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Prostate cancer (PCA) is the most invasive and frequently diagnosed malignancy in elderly males in western world, and is the second leading cause of cancer-related deaths. Early stage of PCA or the malignancy that is confined only within the prostate is conventionally cured with surgical prostatectomy or radiation therapy; some low-risk patients, however, also choose watchful waiting. The disease that has spread beyond the prostate is generally first treated with hormonal ablation, and the addition of cytotoxic chemotherapy is used in selected hormone-refractory patients, which has shown a small (_2 months) survival advantage. Unfortunately, all these treatment approaches suffer from their own limitations together with the emergence of androgen independence during commonly used anti-androgen therapy, suggesting that additional approaches and strategies are needed to control initial phases of PCA development, as well as its progression to advanced and androgen-independent stage. Since PCA is a chronic disease, its prevention and/or therapeutic intervention are emerging as attractive additional strategies for disease control. In recent years, several studies have shown that phyto-chemicals present in diet as well as those consumed as dietary supplements are effective anticancer and/or chemo-preventive agents against several malignancies including PCA. Grape seed extract (GSE) is a complex mixture of various polyphenols, some of which are also present in green tea.
The grape seed polyphenols are generally referred to as procyanidins, and are marketed in USA as _GSE_ with 95% standardized procyanidins as dietary supplement due to multiple health benefits. In addition to grape seeds, procyanidins are a diverse group of poly-phenolics that are also abundant in blackjack oak, horse chestnut, witch hazel and hawthorn, as well as in apples, berries, barley, bean hulls, chocolate, rhubarb, rose hips and sorghum. With regard to anticancer and cancer chemo-preventive effects of GSE, several studies have shown that this mixture inhibits human breast carcinoma MCF-7, human lung cancer A-427 and human gastric cancer CRL-1739 cell growth, but enhances the growth and viability of normal human gastric mucosal and normal J774A.1 murine macrophage cells, Studies have shown that GSE inhibits growth, induces cell-cycle arrest and causes apoptotic death of human breast carcinoma MDA-MB468 and prostate carcinoma DU145 and LNCaP cells in culture. With regard to its anti-carcinogenic effects in animal models, oral feeding of GSE or pro-cyanidinrich fraction from GSE has been shown to prevent azoxymethane-induced aberrant crypt foci formation in rats, and topical application of GSE significantly prevents phorbol estermediated tumor promotion in chemical carcinogen-initiated mouse skin. Observations of skin cancer preventive efficacy of GSE was further verified and confirmed by others in showing that GSE also inhibits ultraviolet B radiation-induced skin tumorigenesis. With regard to the in vivo efficacy of GSE against PCA, we recently reported that oral feeding of GSE strongly inhibits DU145 xenograft growth in nude mice. Together, these studies have convincingly documented the anticancer and chemopreventive efficacy of GSE against various epithelial cancers including PCA, and indicate the presence of biologically active phyto-chemicals in the crude mixture. The composition of GSE has been investigated extensively, and is known to consist largely of gallic acid (GA), catechin (Cat), epicatechin (Epi) and procyanidin dimers and trimers composed of flavan-3-ol units with C4-C8 or C4-C6 inter-flavan linkage. These compounds are also present as esters linked to GA at the aliphatic 3-hydroxyl group in the C ring.
With increasing body of evidence implicating diets rich in fruits and vegetables with lower incidence of cancer, in recent years, efforts have been directed toward identifying and characterizing the phyto-chemicals present in these diets with potential anticancer activity. Though the concept of eating fruits and/or vegetables, i.e. consuming phyto-chemicals naturally, would be more effective in the fight against cancer, the evaluation of biological efficacy of individual components is an important step toward drug discovery and development. This approach is further necessitated by the fact in general that most phyto-chemicals have low bioavailability and may be present in only very small amounts in plant materials. Thus, once an active constituent is identified, there are a number of options available to increase its bioavailability and to make it commercially available in larger amounts. With this rationale, procyanidins are found to be responsible for both anticancer and cancer preventive effects of GSE in numerous cell culture and animal models of cancer. Colorectal cancer (CRC) is the third most common cancer in both men and women; the overall mortality due to this malignancy accounts for 10% of all the cancer-associated deaths. CRC is one of the disease conditions where dietary habits and life style are major etiological factors. Diets rich in fat, animal proteins, and low in fiber are often considered risk factors for developing CRC, whereas those rich in fruits, vegetables, and whole grains are often recommended for reducing the risk of this malignancy. Once a full blown clinically evident case of colorectal cancer emerges, treatment options include surgery, chemotherapy, and radiotherapy; however, most of the time, the cancer resurfaces later and the patients have to undergo additional rounds of radiotherapy or chemotherapy. Because of the severe toxicity and side-effects associated with current treatment regimens for CRC, the patients often also drift towards using complementary and alternative medicine (CAM) practices, such as consumption of health/dietary supplements, chiropractic treatments, massage therapy, herbs, etc, in order to relieve the symptoms of pain and to have better overall health. In the past few years, the increased popularity of CAM, especially among cancer patients, has been well-identified and recognize. With regard to health/dietary supplements, a wide number of herbs and/or herbal extracts, such as milk thistle extract, triptolide, Chinese herb extract, brucea fruit, European mistle toe, green tea extract, soy isoflavones, and grape seed extract (GSE), are being frequently consumed by both healthy people and patients as a CAM practice, mostly because of the strong belief that these agents provide several health benefits.
