- What is beta sitosterol
- Beta sitosterol benefits
- Beta sitosterol prostate
- Beta sitosterol hair loss
- Antihyperlipidemic and Anti-Atherosclerosis Effects
- Central Nervous System
- Cardiovascular System
- Endocrine System
- Reproductive System
- Wound Healing
- Antioxidant Activity
- Angiogenic Effect
- Antipyretic Activity
- Anti-Inflammatory Activity
- Anti-Arthritic Activity
- Immune Modulation and Anti-HIV Effect
- Anti-Cancer Effect
- Anti-Diabetic Effect
- Anti-Pulmonary Tuberculosis Effect
- Antimicrobial Activity
- Beta sitosterol foods
- Beta sitosterol supplement
- Beta sitosterol side effects
- Beta sitosterol benefits
What is beta sitosterol
Beta-sitosterol (24-ethylcholesterol) is a phytosterol with a chemical structure similar to that of cholesterol 1), widely distributed throughout the plant kingdom and known to be involved in the stabilization of cell membranes. Beta-sitosterol is a natural micronutrient in higher plants and is found in the serum and tissues of healthy individuals at a concentration 800–1000 times lower than that of endogenous cholesterol 2). Beta-sitosterol glycoside, sitosterolin, is also present in serum, but in lower concentration 3). Beta-sitosterol molecules are synthesized in plants; whereas animals obtain them through diet 4). Beta sitosterol could be obtained from different plants, but the total biosynthetic pathway, as well as its exact physiological and structural function in plants, have not been fully understood 5).
Beta sitosterol benefits
Beta sitosterol prostate
Five hundred nineteen men from four randomized, placebo‐controlled, double‐blind trials, (lasting 4 to 26 weeks) were assessed 6). Three trials used non‐glucosidic B‐sitosterols and one utilized a preparation that contained 100% B‐sitosteryl‐B‐D‐glucoside. This 1999 Cochrane review found that beta‐sitosterol treatments were well tolerated and improved urinary symptoms and flow measures in men with mild to moderate benign prostatic hyperplasia (nonmalignant enlargement of the prostate). Furthermore, the review authors added that more research into long‐term effects of beta‐sitosterols is needed 7).
Beta sitosterol hair loss
The results of this pilot study in the treatment of hair loss in men (androgenetic alopecia) 8) showed a positive response to treatment. The blinded investigative staff assessment report showed that 60% of (6/10) study subjects dosed with the active study formulation were rated as improved at the final visit. Apart from that small pilot study, there is still no long-term convincing result regarding the efficacy of beta sitosterol against alopecia or hair loss in men.
Antihyperlipidemic and Anti-Atherosclerosis Effects
Beta sitosterol is recommended for the prevention of different cardiovascular diseases 9) and the FDA has approved beta sitosterol for the treatment of hyperlipidemia 10). It prevents the absorption of cholesterol by displacing it from micelles 11) and thereby decreasing the amount in plasma 12). In combination with other statins, it increases the potency of those statins 13). Still further studies are required to resolve existing debate regarding its role in treating hypercholesterolaemia 14). Study regarding the role of beta sitosterol on the upregulation of paraoxonase-2 needs to be conducted in order to substantiate the claim made by Rosenblat et al. 15) regarding the beneficial effect of simvastatin in combination with beta sitosterol. beta sitosterol has also been related to sitosterolemia but not as a causal agent for the development of coronary heart disease in sitosterolemic patients 16). Further experimental evidence is required.
