Potential protective properties of flax lignan secoisolariciresinol diglucoside

SDG can be successfully supplemented in numerous foods due to high stability percentage in finish products. SDG has been found to withstand baking temperatures (250 °C) and can be incorporated in cereal-based bakery products [14]. The SDG concentration of doughs, baked rye breads, graham buns, and muffins was found relatively stable during storage at room temperature for 1 week and at −25 °C for 2 months, respectively [15]. Similarly, macaroni fortified with whole ground flaxseed at levels of 10 to 20 %, dried under ultrahigh temperature (90 °C) and stored for 32 weeks under ambient conditions possessed approximately 80 to 95 % of the SDG contents [16]. Quantitative recovery of SDG from the commercially prepared breads was observed when product formulation was supplemented with pure SDG. However, 73–75 % recovery of SDG was noted from baked bread samples which contained flax meal or aqueous alcohol extracts in product recipe. The extent of grinding of the flaxseed was also shown to have a significant effect on the recovery of SDG from both flax meal breads and baked goods, with extraction of SDG from finely ground samples greater than that from course material [17]. A great part of the SDG content (89 %) was found stable during the heat treatment of ground flaxseed, either alone or as an ingredient in bread, under various conditions of temperature and during storage for several days [18]. Added SDG was retained in the whey fraction and 6 % was found in the cheese curd while up to 25 % of added SDG was lost in whey-based drinks during storage of 6 months at 8 °C [19]. SDG shows natural antioxidant mechanism in foods and prevents oxidation reactions resulting in enhanced shelf life of foods. The ethanolic flaxseed extracts enriched with SDG compounds exhibit antioxidant activity during frozen storage of meat products. However, antioxidant efficiency of the SDG-enriched extracts seems to depend on chemical composition of raw material and flax variety [20]. Moreover, thermal processing has been responsible for slight increase in extractability level of the lignans from raw flaxseed meal which is may be due to increasing porosity of the heated seeds. One recent scientific study reported that the flaxseed samples heated at 250 °C for 3.5 min possessed high SDG contents (1200 mg/100 g) when compared from unheated flaxseed samples (1099 mg/100 g) [14]. However, to conserve the relatively high content of lignans during production of commercial foods products, the initial raw material composition, the water content and the applied temperatures have to be considered.

The biological activity of SDG results from their conversion to the mammalian lignans enterolactone (EL) and enterodiol (ED) by the intestinal microflora in the upper part of the large bowel. The mammalian lignans differ from plant lignans in that mammalian lignans have the hydroxyl groups in the meta position while plant lignans have the oxygenated substituents primarily in the para positions [21]. The mammalian lignans, firstly identified in humans and animals in 1980 [22], are formed in the human body by the action of diverse phylogenetically bacterial strains dominating Peptostreptococcus sp. SDG-1 and Eubacterium sp. SDG-2 present in the gastrointestinal (GI) tract through hydrolyzing the sugar moiety of plant lignan precursors followed by dehydroxylation and demethylation process [23]. Many factors, in addition to diet, such as intestinal microflora, smoking, antibiotics, and obesity affect circulating lignan levels in the body [24]. Due to variations in these factors, large differences among individuals have been observed in lignan bio-activation in urine, fecal and blood samples. Different studies have analyzed human intake of lignans. However, so far research has not shed light on what proportion of ingested mg of plant lignans is metabolized in the gut, absorbed and finally reaches target tissue [23]. Mammalian lignan production from intake of whole or milled flaxseed supplemented baked products is dependent on time and dose but not on processing. The processed flaxseed supplemented muffin or bread did not affect the quantity of lignan excretion in womens which reflect stability and bioavailability of plant and mammalian lignans in human biological metabolism [25].

The animal and human studies have shown the prevention role of SDG against some cancers (breast, lung and colon) as a result of its strong anti-proliferative, antioxidant, anti-oestrogenic and/or anti-angiogenic activity. It is proposed that the anticancer activity of SDG is associated with the inhibition of enzymes involved in carcinogenesis. The growth of crypts and crypts foci are the earlier risk factor for colon cancer. The animal studies have showed that flaxseed SDG and lignan supplementation in rat’s diet resulted in aberrant crypts and it foci showing the anticancer role of these molecules [27]. Similar, the anti carcinogenic effect of SDG molecule has been observed in pulmonary metastasis, mammary gland and breast cancer metastasis. The studies showed that the supplementation of SDG in mice diet resulted in reduction of volume, area and numbers of tumors significantly as compared to control mice group. The two week supplementation of SDG in mice diet led to 22 % more pulmonary metastasis tumors in melanoma cells than average tumors as compared to control group having 59 % more tumors than average [28]. The SDG of flaxseed are proven to initiate the differentiation of enhancement of terminal end buds in mammary gland and thus have role in prevention of breast cancer. The series of studies have shown that progression of N-methyl-N-nitrosourea-induced mammary tumorigenesis results in development of carcinogenesis and SDG has proven to delay the progression of this phenomenon by regulating the terminal end bud differentiation [29, 30]. There are several possibilities that how SDG can biologically involve in delay or prevention of carcinogenic phenomenon. It is supposed that plasma insulin-like growth factor I, endothelial growth factor is responsible for risk factor of breast cancer progression and SDG can lower these growth factors [31, 32]. Another possibility of prevention role of SDG is in mediation of Zn concentration which observed more in breast cancer tissue compared to tissue of normal breast which may provide protection against breast cancer by limiting angiogenesis in such cases [33].

