Similar results were obtained using western blot analysis. Additionally, we observed reductions in the release of some pro-inflammatory cytokines and chemokines as well as an increase in anti-inflammatory IL-10 with SIT treatments. The results also demonstrate the inhibition of STAT1 with SIT treatment. Moreover, translocation of NF-κB to the nucleus was inhibited with SIT as indicated by decreased phosphorylation and the use of ImageStream cytometry. In conclusion, the present study demonstrates the anti-inflammatory effect on macrophages by inactivating STAT1 and NF-κB, which could be mediated by the activation of SHP-1.

Phytosterols ameliorate clinical manifestations and inflammation in experimental autoimmune encephalomyelitis.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Curcumin and obesity: evidence and mechanisms.

The incidence of obesity is increasing worldwide and is hence considered a major public health concern. Obesity underlies the development of several metabolic complications including cardiovascular diseases, diabetes, and inflammation. Research on ways to slow the development of obesity have traditionally focused on dietary and lifestyle modifications such as restricting caloric intake and increasing physical activity. An area that has recently aroused considerable research interest is investigating the potential role of spices, particularly the Asian spice turmeric, for combating obesity. Curcumin is the active ingredient in turmeric. Evidence suggests curcumin may regulate lipid metabolism, which plays a central role in the development of obesity and its complications. The present review addresses the evidence and mechanisms by which curcumin may play a role in downregulating obesity and reducing the impact of associated problems.

Modulation of signal transduction in cancer cells by phytosterols.

Phytosterols are biofactors found enriched in plant foods such as seeds, grains, and legumes. Their dietary consumption is associated with numerous health benefits. Epidemiologic and experimental animal studies indicate that phytosterols are cancer chemopreventive agents particularly against cancers of the colon, breast, and prostate. Phytosterols impede oncogenesis and prevent cancer cell proliferation and survival. The molecular mechanisms underlying these beneficial actions involve effects on signal transduction processes which regulate cell growth and apoptosis. Phytosterols increase sphingomyelin turnover, ceramide formation, and liver X receptor activation. In concert, these actions slow cell cycle progression, inhibit cell proliferation, and activate caspase cascades and apoptosis in cancer cells.

Effect of vitamin D and ß-sitosterol on immune function of macrophages.

Among the many functions of vitamin D (VD) is its role in the immunomodulation of macrophage. As VD deficiency is a wide-spread nutritional problem, there is a tendency for the public to overdose with vitamin D supplementation which can result in hypercalcemia and several associated disorders. The present study was designed to investigate the possibility that combining low doses of vitamin D with ß-sitosterol (SIT), a common phytosterol in the diet without toxicity, enhances the efficacy of the vitamin. Murine macrophages were stimulated with LPS and supplemented with VD3 (80 nM) and SIT (8 µM) for 24 hr and examined for cell proliferation, release of nitric oxide (NO) and cytokines and the activation of NFκB. SIT (8 µM) was found to reduce cell proliferation by 62% while VD3 was found to be not effective. In combination, SIT and VD3 reduced cell proliferation by 75%.The amount of NO released, as influenced by 8 µM SIT or 80 nM VD3 treatments, was not significantly different from control. Combining SIT and VD3, resulted in a 220% greater increase in NO release compared to control. The SIT + VD3 treatment brought about significant increase in all the cytokine release, regardless of whether they were pro- or anti-inflammatory. The effects were either additive or synergistic. We conclude that SIT enhances the action of VD3 on the immune function of macrophages which could be beneficial to vitamin D deficient individuals and to those with autoimmune diseases such as multiple sclerosis.

Comparison of the immunomodulatory effects of the plant sterol beta-sitosterol to simvastatin in peripheral blood cells from multiple sclerosis patients.