Central Nervous System
Beta sitosterol containing plants show antinociceptive 17), anxiolytic, and sedative effects 18) in rats, but such findings in humans are not available. Neither the brain region nor the pathway affected by beta sitosterol has been studied extensively yet. It has been shown that the effect of beta sitosterol is somewhat similar to diazepam but whether the mechanism of action is similar or not has not been studied 19). It has been proposed that beta sitosterol is effectual by interacting with GABAA receptor, but there is no confirmatory evidence for this claim 20). beta sitosterol has been shown to potentiate the binding of other compounds to muscarinic receptors 21). However, whether or not beta sitosterol binds to the muscarinic receptor itself is not known. Studies in immortalized mouse hippocampal cell line HT22 showed that beta sitosterol prevents oxidative damage and neurotoxicity 22) and a series of other studies showed the beneficial effect in preventing neuronal damage 23). There is evidence that beta sitosterol crosses the blood brain barrier (BBB), but fundamental studies regarding the efficacy and efficiency of beta sitosterol to cross blood brain barrier have not been undertaken. A comparative study has been done with other phytosterols like campesterol and sitosterol to check the efficiency in passing the brain endothelial monolayer where the reason behind the irreversible passage of the plant sterols across the endothelial monolayer was found to be the molecular complexity of the sterol side chain. A possible explanation for the difference of phytosterols in passing the blood brain barrier may be the different esterification rate within the endothelial cells 24). Recent studies have shown that beta sitosterol alone 25) or as extract 26) increases neural stem cell proliferation. However, further studies are recommended for potential applications in tissue engineering.
According to the Norwegian Food Safety Authority (Mattilsynet, NFSA, Oslo, Norway), beta sitosterol has a skin conditioning effect and is used in sunscreen, moisturizer, body wash, and anti-aging cosmetic preparations. Skin is one of the paths of beta sitosterol excretion. It has been reported that beta sitosterol inhibits the production and mRNA expression of thymic stromal lymphopoietin through blocking of caspase-1 and nuclear factor-kB (NkB) signal pathways in the stimulated human mast cell line, HMC-1 cells. Even though this study showed the potential therapeutic effect against atopic dermatitis, studies on long-term use of beta sitosterol on the skin need to be conducted 27).
Beta sitosterol has beneficial effects on the cardiovascular system and prevents different cardiovascular diseases except for patients with ABCG5 and ABCG8 mutation 28). However, there is no study regarding its effects on cells within the heart: the cardiomyocytes and the cardiac pacemaker cells. Although some studies point to the possibility that elevated plasma phytosterol concentrations could contribute to the development of premature coronary artery diseases, extensive safety evaluation studies have been conducted for these compounds, and they are considered safe 29).
Beta sitosterol containing diets change the live ultra-structure and such differences are observed in both young and adult mice fed with beta sitosterol 30). Pathophysiology of the liver is also affected by beta sitosterol. For example, beta sitosterol prevents gallstone formation and decreases serum and liver cholesterol 31), but such preventive effects are observed only at high doses 32). The effect of beta sitosterol on different metabolizing enzymes has not been studied and therefore sufficient information regarding the metabolism of drugs that are affected by beta sitosterol is not available.
Beta sitosterol possesses a weakly estrogenic effect and alone or in combination with progesterone, it inhibits the expression of intercellular adhesion molecule-1 33) and testosterone propionate induced prostate hyperplasia 34) as well as reducing pregnenolone production 35). Even though the molecular effect of beta sitosterol on the tonicity of the uterus has been studied 36), the long-term effect of beta sitosterol on different hormones has not been studied and therefore further study is required.
The effect of beta sitosterol on the reproductive system is contradictory. Study on American mink shows increased male fertility due to beta sitosterol intake 37), but other studies in male rats 38) and goats 39) show the opposite effect on reproduction. The level of sex hormones such as testosterone in males and estradiol in females is increased due to beta sitosterol intake in rats 40). Whether or not this increase has any clinical significance has not yet been studied.
Different plants containing phytosterols like Mimosa tenuiflora have been used for decades as a remedy in the treatment of wounds and burns of the skin. This can be explained by the re-epithelialization process in wounded areas which is believed to be aided by beta sitosterol. So, the ability to heal, together with the anti-inflammatory and antimicrobial activity of beta sitosterol demonstrate its potential in tissue engineering applications 41).
Several findings suggest that beta sitosterol has antioxidant property 42). It has also been shown to modulate antioxidant enzymes and human estrogen receptor 43). It has been reported from a study that beta sitosterol reduced Oxygen free radical and Hydrogen Peroxide levels in Phorbol myristate acetate (PMA) stimulated RAW 264.7 cells but does not function as a radical scavenger 44). Glutathione peroxidase (GSH) and Mn superoxide dismutase (SOD) activities are decreased significantly by beta sitosterol treatment 45). Beta sitosterol does not affect Cu-Zn SOD activity, but whether beta sitosterol promotes up-regulation of Mn-SOD needs further investigation.
beta sitosterol plays a role in blood vessel formation and thus possesses potentials in wound healing 46). However, there has been no experimental study on the mechanism of wound healing until now. Choi et al. 47) shows blood vessel formation in ischemia, but further study regarding the feasibility of using beta sitosterol as a therapeutic agent for ischemic stroke has not been conducted.
