In vitro dissolution behaviour and absorption in humans of a novel mixed l-lysine salt formulation of EPA and DHA.

INTRODUCTION: Supplements with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are generally oil-based formulations containing their triacylglycerols, phospholipids or ethyl-esters (EE). Recently, a l-lysine salt of carboxylic EPA and DHA became available (Lys-FFA), which necessitated to study its oral absorption and plasma kinetics in humans. OBJECTIVES: The in vitro dissolution characteristics, oral bioavailability and 48 h plasma profiles of EPA and DHA (as triacylglycerides) of Lys-FFA, relative to a commercially available oil-based EE supplement. METHODS: Dissociation of the lysine from the FFAs was studied in vitro applying simulated gastric (12 h) and intestinal (3 h) conditions. In an open label, randomized, two-way cross-over design, oral administration of Lys-FFA (500 mg EPA plus 302 mg DHA) versus EE (504 mg EPA plus 378 mg DHA) was studied over 48 h, in eight female volunteers. Plasma profiles of EPA and DHA were described by Area Under the Curve (AUC; 0-12 h), Cmax and Tmax. RESULTS: Dissolution studies with Lys-FFA showed complete dissociation under both conditions. In volunteers Lys-FFA showed rapid absorption and high bioavailability indicated by significant differences in both the AUC0-12hr and Cmax when compared to the EE comparator (p<0.001), with AUC0-12hr which was for EPA 5 times higher with Lys-FFA than with the EE formulation. CONCLUSION: This first-in-man study of Lys-FFA demonstrated rapid absorption of EPA and DHA and a considerably higher bioavailability compared to an EE supplement under fasting conditions. The release and absorption characteristics from this solid form offer several new options in terms of formulation technology and dosing.

Dietary docosahexaenoic acid inhibits neurodegeneration and prevents stroke.

Stroke severely impairs quality of life and has a high mortality rate. On the other hand, dietary docosahexaenoic acid (DHA) prevents neuronal damage. In this review, we describe the effects of dietary DHA on ischemic stroke-associated neuronal damage and its role in stroke prevention. Recent epidemiological studies have been conducted to analyze stroke prevention through DHA intake. The effects of dietary intake and supply of DHA to neuronal cells, DHA-mediated inhibition of neuronal damage, and its mechanism, including the effects of the DHA metabolite, neuroprotectin D1 (NPD1), were investigated. These studies revealed that DHA intake was associated with a reduced risk of stroke. Moreover, studies have shown that DHA intake may reduce stroke mortality rates. DHA, which is abundant in fish oil, passes through the blood-brain barrier to accumulate as a constituent of phospholipids in the cell membranes of neuronal cells and astrocytes. Astrocytes supply DHA to neuronal cells, and neuronal DHA, in turn, activates Akt and Raf-1 to prevent neuronal death or damage. Therefore, DHA indirectly prevents neuronal damage. Furthermore, NDP1 blocks neuronal apoptosis. DHA, together with NPD1, may block neuronal damage and prevent stroke. The inhibitory effect on neuronal damage is achieved through the antioxidant (via inducing the Nrf2/HO-1 system) and anti-inflammatory effects (via promoting JNK/AP-1 signaling) of DHA.

Predicting Resolvin D1 Pharmacokinetics in Humans with Physiologically-Based Pharmacokinetic Modeling.

Sjögren's syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid-based specialized pro-resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically-based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS-like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01-10 mg/kg). The first-in-human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.

Dietary supplementation with docosahexaenoic acid rich fish oil increases circulating levels of testosterone in overweight and obese men.