GSE is rich in proanthocyanidins, which are largely responsible for the spectrum of biological activities exhibited by this extract. For example, GSE exerts anti-inflammatory, antibacterial, anti-viral, anti-nociceptive, and other health beneficial effects in human disease conditions such as atherosclerosis, hyperglycemia, etc. Also due to its high proanthocyanidins content, GSE exhibits strong antioxidant activity, which is even more potent than known antioxidants such as vitamin E and ascorbic acid. Regarding its efficacy against malignancy, several studies during the last ten years from our laboratory as well as by others have convincingly demonstrated that GSE exerts strong anti-cancer and cancer chemopreventive potential against different cancers in both cell culture and animal models. However, the major concern with GSE studies had been a lack of availability of uniformly standardized preparation to be used in biological efficacy studies. Even in our own studies, we have initially used the GSE prepared in the laboratory followed by that obtained from different vendors, which raises an important question whether different GSE preparations have comparable biological activity and associated mechanism of action in a given biological system.
GSE is a commonly used dietary supplement marketed in the United States and Europe for its different health benefits including strong antioxidant activity. In the last ten years, several studies by many laboratories have also convincingly documented the anticancer and cancer chemopreventive efficacy of GSE against various cancers; however, the major caveats had been the composition of various preparations of GSE being marketed under different names, and those being used under laboratory conditions. Furthermore, the lack of standardized preparations has also limited the validity and translational potential of the research findings obtained in the laboratory setting using different preparations/source of GSE. The activity of cyclin-CDK complexes, in a controlled cell cycle progression, is regulated by two different families of proteins known as NK4 and CDKI. Cancer manifests itself as uncontrolled proliferation of cells wherein the tight regulation of cell cycle progression is compromised (36). In this regard, several studies have shown that both INK4 and CDKI family members are often non-functional in various malignancies including CRC, which results in an uncontrolled cell cycle progression and cancer growth. Therefore, the molecular players such as cyclins, CDKs and their inhibitors serve as potential targets to halt the uncontrolled proliferation. Specifically, it could be argued that the agents who induce the level and/or function of cell cycle inhibitory regulators (INK4 and Cip/Kip family members) might be useful in the control of various malignancies including CRC. Lastly, we would also like to emphasize here that the observed biological effects of both GSE preparations including an induction of Cip1/p21 seem independent of p53 involvement, as these responses were comparable in non-functional p53 harboring CRC cell lines (HT29 and SW480 cell lines) versus that carrying wild-type p53 (LoVo cell line). As mutation in p53 is a hallmark of CRC growth and progression in both clinical and pre-clinical settings (46), our results showing that GSE exerts its biological efficacy in human CRC cells independent of their p53 status are extremely important outcomes for future translational potential in preventive intervention of CRC in the clinic.
Overexposure of the skin to ultraviolet (UV) radiation has a variety of adverse effects on human health, including the development of skin cancers. There is a need to develop nutrition-based efficient chemopreventive strategies. The proanthocyanidins present in grape seeds (Vitis vinifera) have been shown to have some biological effects, including prevention of photocarcinogenesis. The present communication discusses the in vitro and in vivo studies of the possible protective effect of grape seed proanthocyanidins (GSPs) and the molecular mechanism for these effects. In SKH-1 hairless mice, dietary supplementation with GSPs is associated with a decrease of UVB-induced skin tumor development in terms of tumor incidence, tumor multiplicity, and a decrease in the malignant transformation of papillomas to carcinomas. It is suggested that the chemopreventive effects of dietary GSPs are mediated through the attenuation of UV-induced: (a) oxidative stress; (b) activation of mitogen-activated protein kinases and nuclear factor-κB signaling pathways; and (c) immunosuppression through alterations in immunoregulatory cytokines. Collectively, these studies indicate protective potential of GSPs against experimental photocarcinogenesis in SKH-1 hairless mice, and the possible mechanisms of action of GSPs, and suggest that dietary GSPs could be useful in the attenuation of the adverse UV-induced health effects in human skin.
Flaxseed oil is derived from the seeds of the flax plant (Linum usitatissimum, L.). Flaxseed oil and flaxseed contain substances that promote good health. One of these substances is alpha-linolenic acid (ALA), an essential fatty acid that appears to be beneficial for heart disease, inflammatory bowel disease, arthritis, and other health conditions. Flaxseed, in addition to ALA, contains a group of chemicals called lignans that may play a role in the prevention of cancer. ALA, as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), belongs to a group of substances called omega-3 fatty acids. EPA and DHA are found primarily in fish while ALA is mostly found in flaxseed oil and other vegetable oils. Although similar in structure, the benefits of ALA, EPA, and DHA are not necessarily the same.