A study on rats has shown that the antipyretic effect of beta sitosterol is comparable to that of aspirin 48). The preparations and extracts of plants containing beta sitosterol have also been shown to have antipyretic activity 49). This effect is comparable to that of the standard antipyretic drug, aspirin, but the detailed mechanism has not yet been studied.
Beta sitosterol possesses anti-inflammatory activity in human aortic cells 50) as well as in rats 51). Several studies in animals have indicated that beta sitosterol reduces the secretion of pro-inflammatory cytokines, TNF-α as well as edema 52) and increases anti-inflammatory cytokines 53). Chronic treatment with beta sitosterol reduces its anti-inflammatory potential 54) and it does not affect the mast cells in histamine release 55) and the arachidonic acid pathway 56). Whether beta sitosterol inhibits either myeloperoxidase or adenosine deaminase activity or both needs further investigation. Again, whether beta sitosterol inhibits or not IL-1β and TNF-α levels by increasing calcium uptake in activated neutrophils in a concentration- and time-dependent manner through l-type voltage-dependent calcium channels, phosphoinositide kinase-3, intracellular calcium and microtubule modulation, and thus promotes the anti-inflammatory activity as proposed by Liz et al. 57), requires experimental evidence. Even though Mahanjan and Mehta 58) have shown therapeutic potential in allergic asthma by a chronic study in pigs it has not been used for clinical trials in humans.
It has been reported from a study that the plant extract containing beta sitosterol has significant anti-arthritic activity 59). According to Moreau et al. 60), beta sitosterol decreases the activation of NF-κB transcription factor in PMA-stimulated macrophage cells. However, further investigations are required regarding the therapeutic potential of beta sitosterol to treat arthritis.
Immune Modulation and Anti-HIV Effect
Beta sitosterol has been shown to act as a powerful immune modulator 61). beta sitosterol exhibits immune-modulating activities in HIV-infected patients 62). It has also been reported that beta sitosterol targets specific T-helper (Th) lymphocytes, increasing Th1 activity and improving T-lymphocyte and natural killer (NK) cell activity 63). In another study it was observed that beta sitosterol maintains stable CD 4 cell counts in AIDS, declines apoptosis of CD 4 lymphocytes slightly, thereby slowing HIV. A significant decrease in IL-6 levels in the same study leads to a further claim that there is slowing down of viral replication rates in infected cells thereby decreasing viral load 64). Neurath et al. 65) proposes beta sitosterol as an envelope virus neutralizing compound (EVNC) and thus acting as an HIV-1 entry inhibitor. This claim has been substantiated by the fact that the envelope virus neutralizing compounds in the body fluid neutralize viruses in the blood stream and elicit an immune response to the neutralized authentically folded virus particle 66). Even though the effect of beta sitosterol on entry and exit out of the cell is not available, it is evident that beta sitosterol facilitates the development of a potentially protective immunity against HIV. However, further study for considering beta sitosterol as potential therapeutic agent has not progressed. Therefore, extensive study is suggested.
