Flax

In memory of Dr Johanna Budwig 1908 – 2003

 

Flax, Flaxseed, Flaxseed Oil – A selection of Scientific Studies :

Cardio

Dietary Flaxseed Reduces Central Aortic Blood Pressure Without Cardiac Involvement but Through Changes in Plasma Oxylipins.

Abstract

In the year-long FlaxPAD clinical trial (Flaxseed for Peripheral Artery Disease), dietary flaxseed generated a powerful reduction in brachial systolic and diastolic blood pressure in patients with peripheral artery disease. Oxylipins were implicated as potential mechanistic mediators. However, the ability of flaxseed to impact central aortic hypertension, arterial stiffness, or cardiac performance was not investigated. Additionally, the relationship between central blood pressure (cBP) and oxylipins was not elucidated. Therefore, radial tonometry and pulse wave analysis were used to measure cBP and cardiac function in the FlaxPAD population (n=62). Plasma oxylipins were analyzed with high-performance liquid chromatography mass spectrometry. In patients with high blood pressure at baseline, the average decrease in central systolic and diastolic blood pressures versus placebo was 10 and 6 mm Hg, respectively. Flaxseed did not significantly impact augmentation index or other cardiac function indices. Alternatively, the data support several specific oxylipins as potential mediators in the antihypertensive properties of flaxseed. For example, every 1 nmol/L increase in plasma 16-hydroxyeicosatetraenoic acid increased the odds of higher central systolic and diastolic blood pressures by 12- and 9-fold, respectively. Every 1 nmol/L increase in plasma thromboxane B2 and 5,6-dihydroxyeicosatrienoic acid increased the odds of higher cBP by 33- and 9-fold, respectively. Flaxseed induced a decrease in many oxylipins, which corresponded with a reduced risk of elevated cBP. These data extend the antihypertensive properties of flaxseed to cBP without cardiac involvement but rather through oxylipins.

This study provides further support for oxylipins as therapeutic targets in hypertension.

KEYWORDS:

central blood pressure; flaxseed; hypertension; nutrition; oxylipins; peripheral vascular disease; pulse wave analysis

PMID : 27528063

 

Impact of dietary flaxseed (linum usitatissimum) supplementation on biochemical profile in healthy rats.

Abstract

Flaxseed has been suggested play preventive and therapeutic roles in cardiovascular disease. The aim of this study was to evaluate the influence of flaxseed-supplemented dietary in healthy rats. We used 30 rats divided in three groups (n = 10): Control Group (C) was fed with a casein-based chow (10% protein; 5% fiber; 7% lipid); Flaxseed Group (F) was fed with the casein-based chow supplemented with 25% flaxseed (10% protein; 7% fiber; 11% lipid); Internal Control Group (IC) was fed with the casein-based chow plus soybean oil and fiber (10% protein; 7% fiber; 11% lipid). The blood was obtained by cardiac puncture (after 180 days) and the serum was separated for lipid profile, glucose and uric acid analyses by commercial kit. Although all groups fed the same amount of ration, F group presented low (p < 0.05) body mass than C and IC groups. Total cholesterol and triacylgycerol were similar between all groups. F group presented HDL-C (High-density lipoprotein cholesterol) increase (p < 0.05) in 47% when compared C group. The LDL-C (Low-density lipoprotein cholesterol), glucose and uric acid were reduced (p < 0.05) 22%, 78% 64%, respectively, in F compared to C group.

All results together suggest that the supplementation with 20% o flaxseed might be important to prevent cardiovascular disorders.

PMID : 22470026

 

 

Overview of Flaxseed Patent Applications for the Reduction of Cholesterol Levels.

Abstract

BACKGROUND:

Flaxseed is becoming an increasingly widely used food ingredient. The rising interest of the food industry in this nutraceutical is primarily because of functional nutrients, such as alpha-linolenic acid and lignans, which have health benefits due to their lipid-lowering properties.

OBJECTIVE:

The objective of this study was to provide an overview of the patenting of flaxseed products with cholesterol-lowering effects.

METHOD:

Patent applications filed by country of origin were retrieved from the Derwent Innovations Index®database.

RESULTS:

A total of 307 patent documents were identified, of which 184 claim the use of flaxseed or parts of the flax plant in the product formulation, for their lipid-lowering effect when consumed by humans. A few of the patent applications contain claims for new products based on flaxseed in isolation, including the preparation of foods designed to inhibit the production of cholesterol. Most of the claims were for flaxseed in the form of oil and in association with other lipid-lowering compounds, mainly for the food industry, in the form of dietary supplements or baked products designed to raise their high-density lipoprotein content, and for treating heart problems. China and the United States are the leading countries of flax-related applications.

CONCLUSION:

These results may have important implications for the production of functional food products that meet specific societal demands.

KEYWORDS:

Cholesterol; flaxseed; flaxseed products; functional food; linseed; nutraceuticals; patent

PMID: 26996439

 

Omega-3-fatty acid adds to the protective effect of flax lignan concentrate in pressure overload-induced myocardial hypertrophy in rats via modulation of oxidative stress and apoptosis.

Abstract

Objective of the present investigation was to study the effect of the flax lignan concentrate (FLC) and Omega-3-fatty acid (O-3-FA) on myocardial apoptosis, left ventricular (LV) contractile dysfunction and electrocardiographic abnormalities in pressure overload-induced cardiac hypertrophy. The rats were divided into five groups such as sham, aortic stenosis (AS), AS+FLC, AS+O-3-FA and AS+FLC+O-3-FA. Cardiac hypertrophy was produced in rats by abdominal aortic constriction. The rats were treated with FLC (400mg/kg, p.o.), O-3-FA (400mg/kg, p.o.) and FLC+O-3-FA orally per day for four weeks. The LV function, myocardial apoptosis, and oxidative stress were quantified. FLC+O-3-FA treatment significantly reduced hemodynamic changes, improved LV contractile dysfunction, reduced cardiomyocyte apoptosis and cellular oxidative stress. Moreover, it significantly up-regulated the VEGF expression and decreased TNF-alpha level in serum. The histological analysis also revealed that FLC+O-3-FA treatment markedly preserved the cardiac structure and inhibited interstitial fibrosis.

In conclusion, FLC+O-3-FA treatment improved LV dysfunction, inhibited cardiomyocyte apoptosis, improved myocardial angiogenesis, conserved activities of membrane-bound phosphatase enzymes and suppressed inflammation through reduced oxidative stress in an additive manner than FLC alone and O-3-FA alone treatment in pressure overload-induced cardiac hypertrophy.

KEYWORDS:

Antioxidants; Apoptosis; Cardiac hypertrophy; Electrocardiography; Flax lignan concentrate; Omega-3-fatty acid; ROS; TNF-α; VEGF

PMID : 26277701

 

Impact of dietary flaxseed (linum usitatissimum) supplementation on biochemical profile in healthy rats.

Abstract

Flaxseed has been suggested play preventive and therapeutic roles in cardiovascular disease. The aim of this study was to evaluate the influence of flaxseed-supplemented dietary in healthy rats. We used 30 rats divided in three groups (n = 10): Control Group (C) was fed with a casein-based chow (10% protein; 5% fiber; 7% lipid); Flaxseed Group (F) was fed with the casein-based chow supplemented with 25% flaxseed (10% protein; 7% fiber; 11% lipid); Internal Control Group (IC) was fed with the casein-based chow plus soybean oil and fiber (10% protein; 7% fiber; 11% lipid). The blood was obtained by cardiac puncture (after 180 days) and the serum was separated for lipid profile, glucose and uricacid analyses by commercial kit. Although all groups fed the same amount of ration, F group presented low (p < 0.05) body mass than C and IC groups. Total cholesterol and triacylgycerol were similar between all groups. F group presented HDL-C (High-density lipoprotein cholesterol) increase (p < 0.05) in 47% when compared C group. The LDL-C (Low-density lipoprotein cholesterol), glucose and uric acid were reduced (p < 0.05) 22%, 78% 64%, respectively, in F compared to C group.

All results together suggest that the supplementation with 20% o flaxseed might be important to prevent cardiovascular disorders.

PMID: 22470026

 

 

Mental Health / Cognitive / Neurological

 

Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder.

Abstract

OBJECTIVES:

This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (alpha-LNA), safely reduced symptom severity in youth with bipolar disorder.

METHODS:

Children and adolescents aged 6-17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg alpha-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses.

RESULTS:

There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician-rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: %alpha-LNA (r = -0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = -0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for alpha-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for alpha-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms.

CONCLUSIONS:

Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n-6 levels, individual variations in conversion of alpha-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone.

PMID : 20402707

 

The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors.

Abstract

Numerous studies have linked severe stress to the development of major depressive disorder(MDD) and suicidal behaviors. Furthermore, recent preclinical studies from our laboratory and others have demonstrated that in rodents, chronic stress and the stress hormone cortisol cause oxidative damage to mitochondrial function and membrane lipids in the brain. Mitochondria play a key role in synaptic neurotransmitter signaling by providing adenosine triphosphate (ATP), mediating lipid and protein synthesis, buffering intracellular calcium, and regulating apoptotic and resilience pathways. Membrane lipids are similarly essential to central nervous system (CNS) function because cholesterol, polyunsaturated fatty acids, and sphingolipids form a lipid raft region, a special lipid region on the membrane that mediates neurotransmitter signaling through G-protein-coupled receptors and ion channels. Low serum cholesterol levels, low antioxidant capacity, and abnormal early morning cortisol levels are biomarkers consistently associated with both depression and suicidal behaviors. In this review, we summarize the manner in which nutrients can protect against oxidative damage to mitochondria and lipids in the neuronal circuits associated with cognitive and affective behaviors. These nutrients include ω3 fatty acids, antioxidants (vitamin C and zinc), members of the vitamin B family (Vitamin B12 and folic acid), and magnesium. Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors.

 

A growing body of studies suggests the intriguing possibility that regular consumption of these nutrients may help prevent the onset of mood disorders and suicidal behaviors in vulnerable individuals, or significantly augment the therapeutic effect of available antidepressants. These findings have important implications for the health of both military and civilian populations.

KEYWORDS:

Vitamin; lipid; oxidative stress; suicide; synaptic plasticity; zinc

PMID : 25365455

 

The effects of omega-3 fatty acids and vitamin E co-supplementation on clinical and metabolic status in patients with Parkinson‘s disease: A randomized, double-blind, placebo-controlled trial.

Abstract

The current research was performed to evaluate the effects of omega-3 fatty acids and vitamin E co-supplementation on clinical signs and metabolic status in people with Parkinson‘s disease (PD). This randomized double-blind placebo-controlled clinical trial was conducted in 60 patients with PD. Participants were randomly assigned into two groups to receive either 1000 mg omega-3 fatty acids from flaxseed oil plus 400 IU vitamin E supplements (n = 30) or placebo (n = 30) for 12 weeks. Unified Parkinson‘s disease rating stage (UPDRS) were recorded at baseline and the after 3-month intervention. After 12 weeks’ intervention, compared with the placebo, omega-3 fatty acids and vitamin E co-supplementation led to a significant improve in UPDRS (-3.3 ± 10.0 vs. +4.4 ± 14.9, P = 0.02). Furthermore, co-supplementation decreased high-sensitivity C-reactive protein (hs-CRP) (-0.3 ± 0.6 vs. +0.3 ± 0.3 μg/mL, P < 0.001), and increased total antioxidant capacity (TAC) (+65.2 ± 68.7 vs. +16 ± 52.4 μmol/L, P = 0.003) and glutathione (GSH) concentrations (+41.4 ± 80.6 vs. -19.6 ± 55.9 μmol/L, P = 0.001) compared with the placebo. Additionally, co-supplementation meaningfully decreased insulin (-2.1 ± 4.9 vs. +1.4 ± 6.2 μIU/mL, P = 0.01), homeostasis model of assessment-estimated insulin resistance (-0.7 ± 1.8 vs.+0.3 ± 1.6, P = 0.02) and Beta cell function (-5.9 ± 13.9 vs. +5.7 ± 25.5, P = 0.03), and increased quantitative insulin sensitivity check index (+0.009 ± 0.02 vs. -0.006 ± 0.03, P = 0.03) compared with the placebo.

Overall, our study demonstrated that omega-3 fatty acids and vitamin E co-supplementation in people with PD had favorable effects on UPDRS, hs-CRP, TAC, GSH and markers of insulin metabolism.

KEYWORDS:

Inflammation; Oxidative stress; Parkinson‘s disease; Supplementation

PMID: 28342967

 

 

Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet.

Abstract

Research over the past 15 years has suggested a high comorbidity of depression and coronary heart disease (CHD). However the mechanisms responsible for this relationship are poorly understood. This study was designed to examine the relationships between depressivebehaviors and concentrations of circulating lipids and lipid signaling molecules that may be common to both CHD and depression in a cohort of cynomolgus monkeys (Macaca fascicularis) consuming a ‘Western’ diet, enriched with saturated fat and cholesterol. Socially-housed adult female cynomolgus monkeys (n=36) were fed the Western diet for 27 months and depressive behavior was recorded weekly. Body weight, body mass index and circulating cholesterol profiles were measured in all animals, and fatty acids (FA) and FA-based signaling molecules were measured in the 6 least and 6 most depressed monkeys. Monkeys consuming the Western diet exhibited a broad range of percent time spent in depressive behavior. The percent time spent depressed was positively correlated with total plasma and LDL cholesterol and negatively correlated with HDL cholesterol. Despite being leaner, depressed monkeys had higher concentrations of monounsaturated fats (C16:1 and C17:1), a higher ω6/ω3 polyunsaturated fatty acid (PUFA) ratio and higher concentrations of omega-6 (ω6) PUFAs, particularly C18:2ω6 and C20:3ω6. FA ratios suggest that stearoyl CoA desaturase 1 activity was increased in depressed monkeys. Depressed female cynomolgus monkeys had elevated concentrations of serum lipids and lipid signaling molecules that are typically associated with obesity, insulin resistance and cardiovascular disease, which may account in part for the comorbidity of depression and CHD.

PMID : 21256145

 

Omega-3 Supplementation for Psychotic Mania and Comorbid Anxiety in Children.

Abstract

OBJECTIVES:

Therapeutic benefits of omega-3 fatty acids (Ω3) for mood disorders, psychosis, and anxiety have been reported in the literature. The purpose of the present article is to provide a literature review of Ω3 supplementation for affective disorders and to illustrate the benefits of Ω3 with a case presentation of a young girl with a history of bipolar disorder-type 1 with psychotic features and generalized anxiety disorder.

METHODS:

Reviewed literature includes treatment studies of the impact of Ω3 on child mood disorders supplemented by review of meta-analyses within the adult mood disorders literature. The subject of this case report participated in 11 in-depth diagnostic and functional assessments over 5 years as part of an unrelated study. Three years were presupplementation and 2 years were with supplementation with no other medication changes, thus making a naturalistic multiple-baseline single-subject experiment.

RESULTS:

Augmentation over a 2 year period was notable for clinically significant and sustained improvement in depressive, manic, and psychotic symptoms.

CONCLUSION:

Ω3 supplementation may be a safe, adjunct intervention for treating bipolar disorder in children and adolescents, even in the presence of psychotic and anxious features. The 2 year follow-up in this case offers hope of an accumulating and enduring benefit. Further research into mechanisms of Ω3 action and of combination treatment with other well-known interventions for mood disorders would be beneficial.

PMID : 26288263

Pilot Randomized Controlled Trial of Omega-3 and Individual-Family Psychoeducational Psychotherapy for Children and Adolescents With Depression.

