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Olie® Naturals Lignan Works® Pet Product Research

The flaxseed (Linum usitatissimum L.) is the seed from the flax plant, an annual herb which belongs to Linaceae family with more than 200 species. The Latin name of flaxseed means “very useful”, and it has brown and golden varieties. The shape of flaxseed is flat or oval up to 4–6 mm size with a pointed tip. Flaxseed has been a part of human diet for thousands of years in Asia, Europe, Africa, North America and more recently in Australia. The world flaxseed production remained static about 2.6 million tonnes as compared with other oilseed crops and represents 1 % of total world oilseeds supply. Currently, flaxseed has been the focus of increased interest in the field of diet and disease research due to the potential health benefits associated with some of its biologically active components such as dietary fiber (25–28 %) and α-linolenic acid (50–55 % of total fatty acids composition) [1].

Among the compounds that present biological activity, phenolic compounds are of special interest. Lignans, very complex classes of bioactive polyphenolic phytochemicals, formed by the coupling of two coniferyl alcohol residues are widely distributed in the plant kingdom [2]. There are two general types of lignans: i) those found in plant seeds like secoisolariciresinol diglucoside (SDG), isolariciresinol, matairesinol, lariciresinol and ii) those found in animals and humans known as mammalian lignans [3]. Phenolic lignans are found in most fiber-rich plants, including pumpkin seed, sesame seed, grains such as wheat, barley, rye and oats; legumes such as beans, lentils, and soybeans; and vegetables such as garlic, asparagus, broccoli, and carrots. Flaxseed is particularly the richest known source of lignans (9–30 mg per g), with lignan production at 75–800 times that of other oil seeds, cereals, legumes, and fruit and vegetables [4]. The principal dietary lignan present in flaxseed is SDG which occurs as a component of a linear ester-linked complex. Chemically, the C6-OH of the glucose of SDG is esterified to the carboxylic acid of hydroxymethylglutaric acid. Accumulation of SDG is coherent with LuPLR gene expression and synthesis of PLR enzyme during mature seed development [5]. The understanding of the action mechanism of these SDG compounds is crucial for their possible exploitation as neutraceutical supplement in biological system.

Diabetes is a metabolic syndrome and is characterized by increases in central adiposity, serum triglycerides, serum glucose, blood pressure, inflammation and decreases in HDL-cholesterol that elevates risk of insulin resistance [44]. The animal and human studies revealed that high fat diet containing 0 · 5 to 1 · 0 % SDG reduces liver triglycerides content, serum triglycerides, total cholesterol, and insulin and leptin concentrations that resulted in significantly reduced visceral fat gain as compared to group of mice receiving high fat diet without SDG [45]. Another study have shown that female rats receiving glucosuria induced diet with SDG have 80 % less chances of glucosuria as compared to rats have 100 % chances of glucosuria receiving diet without SDG [46]. SDG reduces C-reactive protein concentrations which are associated with insulin resistance and diabetes mellitus in type 2 diabetics [47]. Daily consumption of low-fat muffin enriched with SDG (500 mg/day) for 6 week can reduce CRP concentrations [48]. The earlier studies indicate that flaxseed lignan supplements have beneficial associations with C-reactive protein and also suggest that lignans have possible lipid- and blood pressure-lowering associations [49].

The occurrence of menopause is associated with an increased risk of cardiovascular events and this has partially been attributed to the decline in circulating levels of estrogen. SDG supplementation produces a dose-related cessation or lengthening (by 18–39 %) of estrous cycles, reduces immature ovarian relative weight and delays puberty in experimental animals [61, 62]. The daily consumption of a low-fat muffin enriched with SDG (500 mg/day) for 6 week had no effect on endothelial functioning in healthy postmenopausal women [63]. Dietary flaxseed SDG (600 mg/day) can appreciably improve lower urinary tract symptoms in benign prostatic hyperplasia subjects [64]. Urinary composition or blood levels of radioactive lignans were not affected by the duration of SDG exposure while chronic SDG exposure alters lignan disposition in rats, however; it does not change the metabolite profile [65]. There were no significant effects of exposing male or female offspring to SDG during suckling on any measured reproductive indices [66]. SDG affects the reproductive development of offspring with caution when consuming flaxseed during pregnancy and lactation [67].