It is important to maintain an appropriate balance of omega-3 and omega-6 (another essential fatty acid) in the diet, as these two substances work together to promote health. These essential fats are both examples of polyunsaturated fatty acids, or PUFAs. Omega-3 fatty acids help reduce inflammation and most omega-6 fatty acids tend to promote inflammation. An inappropriate balance of these essential fatty acids contributes to the development of disease while a proper balance helps maintain and even improve health. A healthy diet should consist of roughly 2 – 4 times more omega-6 fatty acids than omega-3 fatty acids. The typical American diet tends to contain 14 – 25 times more omega-6 fatty acids than omega-3 fatty acids, and many researchers believe this imbalance is a significant factor in the rising rate of inflammatory disorders in the United States.
Omega-3 fatty acids have been shown to reduce inflammation and help prevent certain chronic diseases such as heart disease and arthritis. These essential fatty acids appear to be particularly important for cognitive and behavioral function as well as normal growth and development.
Clinical studies suggest that flaxseed oil and other omega-3 fatty acids may be helpful in treating a variety of conditions. The evidence is strongest for heart disease and problems that contribute to heart disease, but the range of possible uses for flaxseed oil include:
People who follow a Mediterranean diet tend to have an increased high density lipoprotein (also called HDL, or “good”) cholesterol level. The Mediterranean diet consists of a healthy balance between omega-3, omega-6, and omega-9 (found in olive oil) fatty acids. It emphasizes whole grains, root and green vegetables, daily intake of fruit, fish and poultry, olive and canola oils, and ALA (from flaxseed, flaxseed oil, and walnuts), along with discouragement of ingestion of red meat and not much use of butter and cream.
Flaxseed and flaxseed oil have been reported to possess cholesterol-lowering properties in laboratory studies. Human studies have used flaxseed products and measured effects on cholesterol, with mixed results. A recent human study found that dietary flaxseed significantly improved lipid (cholesterol) profile in patients with high cholesterol, and may favorably modify cardiovascular risk factors.
A diet rich in fruits, vegetables, whole grains, nuts or legumes, and ALA-rich foods may substantially reduces the recurrence of heart disease. One of the best ways to help prevent and treat heart disease is to eat a low-fat diet and to replace foods rich in saturated and trans-fat with those that are rich in monounsaturated and polyunsaturated fats (including omega-3 fatty acids from flaxseed). Evidence suggests that people who eat an ALA-rich diet are less likely to suffer a fatal heart attack. ALA may reduce heart disease risks through a variety of biologic mechanisms, including platelet function (making them less “sticky”), inflammation, blood vessel health, and arrhythmia (irregular heart beat).
Several human studies also suggest that diets rich in omega-3 fatty acids (including ALA) may lower blood pressure.
Although further research is needed, preliminary evidence suggests that omega-3 fatty acids may also prove helpful in protecting against certain infections and treating a variety of conditions including autism, ulcers, migraine headaches, preterm labor, emphysema, psoriasis, glaucoma, Lyme disease, systemic lupus erythmatosus (lupus), irregular heart beats (arrhythmias), multiple sclerosis, and panic attacks. Omega-3 fatty acid supplementation may also help to reduce stress and the effects it has on the body.
Flaxseed Oil for Women’s Health
Flaxseed oil is considered as a boon for women’s health. Flaxseed oil, one of the richest sources of omega-3 essential fatty acids, lowers the levels of cholesterol and triglycerides and minimizes the risk of heart attack. It is used to treat various hormone-related problems and inflammatory disorders. Omega-3 fatty acids present in flaxseed oil strengthens the immune system. These essential fatty acids also help to minimize the risk of breast cancer. Recent researches have found that the highest content of omega-3 fatty acids in the breast tissues can reduce the incidence of breast cancer. These essential fatty acids can also reduce the risk of colon cancer, skin cancer and endometrial cancer. Flaxseed oil can be used to treat various women’s health problems such as premenstrual syndrome, menstrual cramps, pre-menopausal symptoms, endometriosis and female infertility. It can also improve uterine function and health.
Flaxseed oil helps to regulate menstrual cycle, balance the progesterone levels and reduce menopause symptoms such as sleep difficulties, headache, anxiety, mood swings, breast cysts, etc. Flaxseed oil consists of lignans, which are naturally occurring plant estrogens. They can effectively balance the hormonal levels as well as promote natural ovulation. Lignans in flaxseed oil are also helpful for prevention of estrogen-related cancers and prevention of metastasis of tumors. The essential fatty acids present in flaxseed oil can prevent the production of prostaglandins, which when released in excess amounts can cause heavy bleeding during menstruation. Phytoestrogens present in flaxseed oil stabilize estrogen-progesterone ratio and help to relieve hot flashes in perimenopause and menopause. Flaxseed oil is an excellent dietary supplement for women, who suffer from osteoporosis.