Abstract

The goal of this study is to evaluate feasibility and estimate effect sizes of omega-3 fatty acids (Ω3), individual-family psychoeducational psychotherapy (PEP), their combination, and moderating effects of maternal depression and psychosocial stressors in youth with depression. In a pilot 2 × 2 randomized controlled trial, 72 youth (ages 7-14; 57% Caucasian, 57% male) with major depression, dysthymia, or depression not otherwise specified were randomized to 12 weeks of Ω3, PEP+placebo, Ω3+PEP, or placebo. Ω3 versus placebo was double-masked. Evaluators masked to condition assessed depressive severity at baseline (randomization) and at 2, 4, 6, 9, and 12 weeks using the Children’s Depression Rating Scale-Revised. Side effects were either absent or mild. PEP was administered with 74% fidelity. Remission was 77%, Ω3+PEP; 61%, PEP+placebo; 44%, Ω3; 56%, placebo. Intent-to-treat analyses found small to medium effects of combined treatment (d = .29) and Ω3 monotherapy (d = .42), but negligible effect for PEP+placebo (d < .10), all compared to placebo alone. Relative to placebo, youth with fewer social stressors responded better to Ω3 (p = .04), PEP (p = .028), and their combination (p = .035), and those with maternal depression responded better to PEP (p = .020) than did those without maternal depression. Remission rates were favorable compared to other studies of psychotherapy and comparable to an existing randomized controlled trial of Ω3; results warrant further evaluation in a larger sample. Ω3 was well tolerated. Active treatments show significantly more placebo-controlled depression improvement in the context of maternal depression and fewer stressors, suggesting that they may benefit depression with a more endogenous than environmental origin.

PMID : 27819485

Omega-3 Fatty Acid Plasma Levels Before and After Supplementation: Correlations with Mood and Clinical Outcomes in the Omega-3 and Therapy Studies.

Abstract

OBJECTIVE:

To examine fatty acid profiles, their response to omega-3 fatty acid (Ω3) supplementation, and associations with clinical status and treatment response in youth with mood disorders.

METHODS:

In a placebo-controlled 2X2 design, 7-14 year-olds (N = 95) in parallel pilot trials (depression N = 72; bipolar N = 23) were randomly assigned to 12 weeks of Ω3 supplementation (1.4 g eicosapentaenoic acid [EPA], 0.2 g docosahexaenoic acid [DHA], and 0.27 g other Ω3 per day); psychoeducational psychotherapy (PEP); their combination; or placebo (mainly oleic and linoleic acid) alone. Blood was drawn at baseline (N = 90) and endpoint (n = 65). Fatty acid levels were expressed as percent of total plasma fatty acids. Correlational and moderator/mediator analyses were done with SPSS Statistics 23.

RESULTS:

At baseline: (1) DHA correlated negatively with alpha-linolenic acid (ALA) (r = -0.23, p = 0.029); (2) Arachidonic acid (AA, Ω6) correlated negatively with global functioning (r = -0.24, p = 0.022); (3) Total Ω3 correlated negatively with age (r = -0.22, p = 0.036) and diastolic blood pressure (r = -0.31, p = 0.006). Moderation: Baseline ALA moderated response to Ω3 supplementation: ALA levels above the sample mean (lower DHA) predicted significantly better placebo-controlled response (p = 0.04). Supplementation effects: Compared to placebo, 2 g Ω3 per day increased EPA blood levels sevenfold and DHA levels by half (both p < 0.001). Body weight correlated inversely with increased EPA (r = -0.52, p = 0.004) and DHA (r = -0.54, p = 0.003) and positively with clinical mood response. Mediation: EPA increase baseline-to-endpoint mediated placebo-controlled global function and depression improvement: the greater the EPA increase, the less the placebo-controlled Ω3 improvement.

CONCLUSION:

Ω3 supplementation at 2 g/day increases blood levels substantially, more so in smaller children. A possible U-shaped response curve should be explored.

KEYWORDS:

mediation; moderation; mood disorders; omega-3 fatty acids; plasma levels; supplementation as treatment

PMID : 28157380

Omega-3 supplementation associated with improved parent-rated executive function in youth with mood disorders: secondary analyses of the omega 3 and therapy (OATS) trials.

Abstract

BACKGROUND:

Improvements in executive functioning (EF) may lead to improved quality of life and lessened functional impairment for children with mood disorders. The aim was to assess the impact of omega-3 supplementation (Ω3) and psychoeducational psychotherapy (PEP), each alone and in combination, on EF in youth with mood disorders. We completed secondary analyses of two randomized controlled trials (RCTs) of Ω3 and PEP for children with depression and bipolar disorder.

METHODS:

Ninety-five youths with depression or bipolar disorder not otherwise specified/cyclothymic disorder were randomized in 12-week RCTs. Two capsules (Ω3 or placebo) were given twice daily (1.87 g Ω3 total daily, mostly eicosapentaenoic acid). Families randomized to PEP participated in twice-weekly 50-min sessions. Analyses assess impact of interventions on the Behavior Rating Inventory of Executive Functioning (BRIEF) parent-report Global Executive Composite (GEC) and two subscales, Behavior Regulation (BRI) and Metacognition (MI) Indices. Intent-to-treat repeated measures ANOVAs, using multiple imputation for missing data, included all 95 randomized participants. Trials were registered with www.clinicaltrials.gov, NCT01341925 & NCT01507753.

RESULTS:

Participants receiving Ω3 (aggregating combined and monotherapy) improved significantly more than aggregated placebo on GEC (p = .001, d = .70), BRI (p = .004, d = .49), and MI (p = .04, d = .41). Ω3 alone (d = .49) and combined with PEP (d = .67) each surpassed placebo on GEC. Moderation by attention-deficit/hyperactivity disorder (ADHD) comorbidity was nonsignificant although those with ADHD showed nominally greater gains. PEP monotherapy had negligible effect.

CONCLUSIONS:

Decreased impairment in EF was associated with Ω3 supplementation in youth with mood disorders. Research examining causal associations of Ω3, EF, and mood symptoms is warranted.

© 2017 Association for Child and Adolescent Mental Health.

KEYWORDS:

School children; bipolar disorder; depression; nutrition; psychotherapy

PMID : 29063592

 

Flaxseed mitigates brain mass loss, improving motor hyperactivity and spatial memory, in a rodent model of neonatal hypoxic-ischemic encephalopathy.

Abstract

Neonatal hypoxic-ischemic (HI) encephalopathy is a major cause of perinatal morbimortality. There is growing evidence that n-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), attenuate brain injury. This study aimed to investigate the possible neuroprotective effect of maternal intake of flaxseed, rich in DHA׳s precursor α-linolenic acid, in the young male offspring subjected to perinatal HI. Wistar rats were divided in six groups, according to maternal diet and offspring treatment at day 7: Control HI (CHI) and Flaxseed HI (FHI); Control Sham and Flaxseed Sham; Control Control and Flaxseed Control. Flaxseed diet increased offspring׳s hippocampal DHA content and lowered depressive behavior. CHI pups presented brain mass loss, motor hyperactivity and poor spatial memory, which were improved in FHI rats.

Maternal flaxseed intake may prevent depressive symptoms in the offspring and promote neuroprotective effects, in the context of perinatal HI, improving brain injury and its cognitive and behavioral impairments.

KEYWORDS:

Depression; Essential fatty acids; Flaxseed; Memory; Neonatal hypoxia-ischemia

PMID : 25865679

Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression.

Abstract

OBJECTIVE:

Studies using augmentation of pharmacotherapies with omega-3 in bipolar disorder have been conducted; however, to date a specific meta-analysis in this area has not been published. Thus, we present the significant findings from meta-analyses of omega-3 in the treatment of bipolar depression and bipolar mania.

DATA SOURCES:

PubMed, CINAHL, Web of Science, and Cochrane Library databases were searched for clinical trials up to September 1, 2010, using the search terms bipolar disorder OR bipolar depression OR bipolar mania OR mania OR hypomania OR cyclothymia with the search terms omega 3 OR essential fatty acids OR polyunsaturated fatty acids OR DHA OR EPA OR fish oil OR flax oil. Clinical trial registries and gray literature (published or unpublished data not readily accessible via main databases) were also searched.

DATA SELECTION:

The analysis included randomized controlled studies 4 weeks or longer, with a sample size > 10, written in English, using omega-3 for diagnosed bipolar depression or mania. No criteria were set for age, gender, or ethnicity.

DATA EXTRACTION:

A random-effects model was used. The model analyzed the standard mean difference between treatment and placebo between baseline and endpoint, combining the effect size (Hedges g) data. Funnel plot and heterogeneity analyses (I²) were also performed.

DATA SYNTHESIS:

The findings of 5 pooled datasets (n = 291) on the outcome of bipolar depression revealed a significant effect in favor of omega-3 (P = .029), with a moderate effect size of 0.34. On the outcome of mania, 5 pooled datasets (n = 291) revealed a nonsignificant effect in favor of omega-3 (P = .099), with an effect size of 0.20. Minor heterogeneity between studies on the outcome of bipolar depression was found (I² = 30%; P = .213), which was not present on the outcome of bipolar mania (I² = 0%; P = .98). Funnel plot symmetry suggested no significant likelihood of publication bias. Meta-regression analysis between sample size and effect size, however, revealed that studies with smaller sample sizes had larger effect sizes (P = .05).

CONCLUSIONS:

The meta-analytic findings provide strong evidence that bipolar depressive symptoms may be improved by adjunctive use of omega-3. The evidence, however, does not support its adjunctive use in attenuating mania.

© Copyright 2012 Physicians Postgraduate Press, Inc.

PMID: 21903025

The antidepressant effect of secoisolariciresinol, a lignan-type phytoestrogen constituent of flaxseed, on ovariectomized mice.

Abstract

Secoisolariciresinol (SECO) is a natural lignan-type phytoestrogen constituent mainly found in flaxseed. It can be metabolized in vivo to mammalian lignans of enterodiol and enterolactone, which have been proven to be effective in relieving menopausal syndrome. Depression is one of the most common symptoms of menopausal syndrome, and is currently treated with estrogen replacement and antidepressant therapy. However, due to the serious side-effects of such agents, there are urgent needs for safer and more tolerable treatments. In this paper, using two classical depression models, the forced swimming test and the tail suspension test, we report the antidepressant effect of SECO on ovariectomized (OVX) mice by intragastric administration for 14 consecutive days at doses of 5, 10 and 20 mg/kg. The results showed that SECO (10 mg/kg) treatment could significantly reduce the duration of immobility of OVX mice in these two models compared with the control group (OVX mice + vehicle), which was similar to the positive control imipramine. In addition, SECO treatment could substantially increase brain monoamine (norepinephrine and dopamine) levels in OVX mice.

The present studies showed that SECO can reverse depressive-like behavior and exhibit monoamine-enhancing effects.

PMID : 22476613

 

Anti-depressive effect of polyphenols and omega-3 fatty acid from pomegranate peel and flax seed in mice exposed to chronic mild stress.

Abstract

AIM:

In this study polyphenols from pomegranate peel, and n-3 fatty acids with polyphenols from flax seed were evaluated for their anti depression properties in mice exposed to chronic mild stress (CMS).

METHODS:

A total of 40 mice initially trained to consume 2% sucrose solution for 3 weeks were then divided into five groups of eight each. The first group was the normal control, the remaining four groups were exposed to CMS but were force fed with either: 10 mL water per kg bodyweight per day; imipramine (a standard antidepressant) 15 mg kg bodyweight; 30 mg per kg bodyweight polyphenol equivalent extract from pomegranate peel; or 30 mg polyphenols per kg bodyweight with omega-3 fatty acids present, for 50 days. At the end, blood and brain were analyzed for various biomarkers of depression.

RESULTS:

The flax seed and imipramine groups had significantly increased sucrose consumption, decreased cortisol (blood), decreased epinephrine and norepinephrine concentration, decreased monoamine oxidase A and B activity, and decreased superoxide dismutase activity. Lipid peroxidation was completely inhibited. In contrast, pomegranate peel extract also completely inhibited lipid peroxidation in the brain, and reduced enzyme activity and hormone concentration but to a lesser extent than flax seed.

CONCLUSION:

Polyphenols from flax seed with omega-3 fatty acids were able to reduce all the CMS effects tested compared to polyphenols from pomegranate peel.

© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

KEYWORDS:

CMS; flax seed; neurotransmitters; pomegranate peel; sucrose

PMID: 24152226

 

Secoisolariciresinol diglucoside is a blood-brain barrier protective and anti-inflammatory agent: implications for neuroinflammation.

Abstract

BACKGROUND:

Secoisolariciresinol diglucoside (SDG), the main lignan in flaxseed, is known for its beneficial effects in inflammation, oxidative stress, heart disease, tumor progression, atherosclerosis, and diabetes. SDG might be an attractive natural compound that protects against neuroinflammation. Yet, there are no comprehensive studies to date investigating the effects of SDG on brain endothelium using relevant in vivo and in vitro models.

METHODS:

We evaluated the effects of orally administered SDG on neuroinflammatory responses using in vivo imaging of the brain microvasculature during systemic inflammation and aseptic encephalitis. In parallel, the anti-inflammatory actions of SDG on brain endothelium and monocytes were evaluated in vitro blood-brain barrier (BBB) model. Multiple group comparisons were performed by one-way analysis of variance with Dunnet’s post hoc tests.

RESULTS:

We found that SDG diminished leukocyte adhesion to and migration across the BBB in vivo in the setting of aseptic encephalitis (intracerebral TNFα injection) and prevented enhanced BBB permeability during systemic inflammatory response (LPS injection). In vitro SDG pretreatment of primary human brain microvascular endothelial cells (BMVEC) or human monocytes diminished adhesion and migration of monocytes across brain endothelial monolayers in conditions mimicking CNS inflammatory responses. Consistent with our in vivo observations, SDG decreased expression of the adhesion molecule, VCAM1, induced by TNFα, or IL-1β in BMVEC. SDG diminished expression of the active form of VLA-4 integrin (promoting leukocyte adhesion and migration) and prevented the cytoskeleton changes in primary human monocytes activated by relevant inflammatory stimuli.

CONCLUSION:

This study indicates that SDG directly inhibits BBB interactions with inflammatory cells and reduces the inflammatory state of leukocytes. Though more work is needed to determine the mechanism by which SDG mediates these effects, the ability of SDG to exert a multi-functional response reducing oxidative stress, inflammation, and BBB permeability makes it an exciting potential therapeutic for neuroinflammatory diseases. SDG can serve as an anti-inflammatory and barrier-protective agent in neuroinflammation.

PMID :

29373982

 

The Neuroprotective Effects of Flaxseed Oil Supplementation on Functional Motor Recovery in a Model of Ischemic Brain Stroke: Upregulation of BDNF and GDNF.

Abstract

Cerebral ischemic stroke is a common leading cause of disability. Flaxseed is a richest plant-based source of antioxidants. In this study, the effects of flaxseed oil (FSO) pretreatment on functional motor recovery and gene expression and protein content of neurotrophic factors in motor cortex area in rat model of brain ischemia/reperfusion (I/R) were assessed. Transient middle cerebral artery occlusion (tMCAo) in rats was used as model brain I/R. Rats (6 in each group) were randomly divided into four groups of Control (Co+normal saline [NS]), Sham (Sh+NS), tMCAo+NS and tMCAo+FSO. After three weeks of pretreatment with vehicle or FSO (0.2 ml~800 mg/kg body weight), the rats were operated in sham and ischemic groups. Ischemia was induced for 1 h and then reperfused. After 24 h of reperfusion, neurologicalexamination was performed, and animals were sacrificed, and their brains were used for molecular and histopathological studies. FSO significantly improved the functional motor recovery compared with tMCAo+NS group (P<0.05). A significant reduction in brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) mRNAs and protein levels were observed in the tMCAo+NS group compared with Co+NS and Sh+NS group (P<0.05). A significant increase of BDNF and GDNF mRNAs and proteins was recorded in the tMCAo+FSO group compared with Co+NS, Sh+NS and tMCAO+NS groups (P<0.05).