Imran M, Ahmad N, Anjum FM, et al. Potential protective properties of flax lignan secoisolariciresinol diglucoside. Nutrition Journal. 2015;14:71. doi:10.1186/s12937-015-0059-3.

Lignan Works - Scientific Research

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Flaxseed is the richest plant source of the ω-3 fatty acid i.e. α-linolenic acid (ALA) (Gebauer et al. 2006). Flaxseed oil is low in saturated fatty acids (9 %), moderate in monosaturated fatty acids (18 %), and rich in polyunsaturated fatty acid (73 %) (Cunnane et al. 1993). Of all lipids in flaxseed oil, α- linolenic acid is the major fatty acid ranging from 39.00 to 60.42 % followed by oleic, linoleic, palmitic and stearic acids (Table 2), which provides an excellent ω-6:ω-3 fatty acid ratio of approximately 0.3:1 (Pellizzon et al. 2007). Although flaxseed oil is naturally high in anti-oxidant like tocopherols and beta-carotene, traditional flaxseed oil gets easily oxidized after being extracted and purified (Holstun and Zetocha 1994). The bioavailability of ALA is dependent on the type of flax ingested (ALA has greater bioavailability in oil than in milled seed, and has greater bioavailability in oil and milled seed than in whole seed) (Austria et al. 2008).

Plant lignans are phenolic compounds formed by the union of two cinnamic acid residues. Lignans are ubiquitous within the plant kingdom and are present in almost all plants (Tarpila et al. 2005). Lignans act as both antioxidants and phytoestrogens. Phytoestrogens can have weak estrogen activity in animals and humans. Flax contains up to 800 times more lignans than other plant foods (Mazur et al. 1996; Westcott and Muir 1996). Lignan content in flaxseed is principally composed of secoisolariciresinol diglucoside (SDG) (294–700 mg/100 g), matairesinol (0.55 mg/100 g), lariciresinol (3.04 mg/100 g) and pinoresinol (3.32 mg/100 g) (Tourre and Xueming 2010; Milder et al. 2005). Johnsson et al. (2000) reported SDG content in the range of 11.7 to 24.1 mg/g and 6.1 to 13.3 mg/g in defatted flaxseed flour and whole flaxseed, respectively. Besides lignans, other phenolic compounds found in flaxseed are p-coumaric acid and ferulic acid (Strandas et al. 2008). The SDG found in flax and other foods is converted by bacteria in the gut to the lignans- enterodiol and enterolactone which can provide health benefits due to their weak estrogenic or anti-estrogenic, as well as antioxidant effects (Adlercreutz 2007). Flax lignans have shown promising effects in reducing growth of cancerous tumors, especially hormone-sensitive ones such as those of the breast, endometrium and prostate (Tham et al. 1998).

Dietary fibers, lignans, and ω-3 fatty acids, present in flaxseed have a protective effect against diabetes risk (Prasad et al. 2000; Prasad 2001; Adlercreutz 2007). Flaxseed lignan SDG has been shown to inhibit expression of the phosphoenolpyruvate carboxykinase gene, which codes for a key enzyme responsible for glucose synthesis in the liver (Prasad 2002). Supplementation of diet of type 2 diabetics with 10 g of flaxseed powder for a period of 1 month reduced fasting blood glucose by 19.7 % and glycated hemoglobin by 15.6 % (Mani et al. 2011). It could be due to lower content of glycemic carbohydrates and higher content of dietary fibers of flaxseed. Several small studies using a fasting glucose tolerance approach have found a reduction in postprandial blood glucose levels of women consuming flaxseed (Cunnane et al. 1993, 1995). Kelley et al. (2009) studied that when conjugated linoleic acid (0.5 %) and flax oil (0.5 %) was supplemented in diet of rats susceptible to obesity and diabetic tumors, a 20 % reduction in glycemia was observed. Kapoor et al. (2011) studied the effect of supplementation of flaxseed powder on diabetic human females. Patients were provided 15 and 20 g/day of flaxseed powder for a period of 2 months. Post-prandial blood glucose levels were found to be decreased by 7.9 and 19.1 %, respectively. Similar results has also been reported by Nazni et al. (2006) who conducted a study on 25 diabetic subjects and supplemented flaxseed powder in bread form for 90 days and reported a significant reduction in blood glucose levels after supplementation. However, Dodin et al. (2008) measured fasting serum glucose and insulin levels and reported no change after flaxseed supplementation. Similarly, ingestion of 10 g/day of flaxseed oil had no effect on fasting blood serum glucose and insulin levels (Barre et al. 2008). Utilization of flaxseed for glycemic control may also be associated to the decrease in risk of obesity and dyslipidemia, since these are risk factors for the development of diabetes and resistance to insulin (Wu et al. 2010; Morisset et al. 2009).