In addition to lessening a woman’s risk of developing cancer, the lignans abundant in flaxseed can promote normal ovulation and extend the second, progesterone-dominant half of the cycle. The benefits of these effects are manifold. For women trying to become pregnant, consistent ovulation significantly improves their chances of conception. For women between the ages of 35 and 55 who are experiencing peri-menopausal symptoms such as irregular menstrual cycles, breast cysts, headaches, sleep difficulties, fluid retention, anxiety, irritability, mood swings, weight gain, lowered sex drive, brain fog, fibroid tumors, and heavy bleeding, a probable cause of all these problems is estrogen dominance. Typically, during the 10 years preceding the cessation of periods at midlife, estrogen levels fluctuate while progesterone levels steadily decline. Flaxseed, by promoting normal ovulation and lengthening the second half of the menstrual cycle, in which progesterone is the dominant hormone, helps restore hormonal balance.
Preliminary research also suggests that flaxseeds may serve a role in protecting postmenopausal woman from cardiovascular disease. In a recent double-blind randomized study, flaxseeds reduced total cholesterol levels in the blood of postmenopausal women who were not on hormone replacement therapy by an average of 6%.
The olive tree, Olea europaea, produces the olive fruit. Olives are grown widely in the Mediterranean basin and parts of Asia Minor. References to the olive tree date back to Biblical and Roman times and to Greek mythology. Historically, the products of Olea europaea have been used as aphrodisiacs, emollients, laxatives, nutritives, sedatives, and tonics. Specific conditions traditionally treated include colic, alopecia, paralysis, rheumatic pain, sciatica, and hypertension. The olive can be consumed whole as either the fully ripe black fruit or as the unripe green fruit. Olive oil, the major source of dietary fat in the countries where olives are grown constitutes part the commonly referred to “Mediterranean diet” of countries that surround the Mediterranean Sea and tend to have a low incidence of chronic degenerative disease. Although there are dietary variations among Mediterranean countries, a common feature is the high consumption of olive oil, either uncooked or as the primary cooking fat.4 Half the total fat consumed in the Mediterranean diet comes from cooking with olive oil, with deep fat frying being the most common method used.4 In the latter part of the 20th century, Keys et al conducted the Seven Countries Study, which revealed the Mediterranean diet is linked to a reduced incidence of degenerative diseases, particularly coronary heart disease (CHD) and cancers of the breast, skin, and colon. This study inspired much research into the Mediterranean diet. In addition to olive oil, the Mediterranean diet is rich in healthful fiber, fish, fruits, and vegetables.6Since olive oil is the major energy source in the Mediterranean diet, recent research has focused on the contribution it makes to reported health benefits of the diet. Compared to diets of other countries, the Mediterranean diet has a relatively high fat content; however, as the diet is associated with a low incidence of cancer and CHD, despite the high fat intake, it has been suggested the type of fat is more important than the total amount consumed. To manufacture olive oil, olives are crushed to create a pomace, which is then homogenized before being pressed to produce oil. The first oil extracted is the high quality extra virgin olive oil – produced using centrifugation and water only. The pomace can then be processed again to yield the lower quality refined virgin olive oil. Further extraction with organic solvents can be undertaken to produce low quality refined husk oil. Olive oil is believed to exert its biological benefits mainly via constituent antioxidants. Although the composition of olive oil is complex, the major groups of compounds thought to contribute to its observed health benefits include oleic acid, phenolics, and squalene all of which have been found to inhibit oxidative stress. Antioxidants in olives protect them from oxidation by the high temperatures and ultraviolet radiation of the Mediterranean climate. The physical methods used to produce olive oil preserve many of its antioxidant compounds. This is not seen with other vegetable and seed oils, which tend to be more refined. Factors affecting the environmental conditions of growing olives alter the constituents of the oil, including its antioxidant properties.
Olive oil is approximately 72-percent oleic acid, a monounsaturated fatty acid. Olive oil is unique with respect to the high oleic acid content because the majority of seed oils are composed primarily of polyunsaturated fatty acids, including the essential omega-6 fatty acid, linoleic acid. Compared to polyunsaturated fatty acids, oleic acid is monounsaturated, meaning it has one double bond, making it much less susceptible to oxidation and contributing to the antioxidant action, high stability, and long shelf life of olive oil. Data concerning the health benefits of oleic acid are conflicting. It has been reported that oleic acid plays a role in cancer prevention. Whether this is a secondary effect of the fatty acid on oil stability (preventing oxidative stress) or a direct anticancer effect remains debatable. Preference for the latter theory is based on the fact that, although oleic acid is found in high concentration in olive oil it is also found in relatively high levels in foodstuffs that form a major part of Western diets in non-Mediterranean countries. For example, beef and poultry contain 30- to 45-percent oleic acid, while oils such as palm, peanut, soybean, and sunflower contain 25- to 49-percent oleic acid. These countries do not have the low incidence of CHD and cancer typical of the Mediterranean countries. This fact could be due to the comparatively low levels of oleic acid and concomitant high levels of other fatty acids.