The results of the current study demonstrated that pretreatment with FSO had neuroprotective effects on motor cortex area following cerebral ischemic stroke by increasing the neurotrophic factors (BDNF, GDNF).

KEYWORDS:

BDNF; Brain stroke; Flaxseed oil; GDNF; Motor cortex

PMID : 29373886

 

α-Linolenic Acid, A Nutraceutical with Pleiotropic Properties That Targets Endogenous Neuroprotective Pathways to Protect against Organophosphate Nerve Agent-Induced Neuropathology.

 

Abstract

α-Linolenic acid (ALA) is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP) nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE) that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long-term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies.

The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals.

Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders.

KEYWORDS:

BDNF; mTOR; natural product; neuroprotection; neurorestoration; nutraceutical; pleiotropic; rat; soman; α-linolenic acid

 PMID :

26569216

 

 Cancer

 

Antitumorigenic Properties of Omega-3 Endocannabinoid Epoxides

Abstract

Accumulating studies have linked inflammation to tumor progression. Dietary omega-3 fatty acids, such as docosahexaenoic acid (DHA), have been shown to suppress tumor growth through their conversion to epoxide metabolites. Alternatively, DHA is converted enzymatically into docosahexaenoylethanolamide (DHEA), an endocannabinoid with antiproliferative activity. Recently, we reported a novel class of anti-inflammatory DHEA-epoxide derivative called epoxydocospentaenoic-ethanolamide (EDP-EA) that contain both ethanolamide and epoxide moieties. Herein, we study the antitumorigenic properties of EDP-EAs in an osteosarcoma (OS) model.

First, we show ∼80% increase in EDP-EAs in metastatic versus normal lungs of mice.

We found significant differences in the apoptotic and antimigratory potencies of the different EDP-EA regioisomers, which were partially mediated through cannabinoid receptor 1 (CB1). Next, we synthesized derivatives of the most pro-apoptotic regioisomer. These derivatives had reduced hydrolytic susceptibility to fatty acid amide hydrolase (FAAH) and increased CB1-selective binding. Collectively, we report a novel class of EDP-EAs that exhibit antiangiogenic, antitumorigenic, and antimigratory properties in OS.

PMID: 29856219

 

FLAX OIL FROM TRANSGENIC LINUM USITATISSIMUM SELECTIVELY INHIBITS IN VITRO PROLIFERATION OF HUMAN CANCER CELL LINES.

Gebarowski TGebczak KWiatrak BKulma APelc KCzuj TSzopa JGasiorowski K.

Abstract

Emulsions made of oils from transgenic flaxseeds significantly decreased in vitro proliferation of six tested human cancer cell lines in 48-h cultures, as assessed with the standard sulforhodamine assay. However, the emulsions also increased proliferation rate of normal human dermal fibroblasts and, to a lower extend, of keratinocytes. Both inhibition of in vitro proliferation of human cancer cell lines and stimulation of proliferation of normal dermal fibroblasts and keratinocytes were especially strong with the emulsion type B and with emulsion type M.

Oils from seeds of transgenic flax type B and M should be considered as valuable adjunct to standard cytostatic therapy of human cancers and also could be applied to improve the treatment of skin lesions in wound healing.

PMID: 29624271

 

Anticancer potentiality of lignan rich fraction of six Flaxseed cultivars.

Ezzat SM1,2Shouman SA3Elkhoely A4Attia YM3Elsesy MS3El Senousy AS5Choucry MA5El Gayed SH5El Sayed AA5Sattar EA5El Tanbouly N5.

Abstract

The objective of our study is to highlight the therapeutic effect and mechanism of action by which purified Flaxseed hydrolysate (PFH) which is a lignan rich fraction exerts its anticancer activity on a human breast cancer cell line (T47D) and in mice bearing tumor. HPLC analysis of PFH of six flaxseed cultivars had shown that PFH of the cultivar Giza 9 (PFH-G9) contains the highest concentration of SDG (81.64 mg/g). The in vitro cytotoxic potentiality of PFH’s of six flaxseed cultivars was screened against a panel of human cancer cell lines. PFH -G9 showed the most significant cytotoxic activity against ER-receptor positive breast cell lines MCF7 and T47D with IC50 13.8 and 15.8 µg/ml, respectively. Moreover, PFH-G9 reduced the expression of the metastasis marker, 1-α, metalloproteinases and vascular endothelial growth factor (VEGF), one of the most potent stimulators of angiogenesis, while it increased the caspase-3 dependent apoptosis. Our study also showed that dietary intake of 10% of Giza 9 Flaxseeds (FS), fixed oil (FSO) or Flax meal (FSM) twice daily for 3 weeks in mice-bearing solid Ehrlich ascites carcinoma (EAC) resulted in reducing the tumor volume, the expression of estrogen, insulin growth factor, progesterone, VEGF and MMP-2, but enhanced expression of caspase-3.

PMID: 29323210

 

The Flaxseed-Derived Lignan Phenolic Secoisolariciresinol Diglucoside (SDG) Protects Non-Malignant Lung Cells from Radiation Damage.

Abstract

Plant phenolic compounds are common dietary antioxidants that possess antioxidant and anti-inflammatory properties. Flaxseed (FS) has been reported to be radioprotective in murine models of oxidative lung damage. Flaxseed’s protective properties are attributed to its main biphenolic lignan, secoisolariciresinol diglucoside (SDG). SDG is a free radical scavenger, shown in cell free systems to protect DNA from radiation-induced damage. The objective of this study was to investigate the in vitro radioprotective efficacy of SDG in murine lung cells. Protection against irradiation (IR)-induced DNA double and single strand breaks was assessed by γ-H2AX labeling and alkaline comet assay, respectively. The role of SDG in modulating the levels of cytoprotective enzymes was evaluated by qPCR and confirmed by Western blotting. Additionally, effects of SDG on clonogenic survival of irradiated cells were evaluated. SDG protected cells from IR-induced death and ameliorated DNA damage by reducing mean comet tail length and percentage of γ-H2AX positive cells. Importantly, SDG significantly increased gene and protein levels of antioxidant HO-1, GSTM1 and NQO1.

Our results identify the potent radioprotective properties of the synthetic biphenolic SDG, preventing DNA damage and enhancing the antioxidant capacity of normal lung cells; thus, rendering SDG a potential radioprotector against radiation exposure.

KEYWORDS:

DNA damage; SDG; antioxidant; flaxseed; ionizing radiation; lignan; phenolic; radioprotection

PMID : 26703588

 

Flax seed oil inhibits metastatic melanoma and reduces lung tumor formation in mice.

Abstract

PURPOSE:

Cancer is one of the leading causes of mortality worldwide. Tumor cells circulating in the blood evidence the migration of tumor from the site of origin to another site leading to the formation of new metastatic lesion and establishment of metastatic tumors. In the present study, cultured metastatic tumor cells were injected into the C57BL/6 mice through tail-vein injection (TVI) and the anti-metastatic properties of flax seed oil (FSO) were evaluated.

METHODS:

Pre-administration of FSO in a dose of 0.3 ml/mice/day was performed for 15 days. On 16th and 21st day, mice were challenged with 2×105 /100 μl murine B10 melanoma (YAC-1 suspended in sterile PBS) cells and continued with FSO administration until the end of the experimental period (40 days) to assess the effect on lung metastasis. At the end of experimental period, mice were sacrificed for plasma and lung tissue samples for biochemical and marker studies. Activities of marker enzymes (AST and ALT), enzymic antioxidants (superoxide dismutase/SOD and catalase/CAT), levels of non/enzymic antioxidants (glutathione), oxidation/stress marker (malondialdehyde/MDA) and cytokines (TNF-alpha, IL-2, IFN-gamma and MMP-9) were assessed.

RESULTS:

Elevated marker enzyme activities in serum and altered enzymic and non-enzymic antioxidants were recovered during FSO treatment. Altered metastatic markers levels favoring the formation of metastatic lesions were observed in the disease group. FSO administration re-altered the levels of these markers in the treatment group contributing to better control of metastasis development.

CONCLUSION:

These results support the protective role of FSO against lung cancer metastasis.

PMID : 26854452

 

Aglycone rich extracts of phytoestrogens cause ROS-mediated DNA damage in breast carcinoma cells.

Abstract

Phytoestrogens are known for their physiological role in lowering risk of osteoporosis, heart disease, breast cancer and menopausal symptoms. They are plant derived potent anti-oxidants, but tend to show pro-oxidant effect at higher concentrations. This study has been undertaken to exploit their pro-oxidant effect in the management of cancer. Cancer cells inherently possess high intracellular ROS levels, however, these levels do not cause harm to the cancer cells because of the anti-oxidant enzyme system. So, there is a need for a treatment strategy which could modulate the ROS levels. Breast cancer cell lines MCF-7 and MDA-MB-231 are treated with various concentrations of soyabean aglycone rich extracts (SARE) and flaxseed aglycone rich extracts (FSARE). The treatment brings about a significant decrease in super oxide dismutase (SOD) and glutathione peroxidase (GPx) activity, thereby leading to accumulation of superoxide ion and peroxide in the cells. The catalase (CAT) activity however, did not show a dose dependent change. The intra-cellular reactive oxygen species (ROS) levels increased and a marked change in mitochondrial membrane potential was detected. Cell cycle arrest was seen at S and G2/M phase in MCF-7 cells and high accumulation of cells in Sub G1 phase was seen in MDA-MB-231 cells. Microscopic evaluation indicated apoptotic morphology and DNA damage.

 

This study suggests an important role of soyabean and flaxseed aglycones in modulating intracellular ROS in breast carcinoma.

 

KEYWORDS:

Aglycones; MCF-7; MDA-MB-231; Mitochondrial membrane potential; Phytoestrogens; Reactive oxygen species

PMID : 27876207

 

 

Secoisolariciresinol diglucoside rich extract of L. usitatissimum prevents diabetic colon cancer through inhibition of CDK4.

Abstract

BACKGROUND:

There is increased risk of colon cancer in both men and women having diabetes. The objective of the study was to evaluate the role of Secoisolariciresinol diglucoside rich extract(SRE) of L.usissatisimum(flaxseed) in colon cancer associated with type 2 diabetes mellitus.

MATERIAL AND METHODS:

Diabetes was induced by administering high fat diet with low dose streptozotocin model. After 6 weeks, diabetes was confirmed and 1,2 dimethylhydrazine(25mg/kg, sc) weekly administration was from 6th to 18th weeks. Rats were treated with the SRE(500mg/kg) orally from 6th to 24th week. After 24 weeks, various biochemical and enzymatic parameters were estimated. Animals were sacrificed and colon tissue was separated and subjected to analysis of histopathological, PCNA studies and mRNA expression of CDK4.

RESULTS:

Disease control rats depicted hyperglycaemia, hyperinsulinaemia, elevated pro-inflammatory cytokines and cancer biomarker levels, and marked presence of proliferating cells. Treatment with SRE controlled hyperglycaemia, hyperinsulinaemia, reduced pro-inflammatory cytokines and cancer biomarker levels, and decreased no. of proliferating cells. We found that disease control rats depicted over expression of CDK4 mRNA levels which were reduced by SRE treatment.

CONCLUSIONS:

SRE of L. usitatissimum exhibited chemopreventive effect in colon cancer associated with type 2 diabetes mellitus which might be mediated through inhibition of CDK4.

Copyright © 2016 Elsevier Masson SAS. All rights reserved.

KEYWORDS:

CDK4; Colon cancer associated with type 2 diabetes mellitus; DMH; L. usitatissimum; Secoisolariciresinol diglucoside

PMID : 27470575

 

Adipokines and Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo – Correlations and Attenuation by Dietary Flaxseed.

Abstract

Exposure to sex steroids increases the risk of breast cancer but the exact mechanisms are yet to be elucidated. Events in the microenvironment are important for carcinogenesis. Diet containing phytoestrogens can affect the breast microenvironment and alter the risk of breast cancer. It has previously been shown that estrogen regulates extracellular levels of leptin, adiponectin, and VEGF in normal breast tissue in vivo. Whether these proteins correlate in breast tissue in vivo or if diet addition of flaxseed, a major source of phytoestrogens in Western diets, alters adipokine levels in breast tissue are unknown. We used microdialysis to sample proteins of normal human breast tissue and abdominal subcutaneous fat in situ in 34 pre-and postmenopausal women. In vitro, co-culture of breast cancer cells and primary human adipocytes was used. In vivo, in normal breast tissue, a significant positive correlation between VEGF and leptin was detected. No correlations were found in fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. The levels of leptin decreased and adiponectin increased after a dietary addition of 25 g of flaxseed/day for one menstrual cycle.

We conclude that VEGF and leptin correlate significantly in normal human breast tissue in vivo and that dietary addition of flaxseed affect adipokine levels in the breast.

KEYWORDS:

Adiponectin; Diet; Estrogen; Flaxseed; Leptin; Microdialysis

PMID : 27059487

 

Flavonoid C-glucosides Derived from Flax Straw Extracts Reduce Human Breast Cancer Cell Growth In vitro and Induce Apoptosis

 

Abstract

Flax straw of flax varieties that are grown for oil production is a by product which represents a considerable biomass source. Therefore, its potential application for human use is of high interest. Our research has revealed that flax straw is rich in flavonoid C-glucosides, including vitexin, orientin, and isoorientin. The objective of this study was to evaluate the cytotoxicity and possible proapoptotic effect of flax straw derived C-glucosides of flavonoids in the human breast adenocarcinoma cell line (MCF-7). The effects of flax straw derived flavonoid C-glucosides on cell proliferation of MCF-7 cells were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and sulforhodamine B assays. The expression of apoptosis-related genes was assessed by real-time PCR. Our data revealed that flax C-glucosides as well as pure compounds are cytotoxic toward MCF-7 cells and inhibit their proliferation. Moreover, the induction of apoptosis was correlated with the changes in the mRNA level of pro-apoptotic genes. Increased expression of bax and caspase-7, -8, and -9 and decreased mRNA expression of bcl-2 was observed, whereas the mRNA levels of p53 and mdm2 were not altered.

These results clearly demonstrated that flax straw metabolites effectively induced growth inhibition and apoptosis in human breast adenocarcinoma cells.

Keywords: flax straw, flavonoid C-glucosides, MCF-7, human breast carcinoma cells, apoptosis

 

Enterolactone Suppresses Proliferation, Migration and Metastasis of MDA-MB-231 Breast Cancer Cells Through Inhibition of uPA Induced Plasmin Activation and MMPs-Mediated ECM Remodeling

Abstract

BACKGROUND:

To enhance their own survival, tumor cells can manipulate their microenvironment through remodeling of the extra cellular matrix (ECM). The urokinase-type plasminogen activator (uPA) system catalyzes plasmin production which further mediates activation of matrix metalloproteinases (MMPs) and plays an important role in breast cancer invasion and metastasis through ECM remodeling. This provides a potential target for therapeutic intervention of breast cancer treatment. Enterolactone (EL) is derived from dietary flax lignans in the human body and is known to have anti-breast cancer activity. We here investigated molecular and cellular mechanisms of EL action on the uPA-plasmin- MMPs system.

METHODS:

MTT and trypan blue dye exclusion assays, anchorage-dependent clonogenic assays and wound healing assays were carried out to study effects on cell proliferation and viability, clonogenicity and migration capacity, respectively. Real-time PCR was employed to study gene expression and gelatin zymography was used to assess MMP-2 and MMP-9 activities. All data were statistically analysed and presented as mean ± SEM values.

