Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.

The Plasma Oxylipidome Links Smoking Status to Peripheral Artery Disease.

Peripheral artery disease (PAD) is prevalent among individuals with a history of tobacco smoking. Although oxidation of lipids may contribute to atherogenesis in vascular disease, enzymatically and nonenzymatically produced oxidized lipids can have varying and contrasting physiological effects. The underlying mechanisms of atherogenic vulnerability can be better elucidated with the recent advances in oxylipidome quantification using HPLC-MS/MS technology. In a randomized, controlled clinical trial, the plasma oxylipidome was analyzed in participants living with PAD by smoking status (n = 98) and in nonsmoking comparators without chronic disease (n = 20). Individuals with PAD had approximately a four-fold higher level of total plasma oxylipins versus the comparator. Cessation of smoking in individuals with PAD was associated with significantly lower levels of linoleic acid-derived TriHOMEs, greater levels of omega-3 fatty acid-derived oxylipins, and greater levels of nonfragmented oxidized phosphatidylcholines (OxPCs). Individuals living with PAD but without a history of smoking, exhibited higher levels of the putative atherogenic fragmented OxPCs versus individuals who currently or previously smoked. These data implicate the plasma oxylipidome in PAD and that smoking cessation is associated with a less inflammatory profile. Furthermore, fragmented OxPCs may play a more significant role in the pathophysiology of PAD in individuals without a history of smoking.

Neurobiological Mechanisms of Nicotine Reward and Aversion.

Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the rewarding actions of nicotine contained in tobacco that establish and maintain the smoking habit. nAChRs also regulate the aversive properties of nicotine, sensitivity to which decreases tobacco use and protects against tobacco use disorder. These opposing behavioral actions of nicotine reflect nAChR expression in brain reward and aversion circuits. nAChRs containing α4 and ß2 subunits are responsible for the high-affinity nicotine binding sites in the brain and are densely expressed by reward-relevant neurons, most notably dopaminergic, GABAergic, and glutamatergic neurons in the ventral tegmental area. High-affinity nAChRs can incorporate additional subunits, including ß3, α6, or α5 subunits, with the resulting nAChR subtypes playing discrete and dissociable roles in the stimulatory actions of nicotine on brain dopamine transmission. nAChRs in brain dopamine circuits also participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing α3 and ß4 subunits are responsible for the low-affinity nicotine binding sites in the brain and are enriched in brain sites involved in aversion, including the medial habenula, interpeduncular nucleus, and nucleus of the solitary tract, brain sites in which α5 nAChR subunits are also expressed. These aversion-related brain sites regulate nicotine avoidance behaviors, and genetic variation that modifies the function of nAChRs in these sites increases vulnerability to tobacco dependence and smoking-related diseases. Here, we review the molecular, cellular, and circuit-level mechanisms through which nicotine elicits reward and aversion and the adaptations in these processes that drive the development of nicotine dependence. SIGNIFICANCE STATEMENT: Tobacco use disorder in the form of habitual cigarette smoking or regular use of other tobacco-related products is a major cause of death and disease worldwide. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder.

Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Dietary modulation of oxylipins in cardiovascular disease and aging.

Oxylipins are a group of fatty acid metabolites generated via oxygenation of polyunsaturated fatty acids and are involved in processes such as inflammation, immunity, pain, vascular tone, and coagulation. As a result, oxylipins have been implicated in many conditions characterized by these processes, including cardiovascular disease and aging. The best characterized oxylipins in relation to cardiovascular disease are derived from the ω-6 fatty acid arachidonic acid. These oxylipins generally increase inflammation, hypertension, and platelet aggregation, although not universally. Similarly, oxylipins derived from the ω-6 fatty acid linoleic acid generally have more adverse than beneficial cardiovascular effects. Alternatively, most oxylipins derived from 20- and 22-carbon ω-3 fatty acids have anti-inflammatory, antiaggregatory, and vasodilatory effects that help explain the cardioprotective effects of these fatty acids. Much less is known regarding the oxylipins derived from the 18-carbon ω-3 fatty acid α-linolenic acid, but clinical trials with flaxseed supplementation have indicated that these oxylipins can have positive effects on blood pressure. Normal aging also is associated with changes in oxylipin levels in the brain, vasculature, and other tissues, indicating that oxylipin changes with aging may be involved in age-related changes in these tissues. A small number of trials in humans and animals with interventions that contain either 18-carbon or 20- and 22-carbon ω-3 fatty acids have indicated that dietary-induced changes in oxylipins may be beneficial in slowing the changes associated with normal aging. In summary, oxylipins are an important group of molecules amenable to dietary manipulation to target cardiovascular disease and age-related degeneration.NEW & NOTEWORTHY Oxylipins are an important group of fatty acid metabolites amenable to dietary manipulation. Because of the role they play in cardiovascular disease and in age-related degeneration, oxylipins are gaining recognition as viable targets for specific dietary interventions focused on manipulating oxylipin composition to control these biological processes.

Specific plasma oxylipins increase the odds of cardiovascular and cerebrovascular events in patients with peripheral artery disease.