Experimental and epidemiological studies have shown the efficacy of beta sitosterol in treating different types of cancer via different pathways. One recent review documented in detail regarding this 67). However, most studies have been carried out with different cancer cell lines, where different cellular factors are affected by beta sitosterol, but ultimately cell lines undergo apoptosis. For breast cancer, MDA-MB-231 68), U937 69), HL60, MCF-7; for colon cancer, HT-29 70), HT116, COLO 320 DM, Caco 2; for prostate cancer, LNCaP 71), PC-3, 22Rv1, DU145; for fibrosarcoma MCA-102 72); for uterine cervix cancer, SiHa cells 73); for larynx carcinoma, Heps 74) have been studied. Studies on the antitumor effect of beta sitosterol in animals are relatively few. For colon carcinogenesis, studies were done on rodents and on rat prostate 75). For the former, the result is positive, but for the later the result is negative. These studies with beta sitosterol are extensive and explain the anticancer mechanism of action. For example, several studies have indicated that beta sitosterol inhibits the growth of various cultured cancer cell lines that are associated with the activation of the sphingomyelin cycle 76); cell cycle arrest 77), and the stimulation of apoptotic cell death 78). Beta sitosterol isolated from various plants promotes apoptosis by increasing first apoptosis signal (Fas) levels and caspase-8 activity 79), phosphorylation of extracellular signal-regulating kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) 80), inhibition of cancer cell proliferation, even at low concentrations with no cytotoxic effect on noncancerous cells 81), modulation of antioxidant enzyme levels in pathogenesis 82), arresting of cells at G2/M phase in cancer cells 83), and decreasing free radical generation in vitro [102,162]. beta sitosterol induces a reduction in membrane sphingomyelin and an increase in the ceramide levels in some tumor cells 84). The efficiency of ceramide playing a role in the activation of the extrinsic pathway as suggested by observations of death receptor clustering in ceramide-rich lipid rafts has not been studied for experimental evidence 85). In addition to the negative effect of beta sitosterol on cell growth, beta sitosterol treatment of tumor cells is associated with increased apoptosis 86). Even with these extensive studies, there is still very little translational research for treating different cancers. One possible explanation could be its lower efficacy and another could be fewer chances of patents by pharmaceutical research organizations. Therefore, research in an academic setting is needed.
Oral treatment with beta sitosterol increases the fasting plasma insulin levels. There is a corresponding decrease in fasting glycemia when beta sitosterol is administered orally. In addition, it improves the oral glucose tolerance test with an increase in glucose-induced insulin secretion 87). These effects are comparable to that of the standard anti-hyperglycemic drug Glibenclamide. However, the hypoglycemic effect manifested by beta sitosterol by increasing circulating insulin levels and the mechanism of this increase need further study. A study has shown that treatment of diabetic rats with beta sitosterol prevents the development of diabetes as well as ameliorating diabetic complications along with other diseases such as arthritis 88). The same study showed that beta sitosterol increases glucose uptake in adipocytes and stimulates adipogenesis in differentiating preadipocytes. Paradoxically, it also induces lipolysis in adipocytes which have not been attenuated by insulin and co-incubation with epinephrine. Like insulin, it down-regulates GLUT4 gene expression, but a confirmatory study is required to ensure that elevation of glucose uptake by beta sitosterol in adipocytes is unrelated to the de novo synthesis of GLUT4 and whether lipolysis is associated with down-regulation of Akt and PI3K genes. Even though due to the unique effects of beta sitosterol on the regulation of glucose uptake, adipogenesis, and lipolysis in adipocytes supports its potential to be utilized in diabetes and weight management 89), no clinical study has yet progressed. Furthermore, a study should be conducted on whether or not beta sitosterol has any role in insulin sensitivity and glucagon secretion.
Anti-Pulmonary Tuberculosis Effect
According to the double-blind, randomized, placebo-controlled trial conducted by Donald et al. 90) on culture-positive pulmonary tuberculosis patients, beta sitosterol has been found to have a significant improvement in weight that is lost due to pulmonary tuberculosis. The same study showed that patients receiving beta sitosterol exhibit notable differences in certain hematological parameters, including increased lymphocyte, eosinophil, and monocyte counts. The detailed mechanism of this effect has not yet been studied. The efficiency of beta sitosterol as immune modulating agent in case of multi-drug-resistant tuberculosis needs further investigation.
beta sitosterol obtained from different plants shows antibacterial and antifungal activity without toxicity in brine shrimp lethality assay 91). The formulation or plant extract containing beta sitosterol shows mosquito larvicidal activities 92) and antitrypanosomal activities 93). beta sitosterol has been reported to have antibacterial activity with a comparable zone of inhibition to other standard antimicrobial agents 94). The prime limitation of these studies is the inadequacy in explaining the mechanism of actions. Kanokmedhakul et al. 95) attributed this to the ability of beta sitosterol to inhibit bacterial cell surface protein, “sortase” thus preventing transpeptidation. Betasitosterol-3-O-glucopyranoside, a derivative of beta sitosterol, inhibits bacterial cell adhesion to a fibronectin indicating that modification of beta sitosterol is needed to exert its antibacterial effect 96). However, no study has been conducted regarding the mechanism of anti-protozoal, anti-larvicidal or anti-fungal effects. Again, no study has been run to ensure any effect of beta sitosterol on the ribosome, RNA transcription, DNA replication or the enzymes involved in central dogma. A detailed study is proposed with a hope of obtaining a good alternative to the antimicrobial agent in this current era of antimicrobial resistance.