RESULTS:

All the findings collectively demonstrated anticancer and antimetastatic potential of EL with antiproliferative, antimigratory and anticlonogenic cellular mechanisms. EL was found to exhibit multiple control of plasmin activation by down-regulating uPA expression and also up-regulating its natural inhibitor, PAI-1, at the mRNA level. Further, EL was found to down-regulate expression of MMP-2 and MMP-9 genes, and up-regulate TIMP-1 and TIMP-2; natural inhibitors of MMP-2 and MMP-9, respectively. This may be as a consequence of inhibition of plasmin activation, resulting in robust control over migration and invasion of breast cancer cells during metastasis.

CONCLUSIONS:

EL suppresses proliferation, migration and metastasis of MDA-MB-231 breast cancer cells by inhibiting induced ECM remodeling by the ‘uPA-plasmin-MMPs system’.

KEYWORDS:

Enterolactone; breast cancer; Urokinase; type plasminogen activator; matrix metalloproteinases

PMID : 28545187

 

Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice.

Abstract

OBJECTIVES:

To investigate the effects of flaxseed supplementation on prostatic neoplasia in the transgenic adenocarcinoma mouse prostate (TRAMP) model.

METHODS:

A total of 135 male TRAMP mice 5 to 6 weeks old were randomized to a control group (AIN-76A diet) or an experimental group (AIN-76A diet plus 5% flaxseed by weight). One half of the mice in each group were treated for 20 weeks and the remainder for 30 weeks. At autopsy, urogenital tissues (four prostatic lobes, seminal vesicles, and emptied bladder), lungs, lymph nodes, and grossly abnormal tissues were collected for histologic evaluation.

RESULTS:

Of the control mice, 100% developed prostate cancer versus 97% of the mice in the flaxseed group. The tumor/urogenital weight was 3.6 +/- 0.4 g in the controls versus 1.9 +/- 0.2 g in the flaxseed-treated mice (P = 0.0005). At 20 weeks, no significant difference in tumor grade was seen between the two groups; however, at 30 weeks, the flaxseed-treated mice had significantly less aggressive tumors than did the controls (P = 0.01). The prevalence of lung and lymph node metastases was 13% and 16%, respectively, in the control mice versus 5% and 12%, respectively, in the experimental group (difference not significant). After 20 weeks of treatment, cellular proliferation (Ki-67) differed significantly between the control and experimental groups (38.1 +/- 2.03 versus 26.2 +/- 2.03; P <0.0001), and the apoptotic index (deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling) was 1.45 +/- 0.14 versus 3.3 +/- 0.31 (P <0.0001). Similar differences were seen after 30 weeks of treatment.

CONCLUSIONS:

A diet supplemented with 5% flaxseed inhibits the growth and development of prostate cancer in the TRAMP model.

PMID: 12429338

 

Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery.

Abstract

BACKGROUND:

Prostate cancer affects one of six men during their lifetime. Dietary factors are postulated to influence the development and progression of prostate cancer. Low-fat diets and flaxseed supplementation may offer potentially protective strategies.

METHODS:

We undertook a multisite, randomized controlled trial to test the effects of low-fat and/or flaxseed-supplemented diets on the biology of the prostate and other biomarkers. Prostate cancer patients (n = 161) scheduled at least 21 days before prostatectomy were randomly assigned to one of the following arms: (a) control (usual diet), (b) flaxseed-supplemented diet (30 g/d), (c) low-fat diet (<20% total energy), or (d) flaxseed-supplemented, low-fat diet. Blood was drawn at baseline and before surgery and analyzed for prostate-specific antigen, sex hormone-binding globulin, testosterone, insulin-like growth factor-I and binding protein-3, C-reactive protein, and total and low-density lipoprotein cholesterol. Tumors were assessed for proliferation (Ki-67, the primary endpoint) and apoptosis.

RESULTS:

Men were on protocol an average of 30 days. Proliferation rates were significantly lower (P < 0.002) among men assigned to the flaxseed arms. Median Ki-67-positive cells/total nuclei ratios (x100) were 1.66 (flaxseed-supplemented diet) and 1.50 (flaxseed-supplemented, low-fat diet) versus 3.23 (control) and 2.56 (low-fat diet). No differences were observed between arms with regard to side effects, apoptosis, and most serologic endpoints; however, men on low-fat diets experienced significant decreases in serum cholesterol (P = 0.048).

CONCLUSIONS:

Findings suggest that flaxseed is safe and associated with biological alterations that may be protective for prostate cancer. Data also further support low-fat diets to manage serum cholesterol.

PMID: 19064574

 

Effects of components present in flaxseed on human colon adenocarcinoma Caco-2 cells: Possible mechanisms of flaxseed on colon cancer development in animals.

Abstract

Previous studies from our laboratory have shown chemopreventive effects of dietary flaxseed on azoxymethane-induced colon tumor development in male Fischer rats and Apc(Min) mice. Tumorigenesis is associated with uncontrolled cell growth and loss of apoptosis. Accordingly, the objective of this investigation was to study the effects of mammalian lignans (enterodiol and enterolactone) and ω-3 polyunsaturated fatty acid α-linolenic acid, principal active components in flaxseed on cell proliferation and apoptosis in human colon adenocarcinoma Caco-2 cells, thus elucidating possible mechanism of action. BrdU incorporation assay was used for cell proliferation and fluorescence-activated cell sorting (FACS) analysis of annexin V/propidium iodide staining was used for determining apoptotic cells. Results showed that enterodiol, enterolactone and α-linolenic acid at different concentrations caused a significant (p < 0.05) increase in apoptotic cells and decrease in cell proliferation. Therefore, dietary flaxseed containing α-linolenic acid and lignans causes a decrease in cell proliferation and an increase in apoptosis resulting in the effective chemoprevention for intestinal and colon tumor development.

PMID: 22491182

 

Enterolactone alters FAK-Src signaling and suppresses migration and invasion of lung cancer cell lines.

Abstract

BACKGROUND:

Systemic toxicity of chemotherapeutic agents and the challenges associated with targeting metastatic tumors are limiting factors for current lung cancer therapeutic approaches. To address these issues, plant-derived bioactive components have been investigated for their anti-cancer properties because many of these agents are non-toxic to healthy tissues. Enterolactone (EL) is a flaxseed-derived mammalian lignan that has demonstrated anti-migratory properties for various cancers, but EL has not been investigated in the context of lung cancer, and its anticancer mechanisms are ill-defined. We hypothesized that EL could inhibit lung cancer cell motility by affecting the FAK-Src signaling pathway.

METHODS:

Non-toxic concentrations of EL were identified for A549 and H460 human lung cancer cells by conducting 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Dephenyltetrazolium Bromide (MTT) assays. The anti-migratory and anti-invasive potential of EL for lung cancer cell lines was determined by scratch wound healing and Matrigel® invasion assays. Changes in filamentous actin (F-actin) fiber density and length in EL-treated cells were determined using phalloidin-conjugated rhodamine dye and fluorescent microscopy. Vinculin expression in focal adhesions upon EL treatment was determined by immunocytochemistry. Gene and protein expression levels of FAK-Src signaling molecules in EL-treated lung cancer cells were determined using PCR arrays, qRT-PCR, and western blotting.

RESULTS:

Non-toxic concentrations of EL inhibited lung cancer cell migration and invasion in a concentration- and time-dependent manner. EL treatment reduced the density and number of F-actin fibers in lung cancer cell lines, and reduced the number and size of focal adhesions. EL decreased phosphorylation of FAK and its downstream targets, Src, paxillin, and decreased mRNA expression of cell motility-related genes, RhoA, Rac1, and Cdc42 in lung cancer cells.

CONCLUSIONS:

Our data suggest that EL suppresses lung cancer cell motility and invasion by altering FAK activity and subsequent activation of downstream proteins needed for focal adhesion formation and cytoskeletal rearrangement. Therefore, administration of EL may serve as a safe and complementary approach for inhibiting lung tumor cell motility, invasion, and metastasis.

KEYWORDS:

Cell motility; Enterolactone; F-actin; Flaxseed; Focal adhesion; Lung cancer cells; Rho GTPases

PMID : 28068967

 

Flaxseed Consumption Inhibits Chemically Induced Lung Tumorigenesis and Modulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/J Mice.

Abstract

Flaxseed consumption is associated with reduced oxidative stress and inflammation in lung injury models and has shown anticancer effects for breast and prostate tissues. However, the chemopreventive potential of flaxseed remains unexplored for lung cancer.

In this study, we investigated the effect of flaxseed on tobacco smoke carcinogen (NNK)-induced lung tumorigenesis in an A/J mouse model. Mice exposed to NNK were fed a control diet or a 10% flaxseed-supplemented diet for 26 weeks. Flaxseed-fed mice showed reduced lung tumor incidence (78%) and multiplicity, with an average of 2.7 ± 2.3 surface lung tumor nodules and 1.0 ± 0.9 H&E cross-section nodules per lung compared with the control group, which had 100% tumor incidence and an average of 10.2 ± 5.7 surface lung tumor nodules and 3.9 ± 2.6 H&E cross-section nodules per lung. Furthermore, flaxseed-fed mice had a lower incidence of adenocarcinomas compared with control-fed mice. Western blotting performed on normal lung tissues showed flaxseed suppressed phosphorylation (activation) of p-AKT, p-ERK, and p-JNK kinases. RNA-Seq data obtained from normal lung and lung tumors of control and flaxseed-fed mice suggested that flaxseed intake resulted in differential expression of genes involved in inflammation-mediated cytokine signaling (IL1, 6, 8, 9, and 12α), xenobiotic metabolism (several CYPs, GSTs, and UGTs), and signaling pathways (AKT and MAPK) involved in tumor cell proliferation.

Together, our results indicate that dietary flaxseed supplementation may be an effective chemoprevention strategy for chemically induced lung carcinogenesis by altering signaling pathways, inflammation, and oxidative stress. Cancer Prev Res; 11(1); 27-37. ©2017 AACR.

PMID : 29074535

 

 

Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo.

Abstract

PURPOSE:

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, which is crucial in cancer progression. We have previously shown that estradiol (E2) increases VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.

EXPERIMENTAL DESIGN:

In the present study, ovariectomized mice were treated with continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or 10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or enterolactone (15 mg/kg body weight).

RESULTS:

We show that flaxseed, enterodiol, and enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the addition of lignans.

CONCLUSIONS:

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.

PMID: 17289903

 

FLAX OIL FROM TRANSGENIC LINUM USITATISSIMUM SELECTIVELY INHIBITS IN VITRO PROLIFERATION OF HUMAN CANCER CELL LINES.

Abstract

Emulsions made of oils from transgenic flaxseeds significantly decreased in vitro proliferation of six tested human cancer cell lines in 48-h cultures, as assessed with the standard sulforhodamine assay. However, the emulsions also increased proliferation rate of normal human dermal fibroblasts and, to a lower extend, of keratinocytes. Both inhibition of in vitro proliferation of human cancer cell lines and stimulation of proliferation of normal dermal fibroblasts and keratinocytes were especially strong with the emulsion type B and with emulsion type M.

Oils from seeds of transgenic flax type B and M should be considered as valuable adjunct to standard cytostatic therapy of human cancers and also could be applied to improve the treatment of skin lesions in wound healing.

PMID : 29624271

 

Whole flaxseed diet alters estrogen metabolism to promote 2-methoxtestradiol-induced apoptosis in hen ovarian cancer.

Abstract

The study reported here demonstrates that a flaxseed-supplemented diet causes ovarian tumors in the laying hen to undergo apoptosis, resulting in a reduction of tumor burden, reducing the frequency and severity of ovarian cancer. We have previously shown in normal ovaries that flaxseed and its components down-regulate ERalpha and alter the expression of enzymes that metabolize estrogen. In this study, we analyzed the effects of the two main components of whole flaxseed, ligan and omega 3 fatty acids on estrogen metabolism and the estrogen receptor in ovarian tumors. ER alpha expression was up-regulated in the ovarian tumors and was not affected by diet. Liver CYP1A1 expression was significantly increased by the whole flaxseed diet with a corresponding increase in 2-methoxyestradiol plasma levels. We also observed increased p38 and ERK 1/2 MAPK activation in the ovary as well as an increase in apoptosis in the tumor epithelium. SMAD 7, a factor involved in the 2-methoxyestradiol-mediated apoptosis pathway was also up-regulated in tumors from the whole flaxseed diet group. 2-methoxyestradiol-induced antitumor effects were further validated by in human ovarian cancer cells.

This study details the effect of flaxseed diet on estrogen metabolism and demonstrates the antiovarian cancer effects of 2-methoxyestradiol.

 

KEYWORDS:

2-Methoxtestradiol; Apoptosis; Estrogen metabolism; Flaxseed; Ovarian cancer

PMID : 28178600

 

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries.

Abstract

Flaxseed has been studied for decades for its health benefits that include anti-cancer, cardio-protective, anti-diabetic, anti-inflammatory properties.

The biologically active components that mediate these effects are the omega-3 fatty acids and the lignan, secoisolariciresinol diglucoside. We have previously shown that whole flaxseed supplemented diet decreases the severity and incidence of ovarian cancer while a 15% dose of flaxseed is most protective against inflammation and estrogen-induced chemical and genotoxicity. The objective of this study was to dissect the independent effects of the two flaxseed components on estrogen signaling and metabolism. Two and half year old hens were fed either a control diet, 15% whole flaxseed diet, defatted flax meal diet or 5% flax oil diet for 3 months after which the animals were sacrificed and blood and tissues were harvested. Whole flaxseed diet caused a decrease in expression of ERα. ERα target gene expression was assessed using RT(2) profiler PCR array. Some targets involved in the IGF/insulin signaling pathway (IRS1, IGFBP4, IGFBP5) were downregulated by flaxseed and its components. Flaxseed diet also downregulated AKT expression. A number of targets related to NF-kB signaling were altered by flaxseed diet including a series of targets implicated in cancer. Whole flaxseed diet also affected E2 metabolism by increasing CYP1A1 expression with a corresponding increase in the onco-protective E2 metabolite, 2-methoxyestradiol.

The weak anti-estrogens, enterolactone, enterodiol and 2-methoxyestradiol, might be working synergistically to generate a protective effect on the ovaries from hens on whole flaxseed diet by altering the estrogen signaling and metabolism.

KEYWORDS:

Estrogen; Flaxseed; Hen; Ovarian cancer

 PMID :

26925929

 

 General

 

Production of enterodiol from defatted flaxseeds through biotransformation by human intestinal bacteria.

 

Abstract

BACKGROUND:

The effects of enterolignans, e.g., enterodiol (END) and particularly its oxidation product, enterolactone (ENL), on prevention of hormone-dependent diseases, such as osteoporosis, cardiovascular diseases, hyperlipemia, breast cancer, colon cancer, prostate cancer and menopausal syndrome, have attracted much attention. To date, the main way to obtain END and ENL is chemical synthesis, which is expensive and inevitably leads to environmental pollution. To explore a more economic and eco-friendly production method, we explored biotransformation of enterolignans from precursors contained in defatted flaxseeds by human intestinal bacteria.

RESULTS:

We cultured fecal specimens from healthy young adults in media containing defatted flaxseeds and detected END from the culture supernatant. Following selection through successive subcultures of the fecal microbiota with defatted flaxseeds as the only carbon source, we obtained a bacterial consortium, designated as END-49, which contained the smallest number of bacterial types still capable of metabolizing defatted flaxseeds to produce END. Based on analysis with pulsed field gel electrophoresis, END-49 was found to consist of five genomically distinct bacterial lineages, designated Group I-V, with Group I strains dominating the culture. None of the individual Group I-V strains produced END, demonstrating that the biotransformation of substrates in defatted flaxseeds into END is a joint work by different members of the END-49 bacterial consortium. Interestingly, Group I strains produced secoisolariciresinol, an important intermediate of END production; 16S rRNA analysis of one Group I strain established its close relatedness with Klebsiella. Genomic analysis is under way to identify all members in END-49 involved in the biotransformation and the actual pathway leading to END-production.