Pre-clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs), in particular, docosahexaenoic acid (DHA) have been shown to affect testosterone synthesis in males. This study is a secondary analysis of a randomized controlled trial which determined the effect of a DHA-enriched fish oil supplement on insulin resistance. The aim of the current study was to determine whether testosterone levels change in response to a DHA-enriched fish oil intervention. Overweight and obese men and women without diabetes were recruited to the study. Participants were stratified by sex and randomly allocated to intervention (860 mg DHA + 120 g EPA/day; FO) or an isocaloric control (corn oil; CO) for 12 weeks. A fasted blood sample was collected pre- and post-intervention. Fatty acid composition of erythrocyte membranes was measured using gas chromatography. Total testosterone and metabolic parameters were measured by an accredited commercial pathology laboratory. Sixty-one participants (CO/FO: n = 29/32) were included in the current analysis (male: n = 22, 36.07%).  DHA-enriched fish oil supplementation increased total testosterone levels in males after adjusting for baseline levels, age and BMI. There was no treatment effect in females. Changes in testosterone levels in males were positively associated with changes to omega-3 PUFAs EPA and DHA and inversely correlated with omega-6 PUFA, arachidonic acid and dihomo-gamma-linolenic acid content in erythrocyte membranes, and was associated with beneficial changes to fasting insulin and HOMA-IR across the course of the study. DHA-enriched fish oil supplementation increases testosterone levels in overweight and obese men. Further research is warranted to substantiate these findings with a larger sample size and a longer follow-up period.

Pharmacokinetics of Single and Multiple Doses of Omega-3 Carboxylic Acids in Healthy Chinese Subjects: A Phase I, Open-Label Study.

In patients with coronary heart disease undergoing primary prevention, hypertriglyceridemia is a residual risk for cardiovascular events. Omega-3 carboxylic acid (OM3-CA), a mixture of the free fatty acid forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be beneficial in reducing triglyceride levels. As part of the clinical development program of OM3-CA in China, this phase I study evaluated the pharmacokinetics, safety, and tolerability profile of OM3-CA in healthy subjects. The pharmacokinetic results of this study were also compared with those of available data for Western populations. Fourteen healthy Chinese subjects (aged 18-45 years) received once-daily oral OM3-CA 4 g for 14 consecutive days. Pharmacokinetic parameters were assessed from both baseline-uncorrected and baseline-corrected plasma concentrations vs time profile of EPA, DHA, and EPA plus DHA. Following single and multiple oral doses of OM3-CA, the absorption of EPA, DHA, and EPA plus DHA was steady with median tmax occurring at 5.5-6 hours after both single and multiple dosing. Close to steady-state concentrations in plasma were reached after 14 days of continuous once-daily dosing, and accumulation was confirmed for EPA, DHA, and EPA plus DHA. Of the 14 subjects treated with OM3-CA, 6 (42.9%) reported at least 1 adverse event (diarrhea) during the study, which was determined as mild and treatment emergent. No serious adverse events were reported. In summary, the pharmacokinetic profile of oral OM3-CA 4 g after single and multiple dosing in healthy Chinese subjects is consistent with that observed in other ethnic populations.

Predictive modeling of aspirin-triggered resolvin D1 pharmacokinetics for the study of Sjögren's syndrome.

OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune disease that causes chronic inflammation of the salivary glands leading to secretory dysfunction. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) reduces inflammation and restores tissue integrity in salivary glands. Specifically, progression of SS-like features in NOD/ShiLtJ mice can be systemically halted using AT-RvD1 prior or after disease onset to downregulate proinflammatory cytokines, upregulate anti-inflammatory molecules, and restore saliva production. Therefore, the goal of this paper was to create a physiologically based pharmacokinetic (PBPK) model to offer a reasonable starting point for required total AT-RvD1 dosage to be administered in future mice and humans thereby eliminating the need for excessive use of animals and humans in preclinical and clinical trials, respectively. Likewise, PBPK modeling was employed to increase the range of testable scenarios for elucidating the mechanisms under consideration. MATERIALS AND METHODS: Pharmacokinetics following intravenous administration of a 0.1 mg/kg dose of AT-RvD1 in NOD/ShiLtJ were predicted in both plasma and saliva using PBPK modeling with PK-Sim® and MoBi® Version 7.4 software. RESULTS: The model provides high-value pathways for future validation via in vivo studies in NOD/ShiLtJ to corroborate the findings themselves while also establishing this method as a means to better target drug development and clinical study design. CONCLUSIONS: Clinical and basic research would benefit from knowledge of the potential offered by computer modeling. Specifically, short-term utility of these pharmacokinetic modeling findings involves improved targeting of in vivo studies as well as longer term prospects for drug development and/or better designs for clinical trials.