Statins as hypocholesterolimic drugs have recently shown to have ant-inflammatory properties and thus are being assessed for the treatment of multiple sclerosis (MS). Dietary phytosterols such as beta-sitosterol (SIT) are also hypocholesterolemic compounds and from preliminary studies they appear to have also anti-inflammatory properties. In this communication, we report on studies to investigate the immunomodulatory effects of SIT on proliferation and release of key cytokines from peripheral blood mononuclear cells (PBMC) of MS patients. In PBMC of MS patients, 16 microM SIT had no effect on cell proliferation; however simvastatin (SV) at 10 and 20 microM reduced cell proliferation by as much as 60%. SIT (4 microM) reduced TNF-alpha release by 24% in PBMC of MS patients whereas 10 microM SV reduced TNF-alpha release by 94%. SIT reduced IL-12 release in MS patients at 4 and 16 microM by 27% and 30%, respectively. In healthy subjects, 16 microM SIT increased the anti-inflammatory cytokine IL-10 by 47% whereas 10 microM SV decreased IL-10 by 30%. In PBMC of MS patients, SIT had no effect on IL-10 release whereas 10 microM SV reduced IL-10 by 62%. SIT (4 microM) reduced IL-5 release by 47% in MS patients while 10 microM SV reduced IL-5 by 89%. The results show that SIT is effective in modulating the secretion of pro/anti-inflammatory cytokines and suggest a potential beneficial effect of SIT in MS management without the side effects associated with statin therapy.

beta-Sitosterol enhances tamoxifen effectiveness on breast cancer cells by affecting ceramide metabolism.

The objective of this study was to investigate the effects of the dietary phytosterol beta-sitosterol (SIT) and the antiestrogen drug tamoxifen (TAM) on cell growth and ceramide (CER) metabolism in MCF-7 and MDA-MB-231 human breast cancer cells. The MCF-7 and MDA-MB-231 cell lines were studied as models of estrogen receptor positive and estrogen receptor negative breast cancer cells. Growth of both cell lines as determined using the sulforhodamine B assay was inhibited by treatment with 16 microM SIT but only MCF-7 cell growth was inhibited by treatment with 1 microM TAM. The combination of SIT and TAM further inhibited growth in both cell lines, most significantly in MDA-MB-231 cells. CER is a proapoptotic signal and CER levels were increased in both MCF-7 and MDA-MB-231 cells by individual treatment with SIT and TAM and the combined treatment raised cellular CER content even further. SIT and TAM raised CER levels by different means. SIT potently activated de novo CER synthesis in both MCF-7 and MDA-MB-231 cells by stimulating serine palmitoyltransferase activity; whereas TAM promoted CER accumulation in both cell types by inhibiting CER glycosylation. These results suggest that the combination regimen of dietary SIT and TAM chemotherapy may be beneficial in the management of breast cancer patients.

Phytosterols as anticancer compounds.

Phytochemicals have been proposed to offer protection against a variety of chronic ailments including cardiovascular diseases, obesity, diabetes, and cancer. As for cancer protection, it has been estimated that diets rich in phytochemicals can significantly reduce cancer risk by as much as 20%. Phytosterols are specific phytochemicals that resemble cholesterol in structure but are found exclusively in plants. Phytosterols are absorbed from the diet in small but significant amounts. Epidemiological data suggest that the phytosterol content of the diet is associated with a reduction in common cancers including cancers of the colon, breast, and prostate. The means by which dietary phytosterols may be achieving these effects is becoming clearer from molecular studies with tumorigenic research models. Phytosterols affect host systems potentially enabling more robust antitumor responses, including the boosting of immune recognition of cancer, influencing hormonal dependent growth of endocrine tumors, and altering sterol biosynthesis. In addition, phytosterols have effects that directly inhibit tumor growth, including the slowing of cell cycle progression, the induction of apoptosis, and the inhibition of tumor metastasis. This review summarizes the current state of knowledge regarding the anticancer effects of phytosterols.

Effects of different phytosterol analogs on colonic mucosal cell proliferation in hamsters.

OBJECTIVE: The aim of this study was to investigate the effects of different phytosterols and their analogs on colonic mucosal cell proliferation in hamsters. METHOD: Hamsters (n=70) were randomly assigned to seven groups after a 2-week acclimation and fed the experimental diet for 5 weeks. Diets included (i) the semipurified diet with no cholesterol (Con), (ii) the Con diet plus 0.25% cholesterol (Ch-con), or the Ch-con diet with (iii) 1% phytosterols (Ste), (iv) 1% phytostanols (Sta), (v) 1.76% sterol esters (esterified to fish oil, SteF), (vi) 0.71% stanol esters (esterified to ascorbic acid [disodium ascorbyl phytostanol phosphate, FM-VP4], 0.7% StaA) and (vii) 1.43% stanol esters (1.4% StaA), respectively. After 5 weeks on experimental diet, hamsters were sacrificed, and colons were collected. Colonic mucosal cell proliferation was measured by immunohistochemistry using monoclonal antibodies against antigen Ki-67. RESULTS: Colonic mucosal cell proliferation was 21.4% (P<.01) lower in the 0.7%, but not 1.4%, StaA relative to the Ch-con group. In addition, a lower (-13.9%) cell proliferation was observed in the SteF group in comparison to the Ch-con group; however, this difference achieved only a borderline level of statistical significance (P=.069). No differences were observed between Con and Ch-con, as well as among Ste, Sta, 1.4% StaA and Ch-con treatments. CONCLUSION: Plant stanols esterified to ascorbic acid may possess anticarcinogenic properties in the colon by suppressing colonic mucosa cell proliferation; however, this effect was not observed with free plant sterols or stanols.

Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients.

OBJECTIVES: To determine whether a low fat diet supplemented with omega-3 positively affects quality of life (QOL) in relapsing-remitting MS (RRMS) patients. In this 1-year long double-blind, randomized trial, patients were randomized to two dietary interventions: the "Fish Oil" (FO) group received a low fat diet (15% fat) with omega-3 FOs and the "Olive Oil" (OO) group received the AHA Step I diet (fat 30%) with OO supplements. The primary outcome measure was the Physical Components Summary Scale (PCS) of the Short Health Status Questionnaire (SF-36). Additional measures using MS specific QOL questionnaires, neurological status and relapse rate were obtained. RESULTS: 31 RRMS patients were enrolled, with mean follow up over 11 +/- SD 2.9 months. Clinical benefits favoring the FO group were observed on PCS/SF-36 (P = 0.050) and MHI (P = 0.050) at 6 months. Reduced fatigue was seen on the OO diet at 6 months (P = 0.035). The relapse rate decreased in both groups relative to the rates during the 1 year preceding the study: mean change in relapse rate in the FO group: -0.79 +/- SD 1.12 relapses/year (P = 0.021) vs. -0.69 +/- SD 1.11 (P = 0.044) in the OO group. This study suggests that a low fat diet supplemented with omega-3 PUFA can have moderate benefits in RRMS patients on concurrent disease modifying therapies.

beta-Sitosterol stimulates ceramide metabolism in differentiated Caco2 cells.

Previous studies from our laboratory on tumor cells suggest that phytosterols stimulate ceramide production, which was associated with cell growth inhibition and stimulation of apoptosis. The objective of the present study was to examine the effect of phytosterols on ceramide metabolism in small intestinal cells that represent the first cells in contact with dietary phytosterols. Caco(2) cells, an accepted model for human intestinal epithelial cells, were used in this study. Ceramide and ceramide-containing lipids were examined by labeling the ceramide pool with (3)H-serine. Cells were supplemented with 16 microM of sterols (cholesterol, beta-sitosterol or campesterol) for 16 days postconfluence and continued to differentiate. Of the two phytosterols, beta-sitosterol, but not campesterol, induced more than double the serine labeling when compared with cholesterol. This increase was uniform in sphingomyelin (SM), ceramide and sphingosine labeling. Sterols had no effect on SM concentration in the cells. In addition, sterol had no effect on the activity of SM synthase or sphingomyelinases. There was an inhibition of ceramidases with campesterol supplementation. These data suggest that the observed increases in SM and sphingosine labeling were due to an increase in ceramide turnover. The increase in ceramide turnover with beta-sitosterol supplementation was not associated with growth inhibition but was with increases in ceramide glycosylation products such as cerebrosides and gangliosides. It was concluded that beta-sitosterol has no effect on differential Caco(2), a model of normal small intestinal cells. The increase in the glycosylated ceramide products may offer a means to protect the cells from the harmful effect of ceramide by excreting them with lipoproteins.

Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells.