Oxylipins and fatty acids may be novel therapeutic targets for cardiovascular disease. The objective was to determine if plasma oxylipins or fatty acids can influence the odds of cardiovascular/cerebrovascular events. In 98 patients (25 female, 73 male) with peripheral artery disease, the prevalence of transient ischemic attacks, cerebrovascular accidents, stable angina, and acute coronary syndrome was n = 16, 10, 16, and 24, respectively. Risk factors such as being male, diagnosed hypertension, diabetes mellitus, and hyperlipidemia were not associated with events. Plasma fatty acids and oxylipins were analyzed with gas chromatography and HPLC-MS/MS, respectively. None of 24 fatty acids quantified were associated with events. In contrast, 39 plasma oxylipins were quantified, and 8 were significantly associated with events. These 8 oxylipins are known regulators of vascular tone. For example, every 1 unit increase in Thromboxane B2/Prostaglandin F1α and every 1 nmol/L increase in plasma 16-hydroxyeicosatetraenoic acid, thromboxane B2, or 11,12-dihydroxyeicosatrienoic acid (DiHETrE) increased the odds of having had ≥2 events versus no event (p < 0.05). The greatest predictor was plasma 8,9-DiHETrE, which increased the odds of acute coronary syndrome by 92-fold. In conclusion, specific oxylipins were highly associated with clinical events and may represent specific biomarkers and (or) therapeutic targets of cardiovascular disease.

An output evaluation of a health research foundation's enhanced grant review process for new investigators.

BACKGROUND: We assessed the ability of the Manitoba Medical Service Foundation (MMSF, a small not-for-profit foundation affiliated with Manitoba Blue Cross) to determine the best candidates for selection to receive research funding support among new researchers applying to the Research Operating Grants Programme (ROGP). METHODS: Using bibliometric and grants funding analyses, we retrospectively compared indices of academic outputs from five cohorts of MMSF-funded and not MMSF-funded applicants to the annual MMSF ROGP over 2008 to 2012, from 1 to 5 years after having received evaluation decisions from the MMSF enhanced grant review process. RESULTS: Those researchers funded by the MMSF competition (MMSF-funded) had a statistically significant greater number of publications, a higher h-index and greater national Tri-Council (TC) funding, versus those not selected for funding (not MMSF-funded). MMSF-funded applicants and the Manitoba research community have created a strong and rapid (within 1 to 5 years of receiving the MMSF grant) local economic return on investment associated with the MMSF ROGP that supports new investigators, of approximately nine-fold for TC grants by the principal investigator, and of 34-fold for the principal investigator on collaborative (total) TC grants. CONCLUSIONS: The use of small amounts of seed money for competitive research grants at early stages of an MMSF-funded applicant's career correlates with future short-term success of that applicant. The ability to correctly select promising candidates who subsequently demonstrate greater academic performance after the MMSF funding shows the selection process and the ROGP to be of merit. Multiple components may have contributed to this outcome, including a direct presentation and interview process of the candidate with five-person selection subcommittees, plus an assessment by an external reviewer (the enhanced grant review process). The selection methods used here may add value to the research grant selection processes of new researchers.

Gastric bypass surgery stimulates the dormant gut-brain axis in obesity.

To truly reduce the rates of chronic kidney disease, a root cause of kidney damage, obesity, must be targeted. Weight loss is often unsustainable because imbalances in satiety regulators are frequently not addressed to ensure maintenance of weight loss. In a recent study, gastric bypass surgery rebalanced satiety signals through resensitization of the gut-brain axis in obesity. This research may lead to noninvasive strategies to reduce obesity and obesity-related kidney disease.

Alarming Prevalence of Emergency Hypertension Levels in the General Public Identified by a Hypertension Awareness Campaign.

BACKGROUND: Hypertension is a major cause of mortality and morbidity today. The "silent" nature of hypertension makes it critical to determine its prevalence and its severity in the general public and to identify strategies to identify people unaware of its presence. A mobile hypertension awareness campaign was created to: (i) determine the prevalence and types of hypertension in an urban North American center, (ii) increase hypertension awareness, and (iii) identify reasons for lack of therapy adherence. METHODS: Mobile clinics were provided at shopping malls, workplaces, hospitals, and community centres to measure blood pressure in the public. Blood pressure recordings were done on a voluntary basis. RESULTS: Of 1097 participants, 50% presented with high blood pressure which was higher than expected. Of particular clinical significance, an unexpectedly large number of participants (2%) exhibited a hypertensive urgency/emergency. Most of these people were not adherent to medications (if their hypertension was detected previously), were unaware of their hypertensive state, and/or unwilling to acknowledge or ignored the clinical significance of the extremely high blood pressure readings. Reasons for lack of adherence included: denial, being unaware of health consequences, and proper management of hypertension. CONCLUSIONS: A relatively large segment of an urban population lives unaware of severe emergency levels of hypertension. A public mobile hypertension clinic provides a valuable strategy for identifying hypertension in the general public and for knowledge translation of hypertension management.

A review of the relative efficacy of dietary, nutritional supplements, lifestyle, and drug therapies in the management of hypertension.

Despite advancements in hypertensive therapies, the prevalence of hypertension and associated morbidities are still immense. Physicians are in great need for updated information on novel and effective antihypertensive therapies. Therefore, the study objective was to provide comprehensive information on the efficacy of available antihypertensive therapies. Antihypertensive therapies were divided into four general approaches: diet, nutritional supplements, lifestyle modification, and conventional antihypertensive medications. A search of PubMed and Google Scholar resulted in an analysis of 30 antihypertensive therapies from meta-analyses and randomized-controlled trials (RCTs). The studies were analyzed using the American Heart Association/American College of Cardiology classification system. Calculated average blood pressure reductions were: (systolic/diastolic) 6/4 mmHg, 4/2 mmHg, 5/3 mmHg, and 9/5 mmHg for dietary, nutritional supplements, lifestyle, and medications, respectively. The results demonstrate that dietary, nutritional supplement and lifestyle strategies have a solid level of evidence to support their efficacy as antihypertensive strategies. These strategies can be as effective as medications and, in some cases, even more effective. Dissemination of this information to physicians/dietitians can help facilitate an