Lipase Treatment of Dietary Krill Oil, but Not Fish Oil, Enables Enrichment of Brain Eicosapentaenoic Acid and Docosahexaenoic Acid.

SCOPE: Currently available omega-3 fatty acid supplements do not enrich the docosahexaenoic acid (DHA) of the adult brain because they are absorbed as triacylglycerol, whereas the transporter at the blood brain barrier requires lysophosphatidylcholine (LPC)-DHA. The hypothesis that treatment of krill oil (KO), which contains DHA/eicosapentaenoic acid (EPA) at the SN2 position of phosphatidylcholine, with SN1-specific lipase will generate LPC-DHA/EPA and which can be absorbed intact and transported into the brain, is tested. METHODS: KO and fish oil (FO) are treated with Mucor meihei lipase, incorporated into AIN 93G diet, and fed to 2-month-old mice for 30 days. Fatty acid composition is analyzed by gas chromatography/mass spectroscopy. Brain derived neurotrophic factor (BDNF) is measured by ELISA. RESULTS: Lipase-treated (LT) KO increases brain DHA and EPA, respectively, 5-and 70-fold better than untreated (UT) KO. FO, whether lipase-treated or not, has no effect on brain DHA/EPA. LTKO is also more efficient in enriching liver DHA/EPA, but less efficient than UTKO and FO in enriching adipose tissue and heart. Brain BDNF is significantly increased by LTKO, but only marginally by other preparations. CONCLUSIONS: Pretreatment of dietary KO with lipase enables it to efficiently increase brain DHA/EPA because of the generation of LPC-DHA/EPA.

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

Oxidized lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids, collectively known as oxylipins, are bioactive signaling molecules that play diverse roles in human health and disease. Supplementation with n-3 docosahexaenoic acid (DHA) during pregnancy has been reported to decrease the risk of preterm birth in singleton pregnancies, which may be due to effects of DHA supplementation on oxylipins or their precursor n-6 and n-3 fatty acids. There is only limited understanding of the levels and trajectory of changes in plasma oxylipins during pregnancy, effects of DHA supplementation on oxylipins and unesterified fatty acids, and whether and how oxylipins and their unesterified precursor fatty acids influence preterm birth. In the present study we used liquid chromatography-tandem mass spectrometry to profile oxylipins and their precursor fatty acids in the unesterified pool using plasma samples collected from a subset of pregnant Australian women who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) study. ORIP is a large randomized controlled trial testing whether daily supplementation with n-3 DHA can reduce the incidence of early preterm birth compared to control. Plasma was collected at study entry (≈pregnancy week 14) and again at ≈week 24, in a subgroup of 48 ORIP participants-12 cases with spontaneous preterm (<37 weeks) birth and 36 matched controls with spontaneous term (≥40 weeks) birth. In the combined preterm and term pregnancies, we observed that in the control group without DHA supplementation unesterified AA and AA-derived oxylipins 12-HETE, 15-HETE and TXB2 declined between weeks 14-24 of pregnancy. Compared to control, DHA supplementation increased unesterified DHA, EPA, and AA, DHA-derived 4-HDHA, 10-HDHA and 19,20-EpDPA, and AA-derived 12-HETE at 24 weeks. In exploratory analysis independent of DHA supplementation, participants with concentrations above the median for 5-lipoxygenase derivatives of AA (5-HETE, Odds Ratio (OR) 8.2; p = 0.014) or DHA (4-HDHA, OR 8.0; p = 0.015) at 14 weeks, or unesterified AA (OR 5.1; p = 0.038) at 24 weeks had higher risk of spontaneous preterm birth. The hypothesis that 5-lipoxygenase-derived oxylipins and unesterified AA could serve as mechanism-based biomarkers predicting spontaneous preterm birth should be evaluated in larger, adequately powered studies.