The objective of this project was to identify some possible mechanisms by which two common phytochemicals, resveratrol and beta-sitosterol, inhibit the growth of human prostate cancer PC-3 cells. These mechanisms include the effect of the phytochemicals on apoptosis, cell cycle progression, prostaglandin synthesis and the production of reactive oxygen species (ROS). Prostaglandins have been known to play a role in regulating cell growth and apoptosis. PC-3 cells were supplemented with 50 microM resveratrol or 16 microM beta-sitosterol alone or in combination for up to 5 days. Phytochemical supplementation resulted in inhibition in cell growth. beta-Sitosterol was more potent than resveratrol and the combination of the two resulted in greater inhibition than supplementation with either alone. Long-term supplementation with resveratrol or beta-sitosterol elevated basal prostaglandin release but beta-sitosterol was much more potent than resveratrol in this regard. beta-Sitosterol was more effective than resveratrol in inducing apoptosis and the combination had an intermediate effect after 1 day of supplementation. Cells supplemented with resveratrol were arrested at the G1 phase and at the G2/M phase in the case of beta-sitosterol while the combination resulted in cell arrest at the two phases of the cell cycle. beta-Sitosterol increased ROS production while resveratrol decreased ROS production. The combination of the two phytochemicals resulted in an intermediate level of ROS. The observed changes in prostaglandin levels and ROS production by these two phytochemicals may suggest their mediation in the growth inhibition. The reduction in ROS level and increase by resveratrol supplementation in PC-3 cells reflects the antioxidant properties of resveratrol. It was concluded that these phytochemicals may induce the inhibition of tumor growth by stimulating apoptosis and arresting cells at different locations in the cell cycle and the mechanism may involve alterations in ROS and prostaglandin production.

Effect of dietary fat intake and exercise on inflammatory mediators of the immune system in sedentary men and women.

OBJECTIVE: Dietary fat intake and exercise affect the immune system. This study determined the changes in inflammatory components of the immune system in response to maximal exercise with three levels of dietary fat intake: 19%, 30%, and 50% of total calories. METHODS: Five men and six women were randomly assigned to consume diets with 19% and 50% calories from fat for three weeks each, with a one-week washout. The habitual and washout diets were 30% calories from fat. At the beginning and the end of each diet, body composition and maximal exercise tests were performed. Blood samples were collected before and after exercise to determine the immunological parameters. RESULTS: The subject's energy intake was balanced to expenditure on the 30% and 50% diets, but was in negative balance on the 19% diet. Exercise led to significant increases in the concentrations of leukocytes, neutrophils, lymphocytes, monocytes, plasma tumour necrosis factor (TNF)-alpha, plasma interleukin (IL)-2, plasma soluble vascular cell adhesion molecule (sVCAM)-1, and the production of IL-1beta and IL-6 by peripheral blood mononuclear (PBMN) cells stimulated with lipopolysaccharide (LPS), irrespective of diets (p < 0.05). The 19% fat diet resulted in increased plasma soluble intercellular adhesion molecule (sICAM)-1 after exercise. Leukotriene (LT) B4 concentration released by neutrophils stimulated with LPS was higher in the 50% fat diet, compared to the lower fat diets, and the sICAM-1 production of neutrophils stimulated with LPS was significantly increased after exercise only with 30% fat diet. CONCLUSION: While a short, intense bout of exercise increased pro-inflammatory mediators of the immune system, decreasing fat intake to 19% on a caloric deficient diet caused a greater increase in plasma TNF-alpha, sVCAM-1 and sICAM-1 concentration than the 30% and 50% fat diets in male and female subjects. Increasing fat calories to 50% with caloric balance did not exacerbate pro-inflammatory mediators compared to a 30% fat diet.

Combination of phytosterols and omega-3 fatty acids: a potential strategy to promote cardiovascular health.

Phytosterols and omega-3 fatty acids (n-3) are natural food ingredients with potential cardiovascular benefits. Phytosterols inhibit cholesterol absorption, thereby reducing total cholesterol (TC) and LDL-cholesterol levels. Numerous clinical studies have shown that a daily intake of 1.5-2.0 g of phytosterols can result in a 10-15 % reduction in LDL levels, while consumption of n-3 is associated with a significant reduction in plasma triglyceride (TG) concentrations. Furthermore, n-3 may also beneficially modify a number of other risk factors of coronary heart disease (CHD). Thus, it is reasonable to suggest that combination of phytosterols and n-3 may further reduce cardiovascular risk factors. Esterification of phytosterols with non-n-3 fatty acids has substantially improved their incorporation into a variety of foods without affecting the efficacy of phytosterols. Therefore, it is assumed that esterification of phytosterols with n-3 may have advantages for both food industry and health. Evidence suggests that this combination is effective in reducing the levels of several cardiovascular risk factors including TC and TG concentrations, pro-aggregatory factors, arrhythmic eicosanoid and thromboxane A2 levels. In this mini-review, we have critically reviewed and summarized data from clinical and animal studies in which phytosterols and n-3, alone or in combination, were used. We have also provided information on structure-function relationship for these two natural compounds. Biological properties of several phytosterol derivatives including phytosterol-glucoside have been also discussed. Although the animal studies are supportive of this combination therapy, human studies are needed to address its long term effects.