Human studied have shown that there could be consisted possibility of correlation between SDG and cancer. SDG may affect hormonal levels and may influence cancer progression. The potential effects of SDG are attributed to concomitant fat restriction. The research studies conducted by Demark-Wahnefried and co-workers [34, 35] on prostate cancer proliferation in human subjects have shown that flaxseed-supplemented could affect the biomarkers of prostatic neoplasia. A randomized controlled trial test on 161 prostate cancer patients for 30 days before prostatectomy were conducted by assigning diet without flaxseed supplementation and flaxseed-supplemented of 30 g/day. The proliferation (Ki-67, the primary endpoint) and apoptosis were assessed for tumor development. Proliferation rates were significantly lowers among men assigned to the flaxseed supplemented diets. Their findings suggest that flaxseed is associated with biological alterations that may have prevention role against prostate cancer. The studies from two research groups of Boccardo et al. [36] and Pietinen et al. [37] have demonstrated a strong correlation between SDG metabolites and breast cancer in women. The serum level of intestinal microbial derived SDG metabolites enterodial and enterolactone have inversed association with breast cancer when studies were conducted on 508 breast cancer women cases. The overall animal and human studies have been suggested SDG and its metabolites may provide prevention against cancer as result of its antioxidant activity or ability to inhibit enzyme action involved in steroid hormone metabolism.

The major hearts diseases are stock, coronary artery disease, peripheral artery disease which are resulted from oxidative stress, inflammation, obesity, diabetes, dyslipidemia and hypertension and contribute to an atherogenic environment that promotes the development of myocardial infarction and stroke, leading causes of mortality among industrialized nations [38, 39]. The animal and human studies have suggested that SDG and its metabolites mediate the serum total cholesterol, low density lipoprotein, total cholesterol and high density lipoprotein ratio which lead to less androgenic complication and antioxidative prevention [40]. A series of research studies indicates that regular flaxseed with α-linolenic acid and flax lignan polymer (containing 34–38 % SDG, 10–11 % 3-hydroxy-3-methylglutaric acid and 15–21 % cinnamic acids) as potential bioactive components or purified SDG in equimolar concentration have similar antiatherogenic effects [41].

Similarly, the human studies showed the SDG as potential cardiovascular protector by mediating the mechanisms of total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerides and glucose metabolism. It was observed that 20 hypercholesterolaemia and hypertriglyceridaemia subjects receiving 600 mg SDG per day for 8 weeks led to significant reductions in total cholesterol, LDL-cholesterol and glucose concentrations compared with the placebo group [42]. Several other studies have shown that SDG anti-cardiovascular effects are associated with enterolactone mediating increased expression of vascular endothelial growth factor, endothelial NO synthase and haeme oxygenase-1 mediated myocardial angiogenesis. Overall, the majority of studies that used purified SDG found improvements in markers of CVD [43].

Diabetes is a metabolic syndrome and is characterized by increases in central adiposity, serum tirglycerides, 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 free radicals and reactive oxygen species (ROS) are produced as a result of exogenous chemicals and/or to the endogenous metabolic processes involving redox enzymes and bioenergetic electron transfer in the biological system. These free radicals and ROS thus induce oxidative stress leading to damage of proteins, lipids and nucleic acid and results in cancer, diabetes, atherosclerosis, hepatic diseases. The actions of these molecules can be nullified through antioxidants mechanism [50, 51]. Antioxidant potential of SDG and its metabolites have been reported in several animal and human models. Animal studies have shown that SDG containing flaxseed extract significantly increases the levels of serum ALP, ALT, AST, Bilirubin, blood urea and creatinine with decrease in the levels of total protein and albumin in experimental rabbits exposed with induced hepatotocxicity compared to the control group. The SDG polymer complex can significantly prevent liver and renal damage from paracetamol induced hepatonephrotoxicity in rabbits. Thus, the flaxseed lignan act as a therapeutically useful hepato-nephroprotective agent [52]. Flaxseed supplementation may provide a new therapeutic strategy to reduce hypertriglyceridemia and fatty liver in rats [53]. Another study reported the rabbits exposure to SDG lignans for consecutive 8 weeks to assess histopathologic evaluation score of non-alcoholic fatty liver disease and suggested that SDG (8 mg/kg) can protective from liver diseases [54].

Intervention studies have shown that Flaxseed lignan can decreases liver disease risk factors in moderately hypercholesterolemia mens. The oral administration of SDG would decrease the level of blood cholesterol and liver disease risk factors induced by hypercholesterolemia in humans. Thirty men received placebo and capsules of SDG for 12 weeks and subjects received 100 mg of SDG exhibited a significant reduction in the ratio of low-density lipoprotein/high-density lipoprotein cholesterol, a significant percentage decrease in the levels of glutamic pyruvic transaminase and γ–glutamyl transpeptidase and a significant percentage decrease in the level of γ–glutamyl transpeptidase which may reduce the hepatic diseases risks [55].

Faxseed SDG has a therapeutic role in animal and human lupus nephritis. SDG significant delays the onset of proteinuria with preservation in GFR and renal size in a dose-dependent fashion [56]. Purified SDG during early life of a young rat animal sensitize bone strength due to low endogenous levels of sex hormones but having no negative effects on bone strength and bone health, as measures of bone mass in adulthood [57, 58]. SDG in addition with low-dose estrogen therapy, provides the greatest protection against ovariectomy-induced bone loss [59]. However, SDG shows no effect on bone mineral density content, body composition, lipoproteins, glucose level and inflammation [44]. SDG have a beneficial role in chronic renal disease like reduces weight, renal inflammation and lipid peroxides in polycystic kidney disease [60].

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].

Flax lignan SDG may be associated with the least increase in peripheral resistance as result the greatest reduction in plasma cortisol and the smallest increase in plasma fibrinogen measured during mental stress [68, 69]. SDG has long acting hypotensive effect mediated through the guanylate cyclase enzyme. SDG supplementation shows no significant effects on lymphocyte proliferation indicating that SDG has no side effects on the immune system [70].