Several in vitro and in vivo studies have examined the effect of oleic acid on cancer. Llor and Pons conducted in vitro experiments on the effect of olive oil or isolated oleic acid on colorectal neoplasia. They concluded olive oil induces apoptosis and cell differentiation and down-regulates the expression of cyclooxygenase-2 (COX-2) and Bcl-2. COX-2 is believed to play an important role in colorectal cancer development, while Bcl-2 is an intracellular protein that inhibits apoptosis. Oleic acid alone exhibited cell-line specific apoptotic induction, since HT-29 cells were affected but not Caco-2 cells. Oleic acid had no effect on the down-regulation of COX-2 and Bcl-2. Olive oil was found to have no effect on cell proliferation. The researchers concluded oleic acid plays a minor role, if any, in colorectal chemoprotection and that other components of olive oil are involved in this protective process. In vitro studies conducted by Menendez et al examined the effect of oleic acid on breast cancer cell lines. The study results are encouraging and support the theory that oleic acid is important in chemoprotection. The researchers reported oleic acid down-regulates the over-expression of Her-2/neu, an oncogene over-expressed in approximately 20-percent of breast carcinomas. The gene, also know as erb-B2, encodes for the p185Her-2/neu oncoprotein, a transmembrane tyrosine kinase orphan receptor that, under normal cellular conditions, is highly regulated because it controls many cell functions, such as differentiation, proliferation, and apoptosis. Deregulation of p185Her-2/neu greatly increases the risk of cancer development. In addition to oleic acid alone, the authors also looked at the effect of oleic acid when compared to, and given simultaneously with, the anticancer drug trastuzumab (HerceptinR). Trastuzumab is a human monoclonal antibody that targets p185Her-2/neu. Menendez et al found oleic acid acts synergistically with trastuzumab to enhance its action when used against cell cultures that over-express the Her-2/neu oncogene. Following these results, Menendez et al sought to identify the mechanism of action for the down-regulation of the Her-2/ neu oncogene by oleic acid.14 The research focused on polyomavirus enhancer activator 3 (PEA3), a protein that represses the expression of Her-2/neu. They found oleic acid up-regulates PEA3. Low levels of PEA3 are found in cells over-expressing Her-2/neu; whereas, high levels of PEA3 are associated with low p185Her-2/ neu expression. Since these data are from in vitro cell lines, the authors warn the results cannot be extrapolated to prove exogenous consumption of oleic acid downregulates Her-2/neu expression via up-regulation of PEA3 in vivo.
A range of phenols in olive oil provides some of its health benefits. The total phenolic content has been reported to be in the range of 196-500 mg/kg. Although the reported levels of phenolic compounds in olive oil vary widely, one consistent conclusion is that extra virgin olive oil has a higher phenolic content than refined virgin olive oil. Owen et al showed this difference was reflected in the levels of individual phenols as well as the total quantity of phenols in the oil. The concentration of phenols depends on a number of factors, including environmental growth conditions, method of oil production, and storage conditions. Olive oil phenols can be divided into three categories: simple phenols, secoiridoids, and lignans, all of which inhibit auto-oxidation. Major phenols include hydroxytyrosol, tyrosol, oleuropein and ligstroside. Hydroxytyrosol and tyrosol are simple phenols and oleuropein is a secoiridoid. The simple phenols hydroxytyrosol and tyrosol are formed from the hydrolysis of the secoiridoid aglycones of oleuropein and ligstroside. Hydrolysis of oleuropein, which occurs during olive oil storage results in the formation of hydroxytyrosol, tyrosol, and ethanol. As well as being present in olive oil, hydroxytyrosol is endogenous to the brain as a catabolite of neurotransmitter breakdown.