CONCLUSION:

Biotransformation is a very economic, efficient and environmentally friendly way of mass-producing enterodiol from defatted flaxseeds.

PMID : 20398397

 

 

Mastalgia.

Abstract

OBJECTIVE:

To review the current management of women with breast pain.

OPTIONS:

The effect of various treatment modes and health practices, including medications, was considered for the management of both cyclical and noncyclical breast pain.

OUTCOMES:

Effective and timely management of the woman with breast pain and improved quality of life.

EVIDENCE:

A literature search was performed to identify reports published in English between 1975 and July 2003 using MEDLINE and Cochrane Database of Systematic Reviews.

VALUES:

Levels of evidence, as outlined, have been determined using the criteria outlined by the Canadian Task Force on the Periodic Health Examination. Participants were the principal authors: a clinical dietitian, a surgeon oncologist, and a nurse.

BENEFITS, HARMS, AND COSTS:

Utilizing the information will increase knowledge, enabling a consistent approach, which will reduce the number of ineffective interventions and ensure appropriate use medications.

VALIDATION:

Comparison has been made with management protocols in the literature, but no clinical guidelines have been located. No formal clinical testing has taken place.

SPONSOR:

The Society of Obstetricians and Gynaecologists of Canada (SOGC). Work on these guidelines was initiated by team members to fill a need for practice guidelines at Winnipeg Regional Health Authority Breast Health Centre, Winnipeg, MB.

RECOMMENDATIONS:

1. Education and reassurance is an integral part of the management of mastalgia and should be the first-line treatment. (II-1 A) 2. The use of a well-fitting bra that provides good support should be considered for the relief of cyclical and noncyclical mastalgia. (II-3 B) 3. A change in dose, formulation, or scheduling should be considered for women on HRTHRT may be discontinued if appropriate. (III C) 4. Women with breast pain should not be advised to reduce caffeine intake. (1 E) 5. Vitamin E should not be considered for the treatment of mastalgia. (1 E) 6. There is presently insufficient evidence to recommend the use of evening primrose oil (EPO) in the treatment of breast pain. (II-2 C) 7. Flaxseed should be considered as a first-line treatment for cyclical mastalgia. (I A) 8. Topical non-steroidal anti-inflammatory gel, such as diclofenac 2% in pluronic lethicin organogel, should be considered for pain control for localized treatment of mastalgia. (I A) 9. Tamoxifen 10 mg daily or danazol 200 mg daily should be considered when first-line treatments are ineffective. (I A) 10. Mastectomy or partial mastectomy should not be considered an effective treatment for mastalgia. (III E).

PMID: 16533457

 

 

Abstract

The aim of this study was to examine the influence of dietary flaxseed on the endocrine and ovarian functions of weanling gilts challenged with E. coli and Coronavirus infections treated with dietary probiotic cheeses and to understand the possible mechanisms of its effects on ovarian function. Probiotics were used as a natural substitution for antibiotics and 10% dietary flaxseed is an effective prebiotic which supports the action of probiotics and has other beneficial effects on the organism. Probiotics with or without flaxseed were fed to weanling gilts starting 10 days before and lasting up until 14 days after weaning. The ovaries were measured and histologically analysed. The blood samples for the levels of steroid hormones and insulin-like growth factor I (IGF-I) were assessed using immunoassays and the levels of fatty acids were assessed using gas chromatography. All samples were collected on the day of weaning and 14 days after weaning. On the day of weaning, increased levels of linoleic acid and IGF-I was associated with higher body weight. The steroid hormones were not affected by the diet. The conversion of alpha-linolenic acid (ALA) to timodonic (EPA) and cervonic (DHA) acids were lower compared to controls, and together with high levels of myristic, palmitic and palmitoleic acids was associated with the higher proliferation and lower apoptosis in the primordial, primary and secondary follicles; although the inhibition of the cell cycle was observed in relation to the low level of eicosadienoic acid. The high levels of ALA, EPA and DHA and the low levels of myristic, palmitic and palmitoleic acids may have been the effect of flaxseedfeeding 14 days post-weaning and may have had a reverse effect on the proliferation and apoptosis of ovarian follicles. These data suggest that flaxseed may suppress the follicle development in weanlings via the stimulation of apoptosis and the inhibition of proliferation via the modulation of the metabolism of selected fatty acids.

KEYWORDS:

Apoptosis; Fatty acids; Flaxseed; Insulin-like growth factor I (IGF-I); Pig; Proliferation

 PMID :

29685707

 

Potential protective properties of flax lignan secoisolariciresinol diglucoside

Abstract

Lignans are a group of phytonutrients which are widely distributed in the plant kingdom. Flaxseed is the richest source of providing lignan precursor such as secoisolariciresinol diglucoside (SDG). This article reviews the studies relevant to experimental models in animals and humans demonstrating the possible nutraceutical actions of SDG to prevent and alleviate lifestyle-related diseases. A local and international web-based literature review for this project was carried out to provide information relating to the study. The major key word “SDG” was selected to gather information using the electronic databases pertaining to the current state of flaxseed lignans composition, bioactive compounds, metabolism and to find out their role in terms of chemopreventive action. The extraction methods vary from simple to complex depending on separation, fractionation, identification and detection of the analytes. The majority of studies demonstrate that SDG interferes with the development of different types of diseases like cardiovascular, diabetic, lupus nephritis, bone, kidney, menopause, reproduction, mental stress, immunity, atherosclerosis, hemopoietic, liver necrosis and urinary disorders due to its various biological properties including anti-inflammatory, antioxidant, antimutagenic, antimicrobial, antiobesity, antihypolipidemic and neuroprotective effects.

Moreover, SDG has a defending mediator against various cancers by modulating multiple cell signaling pathways. As discussed in this review, SDG has shown therapeutic potential against a number of human diseases and can be recommended for discerning consumers.

Keywords: Flaxseed, Processing, Lignan, Precursors, Diet, Therapy, Maladies

 

Flaxseed and Diabetes

Abstract

Flaxseed contains 32% to 45% of its mass as oil of which 51% to 55% is α-linolenic acid. Flax lignan complex and secoisolariciresinol diglucoside (SDG) have been isolated from flaxseedFlaxseed and its components have antioxidant, hypolipidemic and hypoglycemic effects. These are mostly due to the SDG content. Oxidative stress has been implicated in both type 1 and type 2 diabetesFlaxseedflaxseed oil and flax lignan complex have not been investigated as to whether they reduce the incidence of diabetes and/or delay the development of diabetes. However, their effects on serum glucose have been studied. Flaxseed and flax lignan complex improve glycemic control. Animal models of type I diabetes involving streptozotocin administration or utilizing Bio-Breed diabetic (BBdp) prone rats are associated with oxidative stress. SDG treatment reduced the incidence of diabetes using serum glucose levels by 75% in the streptozotocin model of diabetes and by 72% in the BBdp rat model of diabetes.

These reductions in development of diabetes were associated with decreases in oxidative stress measured by serum and pancreatic malondialdehyde (MDA). SDG delays the development of diabetes in Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and this effect was associated with a reduction in serum MDA and glycated haemoglobin A1C.

The data suggest that SDG may have a great potential for reducing the incidence of type 1 diabetes and delaying the development of type 2 diabetes in humans.

PMID : 26561065

 

Herbacetin, a flaxseed flavonoid, ameliorates high percent dietary fat induced insulin resistance and lipid accumulation through the regulation of hepatic lipid metabolizing and lipid-regulating enzymes.

Abstract

Healthy plants and their constituents have been considered as a safe remedy for the treatment of obesity and obesity associated diseases. Herbacetin is a dietary flavonoid that has been explored for many pharmacological activities; but, the anti-hyperglycaemic and anti-hyperlipidemic properties of herbacetin have not yet been explored. The present study was performed to evaluate the ameliorative effect of herbacetin on high-fat diet-induced hyperglycaemia and hyperlipidemia in 57BL/6 J mice. Obesity associated insulin resistance was induced by continuously feeding the mice with high-fat diet for 10 weeks. Afterwards, mice were subjected to intragastric administration of herbacetin (different doses) daily along with high-fat diet for the next 5 weeks. At the end of 106th day, changes in body weight, blood glucose, insulin, HOMA-IR, and lipids profiles and lipid-regulating enzymes were evaluated. Herbacetin significantly reduced the body weight, plasma glucose, plasma insulin, and HOMA-IR activity in obesity associated insulin resistant mice (OIR). In addition, herbacetin administration significantly reduced the plasma and hepatic total cholesterol, triglycerides, and free fatty acids in OIR mice. Moreover, herbacetin significantly improved the altered hepatic lipid metabolizing and lipid-regulating enzymes such as SREBP-1c, and 2, fatty acid synthase (FAS), fatty acid β-oxidation (β-oxidation), malic enzyme, glucose 6-phosphate dehydrogenase (G6PD), and carnitine palmitoyltransferase (CPT) when compared to OIR control mice.

Histopathological examination clearly showed that herbacetin decreases lipid droplets in the liver tissue.

Thus, observed results strongly indicate that herbacetin provides remarkable protection against the harmful effects of chronic high-fat diet consumption because of its anti-hyperglycaemic and anti-hyperlipidemic properties through the regulation of hepatic lipid metabolizing and lipid-regulating enzymes.

KEYWORDS:

57BL/6J mice; Anti-hyperglycaemia; Anti-hyperlipidemia; Herbacetin; Insulin resistance; Obesity

 PMID :

29653099

 

Dietary Flaxseed Oil Prevents Western-Type Diet-Induced Nonalcoholic Fatty Liver Disease in Apolipoprotein-E Knockout Mice.

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased globally during recent decades. Intake of n-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), is believed to be beneficial to the development of NAFLD. However, little information is available with regard to the effect of flaxseed oil rich in α-linolenic acid (ALA, C18:3n-3), a plant-derived n-3 PUFA, in improving NAFLD. This study was to gain the effect of flaxseed oil on NAFLD and further investigate the underlying mechanisms. Apolipoprotein-E knockout (apoE-KO) mice were given a normal chow diet, a western-type high-fatand high-cholesterol diet (WTD), or a WTD diet containing 10% flaxseed oil (WTD + FO) for 12 weeks.

Our data showed that consumption of flaxseed oil significantly improved WTD-induced NAFLD, as well as ameliorated impaired lipid homeostasis, attenuated oxidative stress, and inhibited inflammation.

These data were associated with the modification effects on expression levels of genes involved in de novo fatsynthesis (SREBP-1c, ACC), triacylglycerol catabolism (PPARα, CPT1A, and ACOX1), inflammation (NF-κB, IL-6, TNF-α, and MCP-1), and oxidative stress (ROS, MDA, GSH, and SOD).

 PMID :

29081885

 

Therapeutic effect of Linum usitatissimum (flaxseed/linseed) fixed oil on acute and chronic arthritic models in albino rats.

Abstract

The present study was undertaken to assess the activity/anti-inflammatory potential of Linum usitatissimum fixed oil against castor oil-induced diarrhoea, turpentine oil-induced joint oedema, formaldehyde and Complete Freund’s Adjuvant (CFA)-induced arthritis in Wistar albino rats. The oil intraperitoneally, significantly inhibited the castor oil-induced diarrhoea and turpentine oil-induced exudative joint oedema in a dose-dependent manner. Significant inhibitory effect of L. usitatissimum fixed oil was observed in formaldehyde-induced proliferative global oedematous arthritis when given intraperitoneally, with significant checking of the serum glutamic oxaloacetic acid transaminase and serum glutamic pyruvic acid transaminase. Further, L. usitatissimum fixed oil showed a significant dose-dependent protective effect against CFA-induced arthritis as well. Secondary lesions produced by CFA due to a delayed hypersensitivity reaction were also reduced in a significant manner. Anti-inflammatory activity of L. usitatissimum fixed oil can be attributed to the presence of alpha linolenic acid (57.38%, an omega-3 fatty acid, 18:3, n-3) having dual inhibitory effect on arachidonate metabolism resulting in suppressed production of proinflammatory n-6 eicosanoids (PGE(2), LTB(4)) and diminished vascular permeability.

These observations suggest possible therapeutic potential of L. usitatissimum fixed oil in inflammatory disorders like rheumatoid arthritis.

PMID: 20157785

 

Differential effects of dietary flaxseed protein and soy protein on plasma triglyceride and uric acid levels in animal models.

Abstract

The effect of dietary soy protein and flaxseed meal on metabolic parameters was studied in two animal models, F344 rats with normal lipid levels and obese SHR/N-cp rats with elevated levels of cholesterol and triglyceride. The rats were fed AIN 93 diet differing only in the source of protein. The rats were fed either 20% casein, 20% soy protein or 20% flaxseed meal. Plasma was analyzed for cholesterol, triglyceride, uric acid, blood urea nitrogen (BUN), creatinine and total protein.

In both strains of rats, flaxseed meal significantly decreased plasma cholesterol and triglyceride concentrations. The effect of soy protein on lipids was not as striking as that of flaxseed meal. Flaxseed meal also lowered uric acid in F344 rats and BUN in SHR/N-cp rats.

Since cholesterol, triglyceride and uric acid are independent risk factors for cardiovascular disorders, our data show that both flaxseed meal and soy protein may have beneficial effects. Which chemical constituent(s) of flaxseed meal or soybean is (are) responsible for the beneficial effects need to be identified.

PMID: 12550066

 

Beneficial effect of flax seeds in streptozotocin (STZ) induced diabetic mice: isolation of active fraction having islet regenerative and glucosidase inhibitory properties.

Abstract

Diabetes mellitus is a metabolic disorder that affects millions of people worldwide. Present study highlights the antidiabetogenic property of Linum usitassimum active fraction (LU6) in streptozotocin (STZ) induced diabetic Swiss mice. Treatment with LU6 fraction showed improved glucose utilization with increase in liver glucose-6-phosphate dehydrogenase enzyme activity and normal glycogenesis in hepatic and muscle tissues. Reduction in pancreatic and intestinal glucosidase inhibitory activity was observed with LU6 treatment, indicating beneficial effects in reducing postprandial hyperglycemia (PPHG). Normalization of plasma insulin and C-peptide levels were observed in diabetic mice, indicating endogenous insulin secretion after the treatment with LU6.

The histochemical and immunohistochemical analysis on pancreatic islets suggests the role of LU6 fraction in islet regeneration and insulin secretion as evident in increase functional pancreatic islets producing insulin. Furthermore, significant insulin producing islet formation was also observed in in vitro PANC-1 cells after LU6 treatment, indicating the cellular aggregates to be newly formed islets.

This suggests the potential of LU6 fraction in the formation of new islets in vitro, as well as in vivo. Thus, LU6 can be used as a neutraceutical-based first-line treatment for diabetes.

 PMID :

23656171

 

Flaxseed Protects Against Diabetes-Induced Glucotoxicity by Modulating Pentose Phosphate Pathway and Glutathione-Dependent Enzyme Activities in Rats.