Immuno-Resolving Ability of Resolvins, Protectins, and Maresins Derived from Omega-3 Fatty Acids in Metabolic Syndrome.

Omega-3 fatty acid consumption has been suggested to be beneficial for the prevention of type 2 diabetes mellitus (T2DM). Its effects have been attributed to anti-inflammatory activity, with the inhibition of arachidonic acid metabolism playing a central role. However, a more recent view is that omega-3 fatty acids play an active role as the precursors of potent, specialized pro-resolving mediators (SPMs), such as resolvins, protectins, and maresins. Docosahexaenoic acid (DHA)- and eicosapentaenoic-acid-derived SPMs are identified in the adipose tissue but the levels of certain SPMs (e.g., protectin D1) are markedly reduced with obesity, suggesting adipose SPM deficiency, potentially resulting in unresolved inflammation. Supplementation of the biosynthetic intermediates of SPM (e.g., 17-hydroxy-DHA) or omega-3 fatty acids increases the level of adipose SPMs, reduces adipose inflammation (decrease in macrophage accumulation and change to less inflammatory macrophages), and enhances insulin sensitivity. The findings from studies using rodent obesity models must be translated to humans. It will be important to further elucidate the underlying mechanisms by which obesity reduces the levels of and the sensitivity to SPM in adipose tissues. This will enable the development of nutrition therapy to enhance the effects of omega-3 fatty acids in the prevention and/or treatment of T2DM.

Enrichment of brain docosahexaenoic acid (DHA) is highly dependent upon the molecular carrier of dietary DHA: lysophosphatidylcholine is more efficient than either phosphatidylcholine or triacylglycerol.

Docosahexaenoic acid (DHA) is highly concentrated in the brain, and its deficiency is associated with several neurological disorders including Alzheimer's disease. However, the currently used supplements do not appreciably enrich brain DHA, although they enrich most other tissues. We tested the hypothesis that the ability of the dietary carrier to augment brain DHA depends upon the generation of DHA-lysophosphatidylcholine (LPC), the preferred carrier of DHA across the blood brain barrier. We compared the efficacy of DHA-triacylglycerol (TAG), di-DHA phosphatidylcholine (PC) and DHA-LPC to enrich brain DHA following their gavage to normal rats for 30 days, all at a dose of 10 mg DHA/day. The results show that DHA from TAG, which is released as free DHA or monoacylglycerol during digestion and is absorbed as TAG in chylomicrons, was incorporated preferentially into adipose tissue and heart but not into brain. In contrast, LPC-DHA increased brain DHA by up to 100% but had no effect on adipose tissue. Di-DHA PC, which generates both free DHA and LPC-DHA during the digestion, enriched DHA in brain, as well as in heart and liver. Brain-derived neurotrophic factor was increased by di-DHA PC and DHA-LPC, but not by TAG-DHA, showing that enrichment of brain DHA correlated with its functional effect. We conclude that dietary DHA from TAG or from natural PC (sn-2 position) is not suitable for brain enrichment, whereas DHA from LPC (at either sn-1 or sn-2 position) or from sn-1 position of PC efficiently enriches the brain and is functionally effective.

Effects of nano-sizing on lipid bioaccessibility and ex vivo bioavailability from EPA-DHA rich oil in water nanoemulsion.

The physiological efficacy of nutraceuticals is dependent on their physicochemical nature and bioavailability across biological barriers. In the present work, effects of nano-sizing of emulsion-based delivery vehicle on the bioavailability of polyunsaturated fatty acids rich fish oil have been investigated via three-step experimental design; ex vivo rat everted intestinal sac model, cellular lipid uptake and the bioactivity in rat PBMCs. Nanoemulsion in comparison to the conventional emulsion has shown significant higher rate of uptake of polyunsaturated fatty acids in three segments of small intestine. The time-kinetics of such uptake was correlated with appearance of short-chain fatty acids in basal side of the everted sac. The bioavailability of the formulated fish oil and its inhibitory response against lipopolysaccharide-induced nitric oxide production in rat PBMCs were positively correlated. This formulation with nano-sized droplets can be utilized as smart delivery vehicles for designing oral therapies in future.