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Tumor and Cancer reducing effects

Interest in research on the association between flaxseed ingestion and risk of cancer emerged when epidemiologic evidences suggested a beneficial relationship. Research in laboratories has shown that flaxseed inhibits the formation of colon, breast, skin, and lung tumors and also reduces blood vessel cell formation in female rats, all suggesting a protective effect against breast, colon and ovarian cancer (Truan et al. 2012). Higher levels of insulin and insulin-like growth factor 1 (IGF-1) increase cancer risk by stimulating cell proliferation and increasing survival of DNA-damaged cells through antiapoptotic mechanisms (Sturgeon et al. 2011). Blood insulin has also been associated with increased risk of pancreatic and colorectal cancers (Pisani 2008). Various studies suggest that flaxseed added to the diet may lower circulating levels of insulin and IGF-1 (Woodside et al. 2006; Chen et al. 2011a). However, Sturgeon et al. (2011) reported that incorporation of 7.5 g of flaxseed daily for 6 weeks and 15 g of flaxseed for an additional 6 weeks into the diet of healthy postmenopausal women had little short-term effect on blood levels of IGF-1. Flaxseed has a breast tumor-reducing effect, possibly because of its high content of SDG lignan (Truan et al. 2012; Chen et al. 2011a; Chen et al. 2009; Saggar et al. 2010a, b; Wang et al. 2005). Enterodiol (ED) and enterolactone (EL) are produced from flax lignans in animal body. Because they are structurally similar to human estrogen-17β-estradiol (E2), they have binding affinity to estrogen receptors (ER) (Penttinen et al. 2007). Flaxseed and its SDG component have been shown to attenuate tumorigenesis through a reduction in cell proliferation and angiogenesis, as well as an increase in apoptosis via modulation of the estrogen receptor (ER)- and growth factor- signaling pathways (Saggar et al. 2010a; Chen et al. 2009). The potential breast cancer protective effect of flax lignans could be due to their weak estrogenic activity and antioxidant properties. Flaxseed oil with its exceptionally high ALA content was also shown to reduce human estrogen receptor-positive breast tumors (MCF-7) growth by 33 % compared to control (Truan et al. 2010). Chen et al. (2007) studied that the groups of mice that received 5 % and 10 % flaxseed in the diet for 8 weeks inhibited tumor growth by 26 % and 38 %, respectively. The researchers suggested the ability of flaxseed to help maintain more early stages of cancer is due to the fact that flaxseed contains the highest level of plant lignans, which have antioxidant activities (Hall et al. 2006) and have also been shown to alter estrogen metabolism, which may decrease ovarian cancer risk and improve health (McCann et al. 2007).

Based on the information, it is evident that flaxseeds are the richest source of α-linolenic acid and lignans. It is also a considerable potential source of soluble fiber, antioxidants and high quality protein. Its long journey from being a medicine in ancient times to the health food source in 21st century has opened the doors for a large population. The role of flaxseed lignans and ω-3 fatty acid in reducing the risks associated with cardiac and coronary disease, cancer (breast, colon, ovary and prostate) and other human health risk factors has been well known. When healthy heart is one of the most desired and highly demanded health benefits from functional foods; and where food industry’s goal is to develop innovative solutions to address nutritional challenges, flaxseed is going to play a vital role for the same. Flaxseed can contribute in improving the availability of healthy food choices, specifically by improving the nutrient profile of foods through reductions in the salt, sugar and saturated fat content; and by increasing the content of ω-3 fatty acids and other bioactive compounds. With contribution from such factors, worldwide market for healthy heart foods is estimated to grow rapidly in the coming years. As a result, flax and flaxseed oil may be preferred ingredients of functional foods and nutraceuticals in future. There is no doubt that a change to an omega-3 rich and high fiber diet would be beneficial. Therefore the use of flaxseed in whole seed or ground form can be recommended as a dietary supplement. Modern techniques like high power ultrasound, micro-fluidization, spray granulation and nanoencapsulation will pave way for new approaches to the processing, stabilization and utilization of flaxseed oil. Further, enrichment of diets of the animals with flax/flaxseed oil for production of ω-3 enriched eggs, milk, meat and other animal origin products could be another approach in utilizing flaxseeds.