Abstract

This study investigated the effects of flaxseed (Linum usitatissimum L.) intake on general metabolism, pentose phosphate pathway (PPP) and glutathione-dependent enzymes in diabetic rats. Diabetes was induced by streptozotocin injection (40 mg/kg, i.p.) and the enzyme activities were determined spectrophotometrically. Diabetic and control rats were divided in two subgroups, one untreated, and one treated with flaxseed (0.714 g/kg body weight/day; orally) for 12 weeks. Flaxseed ameliorated decreased body weight (p < .05) and increased blood glucose (p < .001), triglyceride (p < .001), ALT (p < .001) and AST (p < .001) in diabetic rats. Diabetes resulted in increased glucose-6-phosphate dehydrogenase (G6PD) (p < .05) and decreased glutathione-S-transferase (GST) (p < .01), but unchanged 6-phosphogluconate dehydrogenase (6PGD) and glutathione reductase (GR) in the brain of rats. These alterations were partially improved by flaxseed in comparison to diabetic untreated group (p < .05). G6PD, 6PGD, GR were elevated (p < .001), while GST unchanged in the lung of diabetic untreated group compared to control. Flaxseed partially prevented the increase in 6PGD (p < .05) and GR (p < .01), but unaffected G6PD in the lung of diabetic rats. G6PD (p < .001), 6PGD (p < .05), GR (p < .001) were augmented, while GST showed a significant (p < .001) depletion in the pancreas of diabetic untreated rats compared to control.

Diabetic alterations observed in pancreatic enzyme activities were significantly prevented by flaxseed. Furthermore, a remarkable decrease in 6PGD (p < .001) and an increase in G6PD (threefold of control) were found in the lens of diabetic untreated group that were completely prevented by flaxseed (p < .001).

Flaxseed has beneficial effects against diabetes-induced glucotoxicity by modulating G6PD, 6PGD, GR and GST activities in tissues.

KEYWORDS:

diabetic rat; flaxseed; glucotoxicity; glutathione-dependent enzymes; pentose phosphate pathway

PMID : 26317558

 

Flaxseed modulates inflammatory and oxidative stress biomarkers in cystic fibrosis: a pilot study.

Abstract

BACKGROUND:

Cystic fibrosis (CF) leads to advanced lung disease despite aggressive care. Persistent inflammation and oxidative stress contribute to exacerbations and disease progression. Flaxseed (FS), a dietary botanical supplement with high fiber, lignan phenolics, and omega-3 fatty acids has anti-inflammatory and antioxidant properties in murine models of acute and chronic lung injury. This pilot study was designed to determine whether CF patients could tolerate FS, evaluate circulating FS metabolites, and study biomarkers of lung damage, as a prelude to studying clinical outcomes.

METHODS:

10 CF patients and 5 healthy volunteers consumed 40 g of FS daily for 4 weeks with safety and tolerability being assessed. Urine was evaluated for systemic oxidative stress and plasma for FS metabolites (enterolignans) and cytokine levels. Buccal swabs were analyzed for gene expression of Nrf2-regulated antioxidant enzymes including Heme Oxygenase-1 (HO-1) and NAD(P)H Quinone Oxidoreductase 1 (NQO1).

RESULTS:

All subjects completed the study without serious adverse events. Plasma levels of enterolignans were detectable in both healthy controls and CF volunteers. CF patients were stratified based on plasma enterolignan levels after 2 weeks of FS administration into high- (174 to 535 nM ED and 232 to 1841 nM EL) and low- (0 to 32 nM ED and 0 to 40 nM EL) plasma lignan cohorts. The low enterolignan level cohort experienced a statistically significant drop in urinary inflammatory IsoP and plasma TNFα levels, while demonstrating higher average NQO1 mRNA levels in buccal epithelium compared to high-lignan patients.

CONCLUSIONS:

This pilot study demonstrated that FS is tolerated by CF patients. FS metabolites could be detected in the plasma. Future studies will assess appropriate dosing and target populations for FS, while exploring clinical outcomes.

TRIAL REGISTRATION:

ClinicalTrials.gov identifier: NCT02014181 .

PMID : 25963404

 

Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA.

Abstract

Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega-3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer’s disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega-3 PUFA biochemistry and metabolism, with particular focus on the central nervous system (CNS), where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzyme-derived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed.

With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined.

KEYWORDS:

Alzheimer’s disease; Parkinson’s disease; aging; docosahexaenoic acid; docosapentaenoic acid; eicosapentaenoic acid; omega-3 fatty acids

PMID : 25954194

 

Omega-3 polyunsaturated fatty acid blood biomarkers increase linearly in men and women after tightly controlled intakes of 0.25, 0.5, and 1 g/d of EPA + DHA.

Abstract

Blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been related to coronary heart disease risk. Understanding the response of EPA + DHA in blood to dietary intake of EPA + DHA would facilitate the use of blood measures as markers of adherence and enable the development of dietary recommendations. The objective of this study is examine the blood response to intakes of EPA + DHA ≤1 g/d with an intervention designed for dietary adherence. It was hypothesized this relationship would be linear and that intakes of EPA + DHA <1 g/d would result in blood levels below those associated with the highest level of protection for cardiovascular events. Background EPA + DHA intake of men and women (n = 20) was determined by food frequency questionnaire and adherence was monitored by weekly fingertip blood sampling for fatty acid determinations. Participants consumed nutraceuticals to achieve intakes of 0.25 g/d and 0.5 g/d EPA + DHA for successive four-week periods. A subgroup (n = 5) had intakes of 1.0 g/d EPA + DHA for an additional 4 weeks. Fatty acid composition of whole blood, erythrocytes, and plasma phospholipids were determined at each time point. Blood levels of EPA and DHA increased linearly in these pools. A comprehensive review of the literature was used to verify the blood-intake relationship. Blood levels of long chain omega-3 polyunsaturated fatty acids reached blood levels associated with the highest levels of primary cardiac arrest reduction and sudden cardiac death risk only with intakes of 1.0 g/d of EPA + DHA. The blood biomarker response to intakes of EPA + DHA ≤1 g/d is linear in a small but highly adherent study sample and this information can assist in determining adherence in clinical studies and help identify dietary intake targets from associations between blood and disease.

KEYWORDS:

Biomarkers; Blood; Docosahexaenoic acid; Dose response; Eicosapentaenoic acid; Humans; Nutrition assessment

PMID : 26500082

 

Hydroalcoholic extract of flaxseed improves polycystic ovary syndrome in a rat model.

Abstract

OBJECTIVES:

Herbal medicines are an alternative choice for treatment or controlling of polycystic ovary syndrome (PCOS). Effect of hydroalcoholic extract of flaxseed was evaluated on ovarian hormones and histological changes of uterus and ovary in a PCOS-induced rat model.

MATERIALS AND METHODS:

Twenty four rats divided into four groups including negative control, positive control, PCOS and treatment groups. Positive control group received hydroalcoholic extract of flaxseed for 30 days. PCOS was induced by single intramuscular injection of estradiol valerate. Treatment group was treated with flaxseed extract 7 weeks after induction of PCOS for 30 days. Ovaries and uterus were dissected out and their sections were used for histomorphometric study. Levels of estradiol, progesterone, testosterone and dehydroepiandrosterone (DHEA) were measured in the serum.

RESULTS:

In the treatment group, flaxseed extract increased level of progesterone (P<0.05), while decreased testosterone (P<0.05) compared with the PCOS group. Concentrations of estrogen and DHEA did not change significantly in comparison with the PCOS group. Histomorphometric study showed that in the treatment group, the number of preantral follicles, antral follicles and corpus luteum increased compared with the PCOS group (P<0.05), but the number of cystic follicles and diameter of antral follicles decreased (P<0.05), and the number of primary follicle did not alter significantly. In the treatment group, the thickness of granulosa layer increased, but the thickness of theca layer and tunica albuginea decreased compared to the PCOS group (P<0.05).

CONCLUSION:

Hormonal profile and histomorphometric features of ovary that were disturbed by PCOS induction were ameliorated by hydroalcoholic extract of flaxseed.

KEYWORDS:

Flax; Ovary; Polycystic ovary syndrome Rats; Sex hormones; Uterus

PMID : 29942457

 

The Effect of Flaxseed Supplementation on Hormonal Levels Associated with Polycystic Ovarian Syndrome: A Case Study

 

Abstract

Flaxseed is a rich source of lignan and has been shown to reduce androgen levels in men with prostate cancer. Polycystic ovarian syndrome (PCOS), a common endocrine disorder among women in their reproductive years, also is associated with high levels of androgens and is frequently accompanied by hirsutism, amenorrhea and obesity. This clinical case study describes the impact of flaxseed supplementation (30 g/day) on hormonal levels in a 31-year old woman with PCOS. During a four month period, the patient consumed 83% of the flaxseed dose. Heights, weights, and fasting blood samples taken at baseline and 4-month follow-up indicated the following values: BMI (36.0 vs. 35.7m/kg2); insulin (5.1 vs. 7.0 uIU/ml); total serum testosterone (150 ng/dl vs. 45 ng/dl); free serum testosterone (4.7 ng/dl vs. 0.5 ng/dl); and % free testosterone (3.1% vs. 1.1%). The patient also reported a decrease in hirsutism at the completion of the study period. The clinically-significant decrease in androgen levels with a concomitant reduction in hirsutism reported in this case study demonstrates a need for further research of flaxseed supplementation on hormonal levels and clinical symptoms of PCOS.

Keywords: Androgens, Flaxseed, Polycystic Ovarian Syndrome, Diet, Intervention Studies

INTRODUCTION

Polycystic Ovarian Syndrome (PCOS) affects approximately 4 to 8% of women of reproductive age. () PCOS is an endocrine disorder defined by four key features: 1) ovulatory and menstrual dysfunction; 2) hyperandrogenemia; 3) clinical features of hyperandrogenism (i.e., hirsutism, acne and androgenic alopecia); and 4) polycystic ovaries ()

To date, the study of diet in the treatment of PCOS has focused on weight reduction since roughly half of women with PCOS are obese, and weight loss is helpful in normalizing hormonal levels and clinical symptoms (). While other components of the diet have been suggested as potentially beneficial in ameliorating the hormonal disequilibrium associated with PCOS, beyond weight management the current dietary recommendations provided for this disease parallel those established for the general population, i.e., a low fat, moderate protein diet with increased amounts of fruits, vegetables, and whole grains. ()

Over the past few decades, high fiber diets have been shown to influence the hormonal milieu () and may hold promise in the treatment of PCOS. Previous research suggests that consumption of high lignan foods may cause binding of testosterone in the enterohepatic circulation and subsequent excretion (). Lignan also has been found to increase levels of sex hormone binding globulin and thus reduce the amount of free circulating testosterone (), though such a reduction has not been observed in all studies (). Lignan also may hinder the production of 5 α–reductase (the enzyme responsible for converting testosterone into dihydrotestosterone, the more biologically active and potent form)(). Subsequent research by  found that high lignan diets may be protective against prostate cancer, another disorder which is linked to high androgen levels.

Flaxseed, a food generally renowned for its omega-3 fatty acid content, also is one of the richest sources of dietary lignan, having levels that are 800-fold over that of most other foods, (). Prior studies on the use of flaxseed or isolated lignan suggest that it may decrease androgen levels and normalize lipid levels; however, most of this research has been conducted in male subjects. (). Currently, there are no published reports on the use of flaxseed in the treatment of PCOS, even though it also is an androgen-related disorder. The following case study provides preliminary evidence that flaxseed supplementation may indeed help regulate androgen levels in women with PCOS.

METHODS

The patient was a 31-year-old college-educated, white female who was newly diagnosed with PCOS. She had yet to begin any sort of pharmacotherapy and expressed an interest in flaxseed supplementation after hearing about an NIH-funded phase II clinical trial that we were conducting among men with prostate cancer (CA85740). The patient was counseled that no data yet existed on flaxseed supplementation and PCOS, however was intrigued by study findings among men with prostate cancer which showed a reduction in serum testosterone. She elected to pursue flaxseed supplementation independently and this report chronicles her experience in the clinical care setting

The flaxseed product that was recommended to this patient was a product that we had used in two previously reported studies and was commercially available (, Demark-Wahnefried et al, 2003); Alena® now marketed under the name of Mega Omega® (ENRECO, Inc, Newton, WI), is comprised primarily of stabilized ground flaxseed (75 g/100g weight), but also contains emulsifiers (for ease of mixing), as well as oat flour and fructose (to increase palatability). The patient was provided with instruction regarding storage and use of the product and was encouraged to start with a dose of 10 grams for the first 3-days, 20 grams for the next 3-days and onto a dose of 30 grams/day for the duration of the 4-month study period. This stepped dose approach had been used successfully in our previous studies, and was helpful in minimizing the gastrointestinal discomfort associated with this high fiber food. (, Demark-Wahnefried et al, 2003). Given that flaxseed is usually not consumed alone but is mixed into various foods, we also provided the patient with a list of foods recommended by previous study participants, such as mixing it into applesauce, yogurt, juices, grits, oatmeal or sprinkling it onto cereal. The patient also received log sheets and was asked to record the dose consumed each day, i.e., all of the dose, less than the full dose but at least ¾ of it, less than ¾’s of the full dose but at least ½ of it, less than ½ of the dose but at least ¼ of it or less than ¼ of the dose. The patient also was contacted weekly throughout the 4-month period to assess if there were questions or problems, and to review adherence.

Measures

At baseline, the patient’s height was measured using a fixed stadiometer, and at both baseline and follow-up her weight was assessed on a routinely calibrated platform scale. At both time points, the patient was instructed to report for phlebotomy after an overnight fast of 12-hours. Blood was drawn via venipuncture and collected in serum separator vacutainers. After allowing the blood to clot at room temperature, the tube was centrifuged, and sera was analyzed directly thereafter using immunochemiluminometric methods on a Beckman Coulter Access 2 system with kits for ultrasensitive insulin and testosterone (Beckman Coulter, Inc., Fullerton, CA)(). Assays were conducted at the Duke University Health System Clinical Laboratory, a College of American Pathologists (CAP) and Clinical Laboratory Improvement Act (CLIA) certified laboratory. To provide high levels of quality assurance test performance was validated prior to patient-sample testing using three levels of assayed commercial control material (BioRad Liquichek Immunoassay Plus) at the beginning of each 8 hour shift (as well as following instrument maintenance or assay calibration). Results were compared to acceptable recovery ranges established by the manufacturer’s assayed values, and overall day-to-day recovery. Cumulative and monthly comparison reports (compared against roughly 40 other CLIA-laboratories) indicated that the Duke laboratory had standard deviation indexes (SDI) which were -.31 for insulin and -.19 for testosterone in the ranges corresponding to the case study’s levels, indicating excellent interlaboratory accuracy. The imprecision associated with the assays themselves were less than 10% for insulin (), and less than 20% for testosterone (). The percentage of free testosterone was derived from assayed androgen levels.

RESULTS

After the initial run-in period, the patient adhered to the daily 30 g. dose of flaxseed 93 days out of a possible 112 days during the observational period. Daily intake over the 4-month period is depicted in Figure 1, with roughly 83% of the recommended dose consumed.

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Daily consumption of flaxseed during 4-month period.

Pre-post levels of physiologic measures are provided in Table 1 along with normal reference ranges. A significant decrease in androgen levels was observed, with a 70% decrease in total serum testosterone, an 89% decrease in free serum testosterone, and a 65% decrease in the % free testosterone observed. The patient also reported a decrease in hirsutism at the conclusion of the 4-month period, though no formal measures were taken, In addition, despite a modest amount of weight loss (0.9 kg) the patient’s insulin levels increased 37%; however, remained well within the reference range.

TABLE 1

Patient’s physiologic measurements at baseline and 4-month follow-up period.