Treatment with DHA Modifies the Response of MDA-MB-231 Breast Cancer Cells and Tumors from nu/nu Mice to Doxorubicin through Apoptosis and Cell Cycle Arrest.

Background: Docosahexaenoic acid (DHA) has been shown to reduce growth of breast cancer cells in vitro and in vivo; it may also benefit the action of cytotoxic cancer drugs. The mechanisms for these observations are not completely understood. Objectives: We sought to explore how pretreatment of MDA-MB-231 breast cancer cells with DHA alters gene expression with doxorubicin (DOX) treatment and confirm that feeding DHA to tumor-bearing nu/nu mice improves the efficacy of DOX. Methods: MDA-MB-231 cells were subjected to 4 conditions: a control mixture of 40 µM linoleic and 40 µM oleic acid (OALA), DHA (60 µM plus OALA), OALA DOX (0.41 µM), or DHA DOX (plus OALA) and assessed for effects on viability and function. Female nu/nu mice (6 wk old) bearing MDA-MB-231 tumors were randomly assigned to a nutritionally complete diet (20 g ± 2.8 g DHA/100 g diet) containing a polyunsaturated:saturated fat ratio of 0.5, with or without injections 2 times/wk of 5 mg DOX/kg for 4 wk. Results: Microarray and protein analysis indicated that DHA DOX cells, compared with OALA DOX, had upregulated expression of apoptosis genes, Caspase-10 (1.3-fold), Caspase-9 (1.4-fold), and Receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIPK1) (1.2-fold), while downregulating cell cycle genes, Cyclin B1 (-2.1-fold), WEE1 (-1.6-fold), and cell division cycle 25 homolog C (CDC25C) (-1.8-fold) (P < 0.05). DHA DOX-treated mice had 50% smaller tumors than control mice (P < 0.05). Analysis of proapoptotic proteins from tumors of DHA DOX mice showed increased Caspase-10 (by 68%) and BH3 interacting domain death agonist (Bid) (by 50%), decreased B-cell CLL/lymphoma 2 (BCL2) (by 24%), and decreased cell cycle proteins Cyclin B1 and Cdc25c (both by 42%), compared with control mice (P < 0.05). Conclusions: Supplementation with DHA facilitates the action of DOX in MDA-MB-231 cells and in nu/nu mice, which may occur via amplification of the effect of DOX on apoptosis and cell cycle genes.

Strategies to improve bioavailability of omega-3 fatty acids from ethyl ester concentrates.

PURPOSE OF REVIEW: To describe recent strategies that have been developed to enhance absorption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from dietary supplements. RECENT FINDINGS: The long-chain omega-3 fatty acids EPA and DHA have important physiologic functions, and numerous potential health benefits have been suggested by results from observational studies and randomized, controlled trials. EPA and DHA intakes in the average American diet are substantially below recommended levels. Dietary supplements are available for consumers wishing to increase their intakes, but many of these are in ethyl ester formulations from which EPA and DHA are poorly absorbed when consumed without a meal containing dietary fat. Technologies have been developed to enhance EPA and DHA absorption through in-situ emulsification, which facilitates bioavailability, even in the absence of a fat-containing meal. Findings from randomized controlled trials of absorption enhancers incorporated into omega-3 fatty acid supplements demonstrate that they can markedly improve the bioavailability of EPA and DHA. SUMMARY: The development of absorption enhancement technology to increase bioavailability of long-chain omega-3 fatty acids has important implications for studies on the health effects of dietary supplement and pharmaceutical products containing EPA and/or DHA.

