Flaxseed lignans alleviates isoproterenol-induced cardiac hypertrophy by regulating myocardial remodeling and oxidative stress.

Cardiovascular diseases, the leading global cause of death, are usually associated with cardiac hypertrophy (CH). CH is an adaptive response of the heart against cardiac overloading, but continuous CH accelerates cardiac remodeling and results in heart failure. Available CH therapies delay the progress of heart failure, but they often fail to control symptoms or restore quality of life. Although flaxseed lignans have been shown to have significant anti-oxidant, anti-hypertensive, anti-inflammatory, and anti-fibrotic effects in various cardiovascular diseases, little is known about their effect on CH. Thus, this study evaluated the therapeutic effect of flaxseed lignans on CH, which was induced by subcutaneous injections with isoproterenol (5 mg/kg b.w) for 14 consecutive days. Flaxseed lignans (200 mg/kg) was given orally for 4 weeks. Cardiac pathological remodeling was evaluated by echocardiography, after which morphometric, biochemical, histological, and ultrastructural analyses were performed. Flaxseed lignans significantly ameliorated CH structural and functional alterations as shown by echocardiography. Lignans also reduced the relative heart weight, significantly decreased the elevated CK-MB and the lipid peroxidation marker malondialdehyde, augmented the myocardial total antioxidant capacity, and ameliorated the histopathological and ultrastructural changes in cardiac tissues and prevented interstitial collagen deposition. The results demonstrate promising anti-hypertrophic effect of flaxseed lignans against isoproterenol-induced cardiac hypertrophy, via regulating myocardial remodeling and oxidative stress. Therefore, lignans could be used as potential pharmacological intervention in the management of CH.

The fate of flaxseed-lignans after oral administration: A comprehensive review on its bioavailability, pharmacokinetics, and food design strategies for optimal application.

Lignans are one of the most important and abundant phytochemicals found in flaxseed-diets. These have shown to possess several health-benefits, including anticancer, antioxidant, neuroprotective, cardioprotective, and estrogenic-properties etc. The potential of lignans health-promoting effects are circumscribed due to their poor-bioavailability resulting from their bound structure. Recent studies have demonstrated that various food design strategies can enhance the release of bound-lignans from agro-industrial residues, resulting in a higher bioaccessibility and bioavailability. This review focuses primarily on the bioavailability of flaxseed lignans, key factors affecting it and their pharmacokinetics, different strategies to improve the contents of lignans, their release and delivery. Present study will help to deepen our understanding of the applications of lignans and their dietary-supplements in the prevention and treatment of diseases. Several absorption issues of lignans have been observed such as impaired-bioavailability and variability in pharmacokinetics and pharmacodynamics. Therefore, the development of novel strategies for optimizing lignan bioavailability is critical to ensure its successful application, such as the delivery of lignans to biological targets via "targeted designs." In addition, some detailed examination is required to identify and understand the basis of variation in lignans bioavailability caused by interactions with the gastrointestinal system.

Influence of Flaxseed Lignan Supplementation to Older Adults on Biochemical and Functional Outcome Measures of Inflammation.

Evidence from the literature suggests that dietary flaxseed lignans have the ability to modulate inflammation, which is recognized as the underlying basis of multiple chronic human diseases in older adults. Our objective was to determine the effects of oral lignan supplementation on biochemical and functional indicators of inflammation as well as safety and tolerability in older healthy adults. We designed a randomized, double-blind, placebo-controlled clinical trial in older healthy adults (60-80 years) to assess flaxseed lignan-enriched complex (∼38% secoisolariciresinol diglucoside [SDG]; 600 mg SDG dose) oral supplementation effects on biochemical and functional indicators of inflammation and safety and tolerability in older healthy adults after 6 months of once-daily oral administration. The clinical trial confirmed that plasma concentration of total flaxseed lignans (free and conjugated forms) secoisolariciresinol (SECO), enterodiol (ED), and enterolactone (ENL) were significantly associated with daily oral supplementation of flaxseed lignan-enriched complex (p < 0.05). A significant decrease in systolic blood pressure (SBP; from a mean of 155 ± 13 mm Hg at baseline to 140 ± 11 mm Hg at 24 weeks) was observed in lignan-supplemented participants stratified into an SBP ≥140 mm Hg subcategory (p = 0.04). No differences were found between treatment or placebo groups in terms of cognition, pain, activity, physical measurements (calf, waist, and upper arm circumstances), and grip strength. With respect to blood inflammatory markers, lipid profiles, and biochemical parameters, no significant differences were found between treatment and placebo groups at the end of the 6-month supplementation. No adverse effects were reported during supplementation. These data further support the safety and tolerability of long-term flaxseed lignan-enriched complex supplementation in older adults and identify an ability to favorably modulate SBP, an important risk factor in cardiovascular disease.

Enterolactone glucuronide and ß-glucuronidase in antibody directed enzyme prodrug therapy for targeted prostate cancer cell treatment.