The phenolic content of the olive fruit changes as it grows and develops. After six months of growth, the major phenols are the glucosides of ligstroside and oleuropein. As the olive matures these compounds are deglycosylated by glucosidase enzymes to free secoiridoids. Unlike the glucosides, free secoiridoids can be detected in olive oil. Because the free secoiridoids are able to cross the oil/water barrier, these compounds partition into the oil. Black olive pericarp extract (from the outer layer of the black olive) has a higher concentration of phenolic compounds and a higher antioxidant capacity than green olive pericarp extract. It has been known for many years that compounds with a catechol group exhibit antioxidant activity. The catechol group is able to stabilize free radicals through the formation of intramolecular hydrogen bonds. Of the three main phenols in olive oil, hydroxytyrosol and oleuropein are catechols and tyrosol is a mono-phenol. It has been suggested that, of all the phenols present in olive oil, only the catechols are important. Hydroxytyrosol and oleuropein scavenge free radicals and inhibit low density lipoprotein (LDL) oxidation. These two phenols show dose-dependent activity and are considered potent antioxidants, demonstrating activity in the micro-molar range. Both are more potent at scavenging free radicals than the endogenous antioxidant vitamin E and the exogenous antioxidants dimethyl sulfoxide (DMSO) and butylated hydroxytoluene (BHT). These two catechols have been shown to scavenge a variety of endogenous and exogenous free radicals and oxidants, including those generated by hydrogen peroxide hypochlorous acid, and xanthine/ xanthine oxidase. Higher concentrations of tyrosol are needed to exert an antioxidant effect. Using hydroxyl radical scavenging as a measure of antioxidant capacity, Owen et al concluded olive oil has a higher antioxidant capacity than seed oils and extra virgin olive oil is more potent than refined virgin olive oil due to its higher concentration of antioxidants. Similar results were obtained when xanthine oxidase and hypochlorous acid were used. Olive oil phenols are capable of scavenging free radicals produced in the fecal matrix, which is thought to explain the epidemiological data suggesting a colonic chemoprotective effect of olive oil. One mechanism associated with the anticancer effects of hydroxytyrosol and oleuropein is prevention of DNA damage, which can prevent mutagenesis and carcinogenesis. Hydroxytyrosol, however, has biological activity beyond its antioxidant capacity, as it can affect a range of enzymes, including cyclooxygenase and NAD(P)H oxidase, and reduce platelet aggregation. Recently a secoiridoid derivative, oleocanthal – the dialdehydic form of deacetoxy-ligstroside aglycone – was identified. This compound, having an extreme irritant effect on the throat, has demonstrated inhibition of cyclooxygenase enzymes and anti-inflammatory activity.
Squalene, ubiquitous in nature, is a triterpene hydrocarbon and a major intermediate in the biosynthesis of cholesterol. Although found in both plants and animals, it is found in vastly different amounts. While olive oil is composed of approximately 0.7-percent squalene, other foods and oils typically have squalene levels in the range of 0.002-0.03 percent. Only a slight difference is observed between the level of squalene in extra virgin and refined virgin olive oils (extra virgin having higher levels). Although squalene is widely distributed throughout the body, the majority is transported to the skin. Sebum has high levels (12%); whereas, adipose tissue has much lower levels (0.001-0.04%).9 Due to squalene’s structure, it is more likely to scavenge singlet oxygen species than hydroxyl radicals. Exposure to high levels of ultraviolet radiation causes the formation of carcinogenic singlet oxygen species within the skin, where a high concentration of squalene may provide a chemoprotective effect. Squalene, found in high amounts in the Mediterranean diet, is believed to be responsible for the lower incidence of skin cancer seen in epidemiological studies of populations consuming this diet. Animal studies have shown topical squalene has an inhibitory action on chemicallyinduced skin carcinomas. Squalene added to the diet of rats resulted in an 80-percent increase in serum squalene levels and inhibition of the hepatic enzyme HMG-CoA reductase. The enzyme inhibition may be due to squalene or its metabolites. HMG-CoA reductase, the rate-limiting enzyme in the biosynthesis of cholesterol, results in decreased production of cholesterol and the intermediates formed during its biosynthesis. These intermediates are commonly needed to activate oncogenes. One important intermediate is the compound farnesyl pyrophosphate (FPP), which is involved in the prenylation of several oncoproteins. Because other dietary substances that cause a reduction in FPP levels cause a reduction in tumor growth, squalene is hypothesized to work in the same manner. Following acute administration of squalene, the rate of cholesterol synthesis increased 9-24 hours postadministration. This apparent conflicting data may be a result of the single acute dose of squalene used in this study; whereas, chronic long-term administration results in reduced HMG CoA reductase activity and increased fecal elimination of cholesterol. Longer-term studies of the effect of chronic squalene intake on serum cholesterol levels have reported increased, decreased, or unchanged levels. These observed differences may be due to the dose of squalene. Short-term studies have shown increased dietary squalene, while increasing serum squalene levels, does not cause an increase in serum cholesterol or atherosclerosis.
Coronary Heart Disease
Epidemiological studies demonstrate the Mediterranean diet reduces the incidence of CHD. The antioxidant effects of olive oil may contribute to these protective effects. To understand how olive oil might help prevent atherosclerosis, a review of atherosclerotic plaque formation is in order. Oxidation of LDL cholesterol has been identified as one of the first steps in the development of atherosclerotic lesions by promoting injury to the arterial wall through several mechanisms, including growth factor and chemotactic protein expression, inflammation, and increased local macrophages. Macrophages bind to and engulf oxidized LDL – an innate immune response to tissue damage. This engulfment produces a fatty foam cell, which, when combined with other cells, produces a fatty streak in the blood vessel. Oxidized LDL can also be taken up directly by endothelial and smooth muscles cells, leading to formation of fatty streaks, which is the first sign of atherosclerosis. The lesions forming atherosclerotic plaques are made up of lipids, endothelial and smooth muscle cells, and extracellular matrix. The plaque environment is proinflammatory. Inflammation occurring prior to the formation of fatty streaks and atherosclerotic lesions causes alterations to the endothelial cell wall, which increases the adhesion of leukocytes, LDL cholesterol, and platelets. This contributes to the development of atherosclerosis and cardiovascular disease. In vitro studies have demonstrated hydroxytyrosol and oleuropein are capable of inhibiting production of isoprostanes, a marker of LDL oxidation. It has been suggested that phenols present in olive oil may act synergistically with these constituents to prevent LDL oxidation.