Relative levels of dietary EPA and DHA impact gastric oxidation and essential fatty acid uptake.

Previous research showed that increasing the proportion of docosahexaenoic acid (DHA) in marine lipid supplements significantly reduces associated health benefits compared with balanced eicosapentaenoic acid (EPA):DHA supplementation Dasilva et al., 2015 [1]. It was therefore hypothesized that the EPA and DHA molecules might have differential resistance to oxidation during gastric digestion and that the oxidation level achieved could be inversely correlated with intestinal absorption and, hence, with the resultant health benefits. Accordingly, we tested this proposed mechanism of action by investigating the degree of oxidation in the stomach, and the levels of bioaccessible lipids, of varying molar proportions of DHA and EPA (2:1, 1:1 and 1:2) using the dynamic gastrointestinal tract model TIM-1. In addition, small intestine enterocyte absorption and metabolism were simulated by Caco-2 cell monolayers that were incubated with these same varying proportions of DHA and EPA, and comparing oxidized and nonoxidized polyunsaturated fatty acids (PUFAs). The results show an inverse correlation between lipid oxidation products in the stomach and the levels of bioaccessible lipids. The balanced 1:1 EPA:DHA diet resulted in lower oxidation of PUFAs during stomach digestion relative to the other ratios tested. Finally, cell-based studies showed significantly lower assimilation of oxidized EPA and DHA substrates compared to nonoxidized PUFAs, as well as significant differences between the net uptake of EPA and DHA. Overall, the present work suggests that the correct design of diets and/or supplements containing marine lipids can strongly influence the stability and bioaccessibility of PUFAs during gastrointestinal digestion and subsequent absorption. This could modulate their health benefits related with inflammation, oxidative stress and metabolic disorders.

Reduced blood-brain barrier expression of fatty acid-binding protein 5 is associated with increased vulnerability of APP/PS1 mice to cognitive deficits from low omega-3 fatty acid diets.

Lower levels of the cognitively beneficial docosahexaenoic acid (DHA) are often observed in Alzheimer's disease (AD) brains. Brain DHA levels are regulated by the blood-brain barrier (BBB) transport of plasma-derived DHA, a process facilitated by fatty acid-binding protein 5 (FABP5). This study reports a 42.1 ± 12.6% decrease in the BBB transport of 14 C-DHA in 8-month-old AD transgenic mice (APPswe,PSEN1∆E9) relative to wild-type mice, associated with a 34.5 ± 6.7% reduction in FABP5 expression in isolated brain capillaries of AD mice. Furthermore, short-term spatial and recognition memory deficits were observed in AD mice on a 6-month n-3 fatty acid-depleted diet, but not in AD mice on control diet. This intervention led to a dramatic reduction (41.5 ± 11.9%) of brain DHA levels in AD mice. This study demonstrates FABP5 deficiency and impaired DHA transport at the BBB are associated with increased vulnerability to cognitive deficits in mice fed an n-3 fatty acid-depleted diet, in line with our previous studies demonstrating a crucial role of FABP5 in BBB transport of DHA and cognitive function.

Omega-3 Polyunsaturated Fatty Acids Suplemented Diet and its preventive effect on tumor growth in nude mice / Dieta suplementada en ácidos grasos poliinsaturados omega-3 y su efecto preventivo sobre el crecimiento tumoral en ratones