Evidence from preclinical and animal studies demonstrated an anticancer effect of flaxseed lignans, particularly enterolactone (ENL), against prostate cancer. However, extensive first-pass metabolism following oral lignan consumption results in their systemic availability primarily as glucuronic acid conjugates (ENL-Gluc) and their modest in vivo effects. To overcome the unfavorable pharmacokinetics and improve their effectiveness in prostate cancer, antibody-directed enzyme prodrug therapy (ADEPT) might offer a novel strategy to allow for restricted activation of ENL from circulating ENL-Gluc within the tumor environment. The anti-prostate-specific membrane antigen (PSMA) antibody D7 was fused with human ß-glucuronidase (hßG) via a flexible linker. The binding property of the fusion construct, D7-hßG, against purified or cell surface PSMA was determined by flow cytometry and Octet Red 384 system, respectively, with a binding rate constant, K d, of 2.5 nM. The enzymatic activity of D7-hßG was first tested using the probe, 4-methylumbelliferone glucuronide. A 3.8-fold greater fluorescence intensity was observed at pH 4.5 at 2 h compared with pH 7.4. The ability of D7-hßG to activate ENL from ENL-Gluc was tested and detected using LC-MS/MS. Enhanced generation of ENL was observed with increasing ENL-Gluc concentrations and reached 3613.2 ng/mL following incubation with 100 µM ENL-Gluc at pH 4.5 for 0.5 h. D7-hßG also decreased docetaxel IC50 value from 23 nM to 14.9 nM in C4-2 cells. These results confirmed the binding and activity of D7-hßG and additional in vitro investigation is needed to support the future possibility of introducing this ADEPT system to animal models.

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs).

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC50=292.17±27.71 µM and 331.94±21.21 µM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC50=275.24±13.15 µM). These values are significantly lower than those of ascorbic acid (EC50=1129.32±88.79 µM) and α-tocopherol (EC50=944.62±148.00 µM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68±0.27; synthetic (S,S)-SDG-1: 2.09±0.16; synthetic (R,R)-SDG-2: 1.96±0.27], peroxyl [natural (S,S)-SDG-1: 2.55±0.11; synthetic (S,S)-SDG-1: 2.20±0.10; synthetic (R,R)-SDG-2: 3.03±0.04] and DPPH [natural (S,S)-SDG-1: EC50=83.94±2.80 µM; synthetic (S,S)-SDG-1: EC50=157.54±21.30 µM; synthetic (R,R)-SDG-2: EC50=123.63±8.67 µM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.

Effect of different structural flaxseed lignans on the stability of flaxseed oil-in-water emulsion: An interfacial perspective.

The influences of the different structural flaxseed lignans on flaxseed oil (FO) emulsions during storage and digestion were investigated, focusing on their interfacial behavior. From perspective of interface, more than 60% of secoisolariciresinol (SECO) and the acidic hydrolysates of flaxseed lignan macromolecule (FLEH) were located on the interface of FO emulsions. It improved the stability of FO emulsions both during storage and digestion by inhibiting of free radical penetration and improving their targeted antioxidative activity. By comparison, the secoisolariciresinol diglucoside (SDG) and the alkaline hydrolysates of flaxseed lignan macromolecule (FLE) largely located in the aqueous and exerted lower antioxidative efficiency in emulsions. Moreover, SDG, SECO, FLE and FLEH slowed down the digestive rate of FO in emulsions, which might be due to flaxseed lignans inhibited the activity of digestive enzymes. These findings suggested that the different structural flaxseed lignans had the potential as antioxidants in emulsions during storage and digestion.

Flaxseed Lignans as Important Dietary Polyphenols for Cancer Prevention and Treatment: Chemistry, Pharmacokinetics, and Molecular Targets.

Cancer causes considerable morbidity and mortality across the world. Socioeconomic, environmental, and lifestyle factors contribute to the increasing cancer prevalence, bespeaking a need for effective prevention and treatment strategies. Phytochemicals like plant polyphenols are generally considered to have anticancer, anti-inflammatory, antiviral, antimicrobial, and immunomodulatory effects, which explain their promotion for human health. The past several decades have contributed to a growing evidence base in the literature that demonstrate ability of polyphenols to modulate multiple targets of carcinogenesis linking models of cancer characteristics (i.e., hallmarks and nutraceutical-based targeting of cancer) via direct or indirect interaction or modulation of cellular and molecular targets. This evidence is particularly relevant for the lignans, an ubiquitous, important class of dietary polyphenols present in high levels in food sources such as flaxseed. Literature evidence on lignans suggests potential benefit in cancer prevention and treatment. This review summarizes the relevant chemical and pharmacokinetic properties of dietary polyphenols and specifically focuses on the biological targets of flaxseed lignans. The consolidation of the considerable body of data on the diverse targets of the lignans will aid continued research into their potential for use in combination with other cancer chemotherapies, utilizing flaxseed lignan-enriched natural products.