As with other aspects of cardiovascular diseases, there is a reduced incidence of hypertension in populations that consume the Mediterranean diet, and adherence to the Mediterranean diet is inversely related to systolic and diastolic blood pressure. Several studies have demonstrated the antihypertensive properties of olive oil. Giliani et al found intravenous administration of olive oil extract reduced systolic, diastolic, and mean arterial blood pressures in normotensive rats. Epidemiological data from studies in three Mediterranean countries – Italy, Greece, and Spain – as well as non-Mediterranean countries, suggest a protective effect for monounsaturated fatty acids or olive oil, while non-Mediterranean countries show little or no positive effects. Ferrara et al compared a diet rich in polyunsaturated fatty acids (from sunflower oil) with a diet high in monounsaturated fatty acids (from olive oil) in patients taking antihypertensive medications38 and found individuals who consumed an olive oil-rich diet were able to reduce the dosage of antihypertensive medication. Olive oil’s precise mechanism of action for blood pressure reduction is unknown, although several theories have been proposed. Giliani et al concluded that olive oil is a calcium channel antagonist, closely mimicking the effects of the calcium channel blocker drug verapamil. Another suggested mechanism is via improved endothelial function. Phenols and oleic acid may contribute to improved endothelial function by reducing ROS. Other potential mechanisms have been suggested, including decreasing vascular tone and changes to the fatty acid and phospholipid composition of the aorta.
Because strong epidemiological evidence suggests people who consume the Mediterranean diet have a lower incidence of certain cancers, including breast, skin, and colon research has focused on possible mechanisms to explain this phenomenon. Oxidation of proteins, DNA, and lipids has been shown to contribute to cancer development, and consumption of antioxidants is believed to reduce the risk of mutagenesis and carcinogenesis. Antioxidants are present in olive oil, fruits, and vegetables that constitute a large part of the Mediterranean diet. The exact contribution olive oil makes to the apparent dietary chemoprotection is debatable; in vitro studies have found olive oil phenols are potent antioxidants, which may provide potential chemoprotective properties, although in vivo data are lacking. Research examining individual phenolic compounds has found hydroxytyrosol is capable of protecting cells from hydrogen peroxide damage and DNA from peroxynitrite-induced damage, blocking cell cycle progression at the G1 phase, and inducing apoptosis. In vivo and in vitro studies on the activity of oleuropein have found, in addition to antioxidant properties, it has antiangiogenic action and inhibits cell growth, motility,and invasiveness. Oleuropein has also been found to cause cell rounding, which disrupts the cell actin cytoskeleton. Oleuropein also affects and disrupts purified actin filaments, providing direct antitumor effects due to cell disruption. In in vivo animal studies, rapid tumor regression was observed when mice were given one-percent oleuropein in drinking water.40 Saturated animal fats and polyunsaturated plant fats in the diet have been implicated in colon, breast, prostate, and ovarian cancers. The substitution of olive oil in the Mediterranean diet may explain its apparent cancer-protective effect and accentuate the importance of the type, rather than the amount, of fat consumed.
The HCAs produced when protein-containing food is fried have been found to induce breast, colon, and pancreatic cancer in rats. Based on this evidence, Galeone et al used data from a multinational, case control study to examine the relationship between fried foods and colorectal cancer. When olive oil was compared to other oils, it was found that fried olive oil has a protective effect against colon cancer. This agrees with data that unheated olive oil is beneficial in protecting against colon cancer. As described previously, when olive oil is used for frying, fewer HCAs are produced than when oils high in polyunsaturated fatty acids are used. Later in vitro research by Gill et al looked at the effect of virgin olive oil phenols on colorectal carcinogenesis. Using specific cell lines, they investigated processes involved in cancer initiation, promotion, and metastasis – the three main stages in cancer development – and concluded olive oil phenols exert beneficial effects in all three stages. The oil extract was shown to reduce DNA damage (initiation), increase barrier function (promotion), and reduce cell invasion of surrounding tissue (metastasis).