Cancer is one of the leading causes of morbidity and mortality worldwide according to the WHO. Strong evidence suggests that food and nutrition are important in modification of cancer process. There is increased evidence that specific dietary patterns or constituents such as n-3 PUFAs, may be associated with reduced risk of BC. Female athymic nude mice were fed since weaning to adulthood with a DHA+EPA (4%w/w) diet or with standard diet during 14-week. At week- 7, tumor cell implantation with MDA-MB-231cell line took place, each mice received 5x106 tumor cells. When tumors became palpable, maximum length, width, and diameters were measured twice a week. Incidence of tumor development was observed in all mice (n=4, 100%) in the control diet group; instead, the n-3 PUFAs diet group, only two mice developed tumor (n=2, 50%), and the development time was longer compared to the control group. These differences were significant (p < 0.001). This study establish the potential effect as a preventive measure to BC. This evidence is consentient with epidemiological data about high n-3 PUFAs diet patterns in some populations may lower risk of BC, highlighting the importance of these components in our diet since childhood to promote the preventive effect. Being thus necessary, setting up recommendations for n-3 PUFAs supplementation from fish oil or, for a minimal dietary fatty fish intake/week, in order to attempt modulate carcinogenesis in populations at high risk, particularly those with a high prevalence of obesity

El cáncer es una de las principales causas de morbilidad y mortalidad en todo el mundo según la OMS. Una fuerte evidencia sugiere que la alimentación y la nutrición son importantes en la modificación de proceso de cáncer. Existe una alta evidencia de que patrones dietéticos específicos constituidos por AGPI n-3, pueden estar asociados con riesgo reducido de BC. Ratones atímicos desnudos femeninos fueron alimentados desde el destete hasta la etapa adulta con una dieta con DHA + EPA (4% p / p) o con una dieta estándar durante 14 semanas. En la semana 7, tuvo lugar la implantación de células tumorales de la línea celular MDA-MB-231 y cada ratón recibió 5x106 células tumorales. Cuando los tumores se hicieron palpables, y de longitud, ancho y diámetros máximos, se midieron dos veces por semana. La incidencia del desarrollo tumoral se observó en todos los ratones (n = 4, 100%) en el grupo de la dieta control ; en cambio, en el grupo de dieta de AGPI n-3, solo dos ratones desarrollaron un tumor (n = 2, 50%), y el tiempo de desarrollo fue más largo en comparación con el grupo de control. Estas diferencias fueron significativas (p <0.001). Este estudio establece el efecto potencial como una medida preventiva para BC. Esta evidencia se corrobora con datos epidemiológicos sobre patrones dietéticos altos en AGPI n-3 que en algunas poblaciones puede disminuir el riesgo de BC, destacando la importancia de estos componentes en nuestra dieta desde la infancia para promover el efecto preventivo. Siendo así necesario, establecer recomendaciones para la suplementación con AGPI n-3 del aceite de pescado o, para una ingesta dietética mínima de pescado / semana para intentar modular la carcinogénesis en poblaciones de alto riesgo, particularmente aquellos con una alta prevalencia de obesidad

A novel self-micro-emulsifying delivery system (SMEDS) formulation significantly improves the fasting absorption of EPA and DHA from a single dose of an omega-3 ethyl ester concentrate.

BACKGROUND: Absorption of EPA and DHA from Omega-3-acid ethyl ester (EE) concentrate supplements occurs most efficiently when taken in context of a fatty meal; adequate fat intake is required to release bile salts that emulsify and pancreatic enzymes that digest omega-3-containing lipids in the intestine. Current guidelines recommend reduction in fat intake and therefore there is a need to optimize the absorption of Omega-3 in those consuming low-fat or no-fat meals. To this end, BASF has developed an Absorption Acceleration Technology, a novel self-micro-emulsifying delivery system (SMEDS) formulation of highly concentrated Omega-3-acid EE which enables rapid emulsification and microdroplet formation upon entering the aqueous environment of the gut therefore enhances the absorption. METHODS: Two separate single dose, crossover studies were conducted to determine the relative bioavailability of omega-3-acid EE concentrate, either as a novel SMEDS formulation (PRF-021) or as control, in healthy fasted male and female adults at two dose levels (Study 1 "low dose": 630 mg EPA + DHA in PRF-021 vs. 840 mg EPA + DHA in control; Study 2 "high dose": 1680 mg EPA + DHA in PRF-021 vs. 3360 mg EPA + DHA in control). Blood samples were collected immediately before supplementation and at defined time intervals for 48 h. Plasma concentration of total EPA and DHA were determined for pharmacokinetic analysis, area under the curve (AUC) and maximum observed concentration (Cmax) was determined. RESULTS: Total EPA plus DHA absorption from SMEDS formulation PRF-021 were 6.4 and 11.5 times higher compared to control in low- and high-dose studies respectively, determined as the ratio of baseline corrected, dose normalized AUC0-24h of PRF-021 over that of control. EPA and DHA individually showed differing levels of enhancement: the AUC0-24h ratio for EPA was 23.8 and 25.7 in low and high dose studies, respectively, and the AUC0-24h ratio for DHA was 3.6 and 5.6 in low and high dose studies, respectively. Cmax was also increased for both EPA and DHA 2.7- to 9.2-fold. CONCLUSION: PRF-021 is a novel SMEDS formulation of Omega-3-acid EE demonstrating a marked improvement in absorption of a single dose of EPA and DHA EE under fasted conditions. This allows adequate absorption of Omega-3 from the supplement without the requirement of a high-fat meal.