Beta sitosterol foods
Beta sitosterol is one of the most abundant dietary phytosterols present in many beans, nuts, and seeds 97). Beta sitosterol has been reported to be present in various dietary and non-dietary plants 98). Beta sitosterol exists in different plant parts such as leaves 99), rhizomes 100), and fruits 101). Beta sitosterol has also been reported to be present in different plant tissue cultures 102). Studies have been reported regarding its membrane stabilizing effect on cell membrane 103), but its role in the cytoplasm and chloroplast has not been studied yet 104). Beta sitosterol-derived phytoecdysteroid is higher in plant tissues which are the most important chemical substance for plant survival, but whether or not beta sitosterol has a significant role in plant protection needs further research 105).
Beta sitosterol supplement
Beta-sitosterol has been used to lower cholesterol and improve symptoms in mild to moderate enlarged prostate. Beta-sitosterol has also been investigated for its immune system and anticancer effects.
Beta sitosterol dosage
Beta-sitosterol is added to margarine, yogurt, or other foods to provide a daily intake of 1.5 to 3 g.
Beta sitosterol side effects
Beta-sitosterol may cause gastrointestinal side effects as well as impotence. In 1 study, side effects related to beta-sitosterol use were gas, discoloration of the feces, appetite changes, stomach problems, leg cramps, skin rash, and low white blood cell count. A 1-year study in healthy patients consuming 1.6 g/day of plant sterols in a dietary spread showed cholesterol-lowering effects and long-term tolerance.
Even though the United States National Toxicology Program reviewed toxicological effects of beta sitosterol about 18 years ago 106), many study results need to be re-evaluated based on the latest findings. A high level of beta sitosterol concentrations in blood has also been correlated with increased severity of heart disease in men who have previously been suffering from heart attacks 107). There are drug interactions of beta sitosterol with Ezetimibe and atorvastatin, pravastatin, simvastatin, and lovastatin or fluvastatin 108). Ezetimibe inhibits the uptake of beta sitosterol which provides the molecular basis for the treatment of sitosterolemia with ezetimibe 109). Short-term repeated administration of beta sitosterol in rats has been reported not to produce gross or microscopic lesions in liver or kidney 110) but such a report on humans taking beta sitosterol for a long time has not been produced. An extensive toxicological study has shown high LD50 (lethal dose 50 is the amount of an ingested substance that kills 50 percent of a test subjects) in rats (>2 gm/kg) 111). According to Joint FAO/WHO Expert Committee on Food Additives (JECFA) (2009), acceptable daily intake (ADI) is 40 mg/kg body weight per day; No-Observed-Adverse-Effect-Level (NOAEL) is 4200 mg/kg body weight per day; Margin of Safety (MOS) is 210 mg/kg body weight per day and 8.3 mg/kg body weight per day for systemic and cosmetic products respectively. These values are calculated approximately from phytosterol mixtures, not directly from beta sitosterol solely and therefore values based on beta sitosterol are highly recommended. Beta sitosterol inhibits mutagenicity 112), prevents chromosomal breaks 113), and shows no genotoxic effects 114). Even though one study found its potentially harmful effect on the reproductive system 115), later study found that it does not have an effect on the reproductive system 116). However, there is no study regarding the long-term effect of beta sitosterol in the human reproductive system. In a recent study, it was shown that high exposure of beta sitosterol is related to impaired hepatic and intestinal ATP-binding cassette transporters G5/8 and possesses potential risks of blood-brain barrier integrity in diabetic rats 117). Another main limitation of beta sitosterol toxicity study is the unavailability of its readily oxidized products.
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