Baseline 4-month follow-up
 Weight (kg) 95.4 94.5
 BMI (kg/m2) 36 35.7
 Insulin (uIU/ml)a 5.1 7.0
 Total serum testosterone (ng/dL)b 150 45
 Free serum testosterone (ng/dL)c 4.7 0.5
 % free testosteroned 3.1 1.1
aThe normal reference range for insulin is 1.9–23 uIU/ml
bThe normal reference range for total serum testosterone for adult females is 12–72 g/dL
cThe normal reference range for free serum testosterone for adult females is 0.3–1.9 g/dL
dThe normal reference range for percentage free testosterone for adult females is 0.9–3.8

DISCUSSION

To our knowledge this is the first report of the effect of flaxseed on PCOS. Findings suggest that flaxseed may have a profound impact on testosterone levels, and also may diminish symptoms associated with hyperandrogenism, such as hirsutism. The reductions in androgen levels observed in this case study far surpass those reported with any other dietary intervention conducted to date. For example,  reported a decrease of 36% in serum testosterone among (n=13) PCOS patients who participated in a weight reduction intervention and experienced a mean weight loss of 12.4 kg. An effect size of similar magnitude was observed by  who reported a 31% decrease in free testosterone levels over a 6–7 month period with a 1000 kcal low fat diet among (n=24) women with PCOS. An earlier study by Pasquali and colleagues (1989) reported comparable results during an 8-month period with a 1000–1500 kcal diet of a 36% decrease in testosterone levels in (n=20) women with PCOS. Further, our results which show significant declines in both free and total testosterone ranging from 70–89% are in clear contrast to those of , who tested a diet and exercise weight management intervention (n=18) and observed a 21% decrease in free testosterone with a concomitant 10% increase in total testosterone. Thus, the data from this case study are intriguing since results suggest that the reductions in androgen levels afforded by flaxseed supplementation are roughly 2–4 fold higher than those reported with other dietary interventions conducted previously.

The reductions in androgen levels observed in this case study of PCOS also exceed those reported with flaxseed supplementations among men with either prostate cancer or abnormal prostatic biopsies. In a pilot study of flaxseed supplementation and concurrent dietary fat restriction among men with prostate cancer (n=25),  found only a 15% decrease in testosterone levels; however this study was only conducted over a period averaging 34-days. Furthermore, no difference in testosterone levels was observed with flaxseed supplementation and dietary fat restriction in a study of men with abnormal prostatic biopsies (n=15) (Demark-Wahnefried et al, 2003). Thus, the magnitude of effect on androgen levels observed in this case study is fairly impressive, as is the accompanying self-report of diminished hirsutism (a troubling and prevalent symptom in this patient population).

Currently the standard of care treatment for women with PCOS ranges from lifestyle modification to pharmacological interventions. Lifestyle modifications are associated with diet, weight loss, and exercise programs. Pharmacological interventions include; antiandrogens (Spironolactone, Flutamide), insulin lower agents (Metformin and thiazolidinediones), and estrogen-progestin combination (Oral contraceptives). () While effective, such treatment is associated with substantial cost and may cause various side effects, such as irregular menstruation, gastrointestinal symptoms, weight gain, and increased insulin resistance. In contrast, the costs and side effects associated with flaxseed supplementation are minimal in comparison and primary relate to flaxseed’s laxative effect.

The limitations of this case study are clear, in that the data emanate from a sample of only one and from data collected at only two time points (baseline and follow-up). Furthermore, while we attempted to reduce variability in androgen assessments by performing phlebotomy during identical windows of time during the day, and by the same laboratory, the direct assays used to assess androgen levels, have been criticized for their unreliability, especially within ranges that fall below 300 ng/dl. (). Finally, clinical symptoms of PCOS were not collected using a standardized protocol and validated instruments. Despite these limitations, the data are still compelling. Such data point to the need for further research in this area, to more thoroughly explore the effects of flaxseed supplementation on hormonal markers and clinical symptoms associated with PCOS.

 

Manipulation of flaxseed inhibits tumor necrosis factor-alpha and interleukin-6 production in ovarian-induced osteoporosis.

Abstract

OBJECTIVE:

To evaluate the potential effects of whole flaxseed (FS), and/or flax oil (FO) incorporation into the diet on the level of pro-inflammatory cytokines in ovariectomized (OVX) rats model of osteoporosis.

METHODS:

This study was performed in the Food Science & Agriculture Collage, King Saud University, Kingdom of Saudi Arabia from October to December 2009. Forty-eight, 3-month-old female Sprague-Dawley rats were randomly divided into 6 groups: Group 1 – sham + control diet; Group 2 – OVX rats + basal diet; Group 3 – OVX + 20% whole FS; Group 4 – OVX rats + 40% FS; Group 5 – OVX rats + 5% FO; Group 6 – OVX rats + 10% FO. All OVX rats underwent bilateral ovariectomy. The experiment was continued for 2 months. Serum bone alkaline phosphatase (B-ALP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), calcium (Ca), phosphorous (P), and magnesium (Mg) were measured.

RESULTS:

A significant increase of serum IL-6 and TNF-alpha concentrations were observed between OVX rats when compared with Group 1, while there was no significant difference in the activity of B-ALP, serum Ca, P, and Mg among all groups. A remarkable significant decrease of serum levels of IL-6 and TNF-alpha was observed in the group of rats that were fed with FS (Groups 3 and 4) and FO (Groups 5 and 6).

CONCLUSION:

This study suggests that FS and FO might be useful in the prevention of estrogen-deficiency induced osteoporosis via decreasing osteoclastogenesis. Further studies are needed to demonstrate their efficacy in humans by using bioactive components of FS, and to clarify their mechanism of action.

PMID : 21483995

 

Incorporation of Flaxseed Flour as a Dietary Source for ALA Increases Bone Density and Strength in Post-Partum Female Rats.

Abstract

In women, bone mass undergoes changes during pregnancy and the postpartum period, which has a risk for subsequent development of osteoporosis. Thus, the present study aims to evaluate the effects of flaxseed flour in femur quality during post-weaning of dam rats. After weaning, the rats were divided into control (C, n = 7) and experimental (F, n = 7) groups treated with a diet containing 25 g of flaxseed flour in the lactating period and 15 g in the maintenance period. After 51 days post-partum, serum hormone, fatty acids composition, bone compartments, computed tomography, and biomechanical analyses were determined. Food intake, length, body mass, hormone analysis, and total bone compartments showed similar results. For biomechanical and computed tomography analysis and fatty acids composition, the F group showed higher maximum force (+12%, p < 0.05), breaking strength (+25%, p < 0.05), rigidity (+17%, p < 0.0001), and femoral head radiodensity (+15%, p < 0.05) and presented lower total polyunsaturated fatty acids (-17%, p < 0.0001) and arachidonic acid (-44%, p < 0.0001) and higher ALA (+695%, p < 0.0001) and EPA (+160%, p < 0.05).

Fatty acids composition of flaxseed flour, as well as its protein profile and calcium content, were able to improve the bone quality, which may be associated with lower serum levels of arachidonic acid and higher EPA, showing an anti-inflammatory profile and increased deposition of organic matrix during the post-weaning period, and may result in prevention of future osteoporosis.

KEYWORDS:

Biomechanical parameters; Gas chromatography; Omega-3; Rat

PMID : 28324248

 

An altered tissue distribution of flaxseed lignans and their metabolites in Abcg2 knockout mice.

Abstract

Lignans are dietary polyphenols, which are metabolized by gut microbiota into the phytoestrogenic metabolites enterolignans, mainly enterolactone and enterodiol. Breast Cancer Resistance Protein (BCRP/ABCG2) is an efflux transporter that affects the plasma and milk secretion of several drugs and natural compounds. We hypothesized here that Abcg2 could influence the levels of lignans and their derived metabolites in target tissues. Consequently, we aimed to evaluate the role of Abcg2 in the tissue distribution of these compounds. We used Abcg2-/- knockout and wild-type male mice fed with a lignan-enriched diet for one week and analysed their plasma, small intestine, colon, liver, kidneys and testicles. High levels of lignans as well as enterolignans and their glucuronide and sulfate conjugates in the small intestine and colon were detected, with higher concentrations of the conjugates in the wild-type compared with Abcg2-/- mice. Particularly relevant was the detection of 24-fold and 8-fold higher concentrations of enterolactone-sulfate and enterolactone-glucuronide, respectively, in the kidney of Abcg2-/- compared with wild-type mice.

 

In conclusion, our study showed that lignans and their derived metabolites were in vivo substrates of Abcg2, which affected their plasma and tissue levels. These results highlight the role of Abcg2 in influencing the health-beneficial properties of dietary lignans.

PMID : 29292449

 

 

 Protective role of Ashwagandharishta and flax seed oil against maximal electroshock induced seizures in albino rats.

Abstract

Ashwagandharishta, an Ayurvedic classical formulation, is the remedy for Apasmara (epilepsy), Murchha (syncope), Unmada (psychosis), etc. Recent studies in animal models have shown that n-3 PUFAs can raise the threshold of epileptic seizures. The indigenous medicinal plant, called Atasi (Linum usitatissimum Linn.) in Ayurveda, or flax seed, is the best plant source of omega-3 fatty acids. The present study is designed to investigate whether Ashwagandharishta and Atasi taila (flax seed oil) protect against maximal electroshock (MES) seizures in albino rats. Further, a possible protective role of flax seed oil as an adjuvant to Ashwagandharishta in its anticonvulsant activity has also been evaluated in the study. MES seizures were induced for rats and seizure severity was assessed by the duration of hind limb extensor phase. Phenytoin was used as the standard antiepileptic drug for comparison. Both flax seed oil and Ashwagandharishta significantly decreased convulsion phase. Pre-treatment with flax seed oil exhibited significant anticonvulsant activity by decreasing the duration of tonic extensor phase. Contrary to the expectations, pre-treatment with flax seed oil as an adjuvant to Ashwagandharishta failed to decrease the tonic extensor phase; however, it significantly decreased the flexion phase (P < 0.001) and duration of the convulsions (P < 0.05).

Both the drugs exhibited an excellent anti-post-ictal depression effect and complete protection against mortality.

KEYWORDS:

Antiepileptic; Ashwagandharishta; flax seed oil; maximal electroshock seizure; omega-3 fatty acid

PMID: 23049195

 

Flax lignan concentrate reverses alterations in blood pressure, left ventricular functions, lipid profile and antioxidant status in DOCA-salt induced renal hypertension in rats.

Abstract

CONTEXT:

Earlier we reported cardioprotective, antihyperlipidemic, and in vitro antioxidant activity of flax lignan concentrate (FLC) obtained from the seeds of Linum usitatissimum L. (Linaceae).

OBJECTIVE:

To investigate the effect of FLC in deoxycorticosterone acetate (DOCA)-salt induced experimental renal hypertension in rats.

MATERIALS AND METHODS:

Hypertension was induced in uninephrectomized (UNTZD) male Wistar rats (230-280 g) by injecting DOCA (25 mg/kg, subcutaneously, twice weekly) and supplementing 1% NaCl in drinking water for 5 weeks. The rats were divided in six groups. Captopril (30 mg/kg, p.o.) and FLC (200, 400 and 800 mg/kg, p.o.) were administered daily to the rats of groups III-VI, respectively, for 5 weeks. Various hemodynamic and biochemical parameters were investigated as well as histology of kidney and heart were carried out.

RESULTS:

In this study, the FLC (400 and 800 mg/kg) significantly (p < 0.01, p < 0.001) decreased the systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure. It also significantly (p < 0.01, p < 0.001) decreased elevated end diastolic pressure (EDP), dP/dt max and dP/dt min, organs weights (kidney and heart) and activities of hepatic, renal and cardiac marker enzymes in the serum. Furthermore, FLC (400 and 800 mg/kg) significantly (p < 0.01, p < 0.001) restored altered antioxidant status, serum electrolyte level, lipid profile values, and histological abnormalities. Captopril (30 mg/kg) showed maximum antihypertensive effect but low dose of FLC (200 mg/kg) was not enough to show the antihypertensive activity.

CONCLUSION:

FLC possessed antihypertensive effect via modulation of endogenous enzymes in DOCA-salt induced renal hypertension in rats.

KEYWORDS:

Antihypertensive activity; DOCA; Linum usitatissimum; flaxseed; renal hypertension

PMID : 26795298

 

Eicosahexanoic Acid (EPA) and Docosahexanoic Acid (DHA) in Muscle Damage and Function.

Abstract

Nutritional supplementation not only helps in improving and maintaining performance in sports and exercise, but also contributes in reducing exercise fatigue and in recovery from exhaustion. Fish oil contains large amounts of omega-3 fatty acids, eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3). It is widely known that omega-3 fatty acids are effective for improving cardiac function, depression, cognitive function, and blood as well as lowering blood pressure. In the relationship between omega-3 fatty acids and exercise performance, previous studies have been predicted improved endurance performance, antioxidant and anti-inflammatory responses, and effectivity against delayed-onset muscle soreness. However, the optimal dose, duration, and timing remain unclear. This review focuses on the effects of omega-3 fatty acid on muscle damage and function as evaluated by human and animal studies and summarizes its effects on muscle and nerve damage, and muscle mass and strength.

KEYWORDS:

docosahexaenoic acid; eicosapentaenoic acid; muscle damage; muscle hypertrophy; muscle strength; n-3; neuromuscular function; omega3; unsaturated fatty acids

PMID : 29710835

 

Dietary flaxseed modulates the colonic microenvironment in healthy C57Bl/6 male mice which may alter susceptibility to gut-associated diseases.

Abstract

Understanding how dietary components alter the healthy baseline colonic microenvironment is important in determining their roles in influencing gut health and gut-associated diseases. Dietary flaxseed (FS) has demonstrated anti-colon cancer effects in numerous rodent models, however, exacerbated acute colonic mucosal injury and inflammation in a colitis model. This study investigates whether FS alters critical aspects of gut health in healthy unchallenged mice, which may help explain some of the divergent effects observed following different gut-associated disease challenges. Four-week-old C57Bl/6 male mice were fed an AIN-93G basal diet (BD) or an isocaloric BD+10% ground FS diet for 3 weeks. FS enhanced colon goblet cell density, mucus production, MUC2 mRNA expression, and cecal short chain fatty acid levels, indicative of beneficial intestinal barrier integrity responses. Additionally, FS enhanced colonic regenerating islet-derived protein 3 gamma (RegIIIγ) and reduced MUC1 and resistin-like molecule beta (RELMβ) mRNA expression which may indicate altered responses in regulating microbial defense and injury repair responses. FS diet altered the fecal microbial community structure (16S rRNA gene profiling), including a 20-fold increase in Prevotella spp. and a 30-fold reduction in Akkermansia muciniphila abundance. A 10-fold reduction in A. muciniphila abundance by FS was also demonstrated in the colon tissue-associated microbiota (quantitative PCR). Furthermore, fecal branched chain fatty acids were increased by FS, indicative of increased microbial-derived putrefactive compounds. In conclusion, consumption of a FS-supplemented diet alters the baseline colonic microenvironment of healthy mice which may modify subsequent mucosal microbial defense and injury-repair responses leading to altered susceptibility to different gut-associated diseases.

KEYWORDS:

Akkermansia muciniphila; Flaxseed; Goblet cells; Microbiota; Mucin; Short chain fatty acids

PMID : 26878783

 

Use of defatted flaxseed meal reduces precancerous colon lesions in C57BL/6 mice.

Abstract

PURPOSE:

To investigate the hemopreventive effect of defatted flaxseed meal in C57BL/6 mice after induction of precancerous colon lesions with 1.2-dimethylhydrazine (DMH).

METHODS:

Thirty-six 12-week-old C57BL/6 mice were divided into three treatment groups(n=12 in each group): (1) diet with 10% defatted flaxseed meal; (2) diet with defatted flaxseed meal and precancerous colon lesions induced by DMH; and (3) precancerous colon lesions induced by DMH, without defatted flaxseed meal. The incidence of aberrant crypt foci (ACF), oxidative processes, expression of tumor suppressor proteins and cyclins, as well as the profile of short-chain fatty acids (SCFA) in animal feces were investigated in the presence and absence of DMH.

RESULTS:

The rats consuming defatted flaxseed meals showed lesions with lower multiplicity and a reduced incidence of lesions. No changes in the expression of tumor suppressor proteins and those involved in cell cycle control were detected.