Changes in Bioavailability of Omega-3 (DHA) through Alpha-Tocopheryl Phosphate Mixture (TPM) after Oral Administration in Rats.

Benefits of Omega-3 Docosahexaenoic acid (DHA) supplements are hindered by their poor solubility and bioavailability. This study investigated the bioavailability of various formulations of Omega-3 and tocopheryl phosphate mixture (TPM), following oral administration in rats, and assessed whether TPM could improve the oral absorption of DHA. The rats were administered with a high (265.7 mg/kg) or low dose (88.6 mg/kg) of DHA. TPM was examined at 1:0.1 w/w (low TPM dose) and 1:0.5 w/w (high TPM dose). Over 24 h, the DHA plasma concentration followed a TPM dose-dependent relationship, reflected in the higher mean Cmax values (78.39 and 91.95 µg/mL) and AUC values (1396.60 and 1560.60) for the low and high TPM, respectively. The biggest difference between the low dose DHA control (LDCont) and TPM formulations was at 4 h after supplementation, where the low and high TPM showed a mean 20% (ns) and 50% (p < 0.05) increase in DHA plasma concentrations versus the control formulation. After correcting for baseline endogenous DHA, the mean plasma DHA at 4 h produced by the LD-HTPM was nearly double (90%) the LDC control (p = 0.057). This study demonstrated that co-administering omega-3 with TPM significantly increases the bioavailability of DHA in the plasma, suggesting potential use for commercially available TPM + DHA fortified products.

Maternal liver docosahexaenoic acid (DHA) stores are increased via higher serum unesterified DHA uptake in pregnant long Evans rats.

Maternal docosahexaenoic acid (DHA, 22:6n-3) supplies the developing fetus during pregnancy; however, the mechanisms are unclear. We utilized pregnant rats to determine rates of DHA accretion, tissue unesterified DHA uptake and whole-body DHA synthesis-secretion. Female rats maintained on a DHA-free, 2% α-linolenic acid diet were either:1) sacrificed at 56 days for baseline measures, 2) mated and sacrificed at 14-18 days of pregnancy or 3) or sacrificed at 14-18 days as age-matched virgin controls. Maternal brain, adipose, liver and whole body fatty acid concentrations was determined for balance analysis, and kinetic modeling was used to determine brain and liver plasma unesterified DHA uptake and whole-body DHA synthesis-secretion rates. Total liver DHA was significantly higher in pregnant (95±5 µmol) versus non-pregnant (49±5) rats with no differences in whole-body DHA synthesis-secretion rates. However, liver uptake of plasma unesterified DHA was 3.8-fold higher in pregnant animals compared to non-pregnant controls, and periuterine adipose DHA was lower in pregnant (0.89±0.09 µmol/g) versus non-pregnant (1.26±0.06) rats. In conclusion, higher liver DHA accretion during pregnancy appears to be driven by higher unesterified DHA uptake, potentially via DHA mobilization from periuterine adipose for delivery to the fetus during the brain growth spurt.