Goyal A, Sharma V, Upadhyay N, Gill S, Sihag M. Flax and flaxseed oil: an ancient medicine & modern functional food. Journal of Food Science and Technology. 2014;51(9):1633-1653. doi:10.1007/s13197-013-1247-9.

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Our results suggest that flaxseed and its lignans have potent antiestrogenic effects on estrogen receptor–positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.

Flaxseed and Its Lignans Inhibit Estradiol-Induced Growth, Angiogenesis, and Secretion of Vascular Endothelial Growth Factor in Human Breast Cancer Xenografts In vivo

Malin Bergman Jungeström, Lilian U. Thompson, Charlotta Dabrosin

Clin Cancer Res Feb 2007 (13) (3) 1061-1067; DOI: 10.1158/1078-0432.CCR-06-1651

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Flaxseed is one of the richest sources of lignans and is increasingly used in food products or as a supplement. Plant lignans can be converted by intestinal bacteria into the so-called enterolignans, enterodiol and enterolactone. For a proper evaluation of potential health effects of enterolignans, information on their bioavailability is essential. The aim of this study was to investigate whether crushing and milling of flaxseed enhances the bioavailability of enterolignans in plasma. In a randomized, crossover study, 12 healthy subjects supplemented their diet with 0.3 g whole, crushed, or ground flaxseed/(kg body weight · d). Each subject consumed flaxseed for 10 successive days separated by 11-d run-in/wash-out periods, in which the subjects consumed a diet poor in lignans. Blood samples were collected at the end of each run-in/wash-out period, and at the end of each supplement period. Plasma enterodiol and enterolactone were measured using LC-MS-MS. The mean relative bioavailability of enterolignans from whole compared with ground flaxseed was 28% (P ≤ 0.01), whereas that of crushed compared with ground flaxseed was 43% (P ≤ 0.01). Crushing and milling of flaxseed substantially improve the bioavailability of the enterolignans.

Among foods consumed by humans, flaxseed contains the highest concentration of enterolignan precursors, mainly secoisolariciresinol diglucoside. Other seeds, nuts, whole grains, fruits and vegetables, and beverages such as coffee and tea contain smaller amounts (24). The most important sources of lignan precursors in Western diets are beverages such as tea and coffee, seeds, cereals, berries, fruits and vegetables (25,26). Flaxseed is a relatively minor dietary component in most countries, but because of its potential health benefits [flaxseed also contains a high quantity of (n-3) fatty acids as well as dietary fiber], it is increasingly being incorporated into a variety of food products, such as bread, muesli bars, and breakfast cereals, or used as a supplement. For example, in the Netherlands, whole flaxseed is used in commercial breads (up to 3.5 g flaxseed/100 g bread); therefore is an important potential source of dietary lignans. In a case-control study carried out in Texas, Strom et al. (27) found that flaxseed bread was one of the main food sources of lignans.

The Relative Bioavailability of Enterolignans in Humans Is Enhanced by Milling and Crushing of Flaxseed1J. Nutr. December 1, 2005, vol. 135 no. 12 2812-2816

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Flax Lignans

Flax is one of the richest sources of plant lignans, being very rich in the lignan secoisolariciresinol diglucoside (SDG). Flax contains other lignans as well – namely, matairesinol, pinoresinol, lariciresinol, isolariciresinol and secoisolariciresinol (often abbreviated Seco or SECO) (143,144).