CONCLUSION:

Defatted flaxseed meal protected the distal colon of mice from precancerous lesions.

PMID : 23896841

Flaxseed extract exhibits mucosal protective effect in acetic acid induced colitis in mice by modulating cytokines, antioxidant and antiinflammatory mechanisms.

Abstract

New treatments for inflammatory bowel disease are of interest due to high rate of remission failure. Natural products have been effective in IBD therapeutics as they have multiple constituents. The aim of the present study was to evaluate the effect of Flaxseed extract (Fs.Cr) on ulcerative colitis and identify the possible mechanisms involved. Colitis was induced by intrarectal administration of 6% AA in BALB/c mice. Colonic mucosal damage was assessed after 24h by calculating disease activity index (DAI), macroscopic and histological damage scores, biochemical measurement of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total glutathione activities. Since cytokines are involved in exacerbating inflammatory cascade with emerging role of innate immune cytokines in IBD therapeutics, we hence assessed the effect on the levels of TNF-α, IFN-γ and IL-17, at 6, 12 and 24h by ELISA. Fs.Cr ameliorated the severity of AA colitis as evident by improved DAI, macroscopic damage and the histopathological scores along with restoration of goblet cells. Fs.Cr decreased MDA and MPO activities and enhanced antioxidant activity compared to the AA group. Finally, Fs.Cr in doses (300 and 500mg/kg) decreased TNF-α and IFN-γ levels at all time points with simultaneous increase in IL-17 levels at 24h as compared to the AA group.

These results suggest that Fs.Cr ameliorates the severity of AA colitis by reducing goblet cell depletion, scavenging oxygen-derived free radicals, reduce neutrophil infiltration that may be attributed due to decreasing IFN-γ and TNF-α and increasing IL-17 levels.

KEYWORDS:

Goblet cells; IL-17, IFN-gamma; Innate immune arm; Natural products; Ulcerative colitis

PMID : 27280586

HOLISM STUDY

HOLISM Study

Professor George Jelinek is Professor and Head of the Neuroepidemiology Unit (NEU) within the Melbourne School of Population and Global Health at The University of Melbourne. The NEU’s charter is to investigate the modifiable lifestyle risk factors that predict the progression of MS with a view to refining a preventive medicine approach to management of the disease.

This large international observational cohort study commenced in 2011 and involved recruitment of an international sample of people with MS through web 2.0 platforms to contribute very detailed, self-reported lifestyle, medication and MS disease outcome data. This is a unique study, being the first study of its type to collect detailed lifestyle data from a very large group of people with MS world-wide and correlate this with outcome, and because it is not funded by industry but by charitable trusts.

PART ONE
The first part of the study collated these data, which are undergoing detailed analysis to determine the association between lifestyle factors and MS disease outcomes as the epidemiological foundation of a secondary and tertiary preventive strategy for managing MS. The database is one of the largest in the world, and is the only database containing a comprehensive suite of modifiable lifestyle risk factors that is independently funded (as opposed to drug company-funded). The study has ethics approval from the Human Research Ethics Committee at St Vincent’s Hospital Melbourne Australia. A number of papers have been published from this database, and further studies are ongoing as follows:

Omega 3 and fish consumption association with MS disease outcomes
This paper reports the strong significant associations of omega 3 intake and frequency of fish consumption with MS disease activity, relapse rate, disability and quality of life for around two and a half thousand people with MS from 57 countries world-wide. It is in this paper that we report the over 60% reduced relapse rate associated with flaxseed oil supplements.

► Jelinek GA, Hadgkiss EJ, Weiland TJ, Pereira N, Marck CH, van der Meer DM. Association of fish consumption and omega 3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis. Int J Neurosci 2013; in press; DOI: 10.3109/00207454.2013.803104 View pdf

Full study : https://overcomingms.org/holism-study/

 

PLANT-BASED FATTY ACIDS MAY LOWER RISK OF MS

A recent study reported at ECTRIMS (European Committee for Treatment and Research in MS) in Barcelona reports that higher intake of plant-based essential fatty acids, such as alpha linolenic acid in flaxseed oil, may reduce the risk of developing Multiple Sclerosis.

Examining data from the Nurses Health Study on nearly 180,000 nurses in the US, investigators found that individuals who consumed the most foods containing plant-based polyunsaturated fatty acids (PUFAs) had one-third lower MS risk than those individuals consuming the least amount. However, they found no significant association between consuming a diet high in fatty acids from fish and MS risk.

Lead researcher Kjetil Bjørnevik, MD (PhD student), research fellow, University of Bergen, Norway, said: “For the last half a century, there has been a lot of interest in PUFAs (Polyunsaturated Fatty Acids), but it has been mainly focused on fish-derived PUFAs — what we get from consuming fish. Here in our study, we don’t actually see an association between those types of PUFAs and MS risk.” Medical professionals can view the study report at Medscape after signing up at this link.

These findings gave support to the unexpected finding from an earlier publication ​from the OMS Research Team in 2013. In their paper from the HOLISM study Association of fish consumption and omega 3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis, they showed that people with MS consuming flaxseed oil had over 60% lower relapse rate than those not consuming it, but fish oil did not have any significant association. 

It concluded: Those consuming fish more frequently and those taking omega 3 supplements had significantly better quality of life, in all domains, and less disability. For fish consumption, there was a clear dose–response relationship for these associations. There were also trends towards lower relapse rates and reduced disease activity; flaxseed oil supplementation was associated with over 60% lower relapse rate over the previous 12 months. Further dietary studies and randomised controlled trials of omega 3 supplementation for people with MS are required, preferably using flaxseed oil.

While the ECTRIMS report was about risk of developing MS, and the HOLISM report focused on the disease-modifying effect of flaxseed oil intake after developing MS, the studies in combination strongly suggest that the plant-based omega-3s are likely to be the preferred source of omega 3 supplementation for people with MS or those at risk of developing MS, such as their close relatives. Clearly flaxseed oil in particular, the most potent source of plant-based omega 3s, is worthy of ongoing study, and the studies to date reinforce the OMS recommendation to take flaxseed oil rather than fish oil.

Full Paper – International Journal Of Neuroscience

 

Flaxseed Oil Attenuates Intestinal Damage and Inflammation by Regulating Necroptosis and TLR4/NOD Signaling Pathways Following Lipopolysaccharide Challenge in a Piglet Model.

Abstract

SCOPE:

Flaxseed oil is a rich source of α-linolenic acid (ALA), which is the precursor of the long-chain n-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This study investigates the protective effect of flaxseed oil against intestinal injury induced by lipopolysaccharide (LPS).

MATERIALS AND RESULTS:

Twenty-four weaned pigs were used in a 2 × 2 factorial experiment with dietary treatment (5% corn oil vs 5% flaxseed oil) and LPS challenge (saline vs LPS). On day 21 of the experiment, pigs were administrated with LPS or saline. At 2 h and 4 h post-administration, blood samples were collected. After the blood harvest at 4 h, all piglets were slaughtered and intestinal samples were collected. Flaxseedoil supplementation led to the enrichment of ALA, EPA, and total n-3 PUFAs in intestine. Flaxseed oil improved intestinal morphology, jejunal lactase activity, and claudin-1 protein expression. Flaxseed oil downregulated the mRNA expression of intestinal necroptotic signals. Flaxseed oil also downregulated the mRNA expression of intestinal toll-like receptors 4 (TLR4) and its downstream signals myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), and nucleotide-binding oligomerization domain proteins 1, 2 (NOD1, NOD2) and its adapter molecule, receptor-interacting protein kinase 2 (RIPK2).

CONCLUSION:

These results suggest that dietary addition of flaxseed oil enhances intestinal integrity and barrier function, which is involved in modulating necroptosis and TLR4/NOD signaling pathways.

KEYWORDS:

flaxseed oil; inflammation; intestinal barrier function; lipopolysaccharide; necroptosis signaling pathway; weaned pigs

PMID : 29510469

 

Dietary α-linolenic acid-rich flaxseed oil prevents against alcoholic hepatic steatosis via ameliorating lipid homeostasis at adipose tissue-liver axis in mice.

Abstract

Low levels of n-3 polyunsaturated fatty acids (PUFAs) in serum and liver tissue biopsies are the common characteristics in patients with alcoholic liver disease. The α-linolenic acid (ALA) is a plant-derived n-3 PUFA and is rich in flaxseed oil. However, the impact of ALA on alcoholic fatty liver is largely unknown. In this study, we assessed the potential protective effects of ALA-rich flaxseed oil (FO) on ethanol-induced hepatic steatosis and observed that dietary FO supplementation effectively attenuated the ethanol-induced hepatic lipid accumulation in mice. Ethanol exposure stimulated adipose lipolysis but reduced fatty acid/lipid uptake, which were normalized by FO. Our investigations into the corresponding mechanisms demonstrated that the ameliorating effect of FO might be associated with the lower endoplasmic reticulum stress and normalized lipid metabolism in adipose tissue. In the liver, alcohol exposure stimulated hepatic fatty acid uptake and triglyceride synthesis, which were attenuated by FO. Additionally, dietary FO upregulated plasma adiponectin concentration, hepatic adiponectin receptor 2 expression, and the activation of hepatic adenosine monophosphate-activated protein kinase.

Collectively, dietary FO protects against alcoholic hepatic steatosis by improving lipid homeostasis at the adipose tissue-liver axis, suggesting that dietary ALA-rich flaxseed oil might be a promising approach for prevention of alcoholic fatty liver.

PMID : 27220557

 

Protective effect of alpha-linolenic acid in encephalomalacia in chickens

Abstract

Encephalomacia is a vitamin E deficiency syndrome which affects the cerebellum of young chicks. The lesion includes degenerative alterations of cellular and fibrillar elements, apparently as the result of the ischaemia caused by thrombotic events in the microvascular system. A supply of linoleic acid, as fatty acid methyl esters prepared from safflower oil (Carthamus tinctorius), caused a high incidence of encephalomalacia. On the other hand, linseed oil esters, rich in alpha-linolenic acid, did not induce any symptoms and protected the chicks to a large extend against the development of signs produced by linoleic acid. Fatty acid esters of cod liver oil, rich in long-chain derivatives of alpha-linolenic acid, exerted a relatively weak protective effect.

The analytical results show that a supply of alpha-linolenic acid led to an accumulation of eicosapentaenoic acid, 20:5 omega 3, and a reduced concentration of arachidonic acid in the phospholipds of liver and plasma.

The results suggest that, under the conditions leading to encephalomalacia, the prostacyclin-thromboxane balance is shifted in direction of an excessive production of TXA2, causing thrombus formation in the capillaries of the cerebellum, alpha-linolenic acid, by modifying the PUFA profile, exerts a multiple action the main result of which appears to be an antithrombotic effect at the level of the microvascular system of the cerebellum.

PMID: 6254420

 

Inhibitory effect of polyunsaturated fatty acids on apoptosis induced by Streptococcus pneumoniae in alveolar macrophages.

Abstract

BACKGROUND & OBJECTIVES:

Apoptosis is considered as a major defense mechanism of the body. Multiple pathogens induce macrophage apoptosis as a mode of immune evasion. In earlier studies, n-3 polyunsaturated fatty acids (PUFA) have been reported to be protective against neuronal apoptosis and neuronal degeneration, seen after spinal cord injury. In this study, we tried to evaluate the role of n-3 polyunsaturated fatty acids on the process of macrophage phagocytic activity and apoptosis in mice.

METHODS:

Mice were divided into three groups (n=60); Group I was fed on sea cod oil; Group II on flaxseed oil supplementation for 9 wk along with standard laboratory chow diet. Group III was fed on standard diet and served as control. After supplementation, phagocytic and apoptotic (morphological staining: acridine orange plus ethidium bromide; H-33342 plus propidium iodide staining and DNA ladder formation) activities of mouse alveolar macrophages were assessed.

RESULTS:

Alveolar macrophages (obtained from sea cod oil and flaxseed oil fed group mice) showed significant increase in bacterial uptake as well as intracellular killing (P 0.05) of Streptococcus pneumoniae. Significant decrease (P<0.05) in apoptotic cells was observed among alveolar macrophages from sea cod and flaxseed oil fed mice whereas maximum apoptosis was observed in control alveolar macrophages on interaction with bacteria in vitro which was confirmed by DNA laddering.

INTERPRETATION & CONCLUSIONS:

These findings suggest that dietary supplementation with n-3 polyunsaturated fatty acids to mice led to enhanced phagocytic capability of their alveolar macrophages as well as provided protection against apoptosis upon challenge with S. pneumoniae.

PMID: 23852301

 

Dietary flaxseed oil supplementation mitigates the effect of lead on the enzymes of carbohydrate metabolism, brush border membrane, and oxidative stress in rat kidney tissues.

Abstract

Lead is a heavy metal widely distributed in the environment. Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Human and animal exposure demonstrates that lead is nephrotoxic. However, attempts to reduce lead-induced nephrotoxicity were not found suitable for clinical use.

Recently, flaxseed oil (FXO), a rich source of ω-3 fatty acids and lignans, has been shown to prevent/reduce the progression of certain types of cardiovascular and renal disorders. In view of this, the present study investigates the protective effect of FXO on lead acetate (PbAc)-induced renal damage. Rats were pre-fed normal diet and the diet rich in FXO for 14 days, and then, four doses of lead acetate (25 mg/kg body weight) were administered intraperitoneally while still on diet.

Various serum parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), and oxidative stress were analyzed in rat kidney. PbAc nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. PbAc increased the activities of lactate dehydrogenase and NADP-malic enzyme, whereas it decreased malate and glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and BBM enzyme activities. PbAc caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased activities of superoxide dismutase, glutathione peroxidase, and catalase. In contrast, FXO alone enhanced the enzyme activities of carbohydrate metabolism, BBM, and antioxidant defense system. FXO feeding to PbAc-treated rats markedly enhanced resistance to PbAc-elicited deleterious effects.

In conclusion, dietary FXO supplementation ameliorated PbAc-induced specific metabolic alterations and oxidative damage by empowering antioxidant defense mechanism and improving BBM integrity and energy metabolism.

PMID: 23613149

 

 

 

Potential Contraindication studies :

Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate.

Abstract

Flaxseed (FS), a dietary oilseed, contains a variety of anti-inflammatory bioactives, including fermentable fiber, phenolic compounds (lignans), and the n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid. The objective of this study was to determine the effects of FS and its n-3 PUFA-rich kernel or lignan- and soluble fiber-rich hull on colitis severity in a mouse model of acute colonic inflammation. C57BL/6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10% FS, 6% kernel, or 4% hull for 3 wk prior to and during colitis induction via 5 days of 2% (wt/vol) dextran sodium sulfate (DSS) in their drinking water (n = 12/group). An increase in anti-inflammatory metabolites (hepatic n-3 PUFAs, serum mammalian lignans, and cecal short-chain fatty acids) was associated with consumption of all FS-based diets, but not with anti-inflammatory effects in DSS-exposed mice. Dietary FS exacerbated DSS-induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL-6 and IL-1β), and NF-κB signaling-related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL-6, IFNγ, and IL-1β) and hepatic cholesterol levels were increased. The adverse effects of FS were not associated with alterations in fecal microbial load or systemic bacterial translocation (endotoxemia).

Collectively, this study demonstrates that although consumption of a 10% FS diet enhanced the levels of n-3 PUFAs, short-chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS-induced colonic injury and inflammation.

KEYWORDS:

experimental colitis; flaxseed; lignans; n-3 polyunsaturated fatty acids; short-chain fatty acids

PMID: 24763556

 

  • PLEASE NOTE : These studies have hyperlinks to the original location in each title. This is simply the reproduction of, for review purposes only. This does not constitute opinion of the author (chooselife) and certainly not medical advice.