Most of the active compounds in olive oil are lipid soluble; however, even though the phenolic glycosides are less so, they are likely to be stored in fat tissue. This may explain the chemo-protective effect against breast cancer and the low incidence of breast cancer in Mediterranean countries. In addition, oleic acid is incorporated into the phospholipid membrane of breast tissue cells, resulting in a reduction in lipid peroxidation. Although in developed countries breast cancer is the most common cancer seen in women, there is vast geographical variation in its incidence. Epidemiological data show women in the Mediterranean basin have a lower incidence of breast cancer than women in other “Western” countries. Case control studies that looked at women in several Mediterranean countries have shown an inverse correlation between olive oil consumption and the incidence of breast cancer. High mammographic breast density (H-MBD) is associated with greater breast cancer risk. Using volunteers from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, Masala et al examined the effect of diet and lifestyle on MBD and concluded consumption of olive oil is inversely related to the risk of H-MBD. Women who reported olive oil intake of ≥30.5 g/day were 30-percent less likely to be classified into the H-MBD group. Using data from the European Community Multicenter Study on Antioxidants, Myocardial Infarction and Breast Cancer (EURAMIC), Simonsen et al looked at the relationship between monounsaturated fat intake, the storage of monounsaturated fatty acids in breast tissue, and postmenopausal breast cancer. They found a strong inverse relationship between oleic acid consumption and breast cancer only in the Spanish group possibly due to the reported high consumption of olive oil in Spain. Animal studies using dimethylbenz(α)anthracene- induced cancer have shown a diet rich in olive oil has a non-promoting effect on carcinogenesis. This effect is backed up by histopathological and morphological features.
In vitro studies have demonstrated the antimicrobial activity of hydroxytyrosol, tyrosol, and oleuropein against several strains of bacteria implicated in intestinal and respiratory infections. Hydroxytyrosol and oleuropein have antimicrobial action against both American Type Culture Collection (ATCC) and patient-derived clinical bacterial strains, with slightly greater activity against ATCC strains. It has been proposed that this action is due to the two ortho-positioned phenolic groups in their structure. A recent study found virgin olive oil has bactericidal action against Helicobacter pylori the primary cause of gastric ulcers and linked to gastric cancers. In recent years some strains have shown resistance to the typical antibiotics used to eradicate the infection and aid ulcer healing, spurring research on other compounds to treat the infection. Because phenolic compounds have been identified as having antibacterial properties, olive oil, with its high phenolic content, has been studied for H. pylori. Romero et al concluded phenols inhibited bacterial growth at low concentration and were stable for several hours in the highly acidic environment of the stomach. They found the secoiridoid aglycones, particularly the dialdehydic form of decarboxymethyl ligstroside, have the greatest anti-H. pylori activity and are not hydrolyzed in the stomach hydrolysis, if it occurs, produces the less active hydroxytyrosol and tyrosol. As the concentration of phenolics needed to kill H. pylori cells is higher than that for antibiotics, the researchers suggest virgin olive oil should be considered as preventive rather than a treatment agent. Because the research was conducted in vitro, the researchers also suggest in vivo testing is needed to confirm or reject the conclusions, an especially important note since other foods that demonstrate good activity against H. pylori in vitro do not appear to have any action in vivo. The mechanism by which phenolic compounds affect H. pylori is unknown at present.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation and damage. The initial autoimmune stimulus is unknown; however, joint and tissue damage occurs by a variety of mechanisms, many of which involve reactive oxygen species. ROS can cause destruction of hyaluronic acid and disruption to collagen, proteoglycans, protease inhibitors, and membrane function, the latter via oxidation of membrane fatty acids. The initiation of RA is believed to result in an increase in the concentration of macrophages and neutrophils in the synovial fluid and free-radicalproducing enzymes. This leads to high levels of ROS in the joints, which increases and prolongs inflammation and damage. The antioxidant effect of olive oil has been found to reduce inflammation. In addition, dietary omega-9 monounsaturated fatty acids, such as oleic acid, have been found to replace omega-6 polyunsaturated fatty acids (PUFAs) in several aspects of cell metabolism. Reducing the competition between omega-6 and omega3-PUFAs can lead to an increased use and incorporation of omega-3-PUFAs. A number of studies that examined the benefits of fish oils in RA used an olive oil placebo for the control groups. Although results highlighted the benefits of fish oils, unexpected significant improvements were also seen in the control groups. Benefits including pain reduction, reduced morning stiffness, and improved patient evaluation of global disease were reported by patients receiving olive oil only. No explanation of the improvements shown by the olive oil groups were proposed, although changes in immune function may be responsible. As a result of these data, Berbert et al conducted research to establish whether olive oil improved RA symptoms in patients already receiving fish oil.51 Olive oil appears to act synergistically with omega-3 fish oils to improve the symptoms of RA; the benefits are thought to be exerted through the oleic acid component. Oleic acid is converted to eicosatrienoic acid (ETA) and then leukotriene A3 (LTA3). LTA3 is a potent inhibitor of pro-inflammatory leukotriene B4 synthesis. It has also been shown that olive oil consumption decreases the risk of developing RA.
By the last few mentioned studies, we wanted to express that conventional medicine has definitely recognized the importance of natural oils. Evidence is mounting by the day that what was considered to be incurable diseases, that the innate healing of the body can greatly benefit simply by the means if natural intervention. Of course, once again, at the end, we would stress the importance of preventive medicine as the best and sometimes only way to maintain good health and longevity.
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