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Metabolism of Lignans

The lignans SDG, SECO, pinoresinol, lariciresinol and matairesinol in flax are converted by bacteria in the colon to the mammalian lignans, enterodiol and enterolactone. [The flax lignan isolariciresinol is not converted to mammalian lignans (145).] Enterodiol and enterolactone are called mammalian lignans or enterolignans because they are produced in the gut of humans and other mammals; they are not found in plants. A simplified diagram showing the conversion of flax lignans to mammalian lignans is given in Figure 4. Enterodiol can be converted to enterolactone (146). The biologic activity of flax and other plant lignans depends on the presence of certain bacteria in the gut (146). Some humans appear to lack either the right type or a sufficient number of gut bacteria to convert SDG and other lignans to mammalian lignans (147), and taking antibiotics virtually stops the production of enterodiol and enterolactone in the gut for several weeks (140). Enterodiol and enterolactone have three metabolic fates: 1) They can be excreted directly in the feces; 2) They can be taken up by epithelial cells lining the human colon, conjugated with glucuronic acid or sulfate and excreted in the feces or enter the circulation (148); or 3) They can be absorbed from the gut and transported to the liver, where free forms are conjugated before being released into the bloodstream (140). Eventually, they undergo enterohepatic circulation – that is, they are secreted into bile and reabsorbed from the intestine – and are excreted in the urine in conjugated form (149). Based on a kinetic study involving 12 healthy adults, the mammalian lignans appear to be absorbed from the colon about 8-10 hours after the plant lignans are eaten and reach a maximum concentration in the bloodstream about 7-10 hours later (150). The concentration of enterodiol and enterolactone in the feces, blood and urine is related to the concentration of plants lignans in the diet – large intakes of plant lignans result in large amounts of these mammalian lignans in biological fluids. Eating flax or flax-containing food products increases the blood levels of mammalian lignans (151-154) and the excretion of mammalian lignans and/or total lignans in feces (155) and urine (151,152,154,156-159). Consuming a diet supplemented with a lignan/SDG complex derived from flax also increases mammalian lignan excretion in urine (160). The bioavailability of the mammalian lignans can be enhanced by crushing and milling flax (161).

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Biological Effects of Lignans

Flax lignans and the mammalian lignans (enterodiol and enterolactone) are biologically active. Lignans have anticancer and antiviral effects, influence gene expression (activation) and may protect against estrogen-related diseases such as osteoporosis (139-141). Diets high in lignans may help maintain good cognitive function in postmenopausal women (164); reduce the risk of uterine fibroids in middle-aged women (165); reduce breast cancer risk in women (166); and reduce the risk of acute fatal coronary events (167) and prostate cancer (168) in men. Specific actions of lignans include the following:

• The main flax lignan SDG is an antioxidant. It scavenges for certain free radicals like the hydroxyl ion (•OH) (169). Our bodies produce free radicals continually as we use (oxidize) fats, proteins, alcohol and some carbohydrates for energy. Free radicals can damage tissues and have been implicated in the pathology of many diseases like atherosclerosis, cancer and Alzheimer disease (170). In a rat study, feeding flax at levels of 5% and 10% in the diet prior to administering a liver toxin protected against oxidative stress in liver tissue compared with a normal diet not containing flax (171). The mammalian lignans, enterodiol and enterolactone, also act as antioxidants (172). Indeed, the antioxidant action of SECO and enterodiol is greater than that of vitamin E (173).

• The mammalian lignans affect receptors found on the surface of cell membranes. For instance, they activate the pregnane X receptor, which is involved in the metabolism of bile acids, steroid hormones and many drugs. Enterolactone is a moderate activator of the receptor, suggesting it has the ability to affect the metabolism of some drugs (174). A study conducted in France suggested that some plant lignans, along with enterodiol and enterolactone, affect hormone receptors in breast tissue. Among 58,049 French women who did not eat soy regularly, a high dietary intake of lignans (>1395 μg/day) was associated with a reduced risk of breast cancer. The benefit was limited to women with estrogen receptor positive (ER+) and progesterone receptor positive (PR+) tumours, suggesting that the biologic effects of lignans derive in part from their effects on cell hormone receptors (166).

• The mammalian lignans stimulate the synthesis of sex hormone-binding globulin (SHBG) (175), which binds sex hormones and reduces their circulation in the bloodstream, thus decreasing their biologic activity. In a meta-analysis, higher blood levels of SHBG were associated with an 80% lower risk of type 2 diabetes in women and a 52% lower risk in men (176). Low blood levels of SHBG have been found in postmenopausal women with breast cancer (177).

• The mammalian lignans inhibit the activity of aromatase, an enzyme involved in the production of estrogens (178). Decreased aromatase activity may be one way in which lignans protect against breast cancer (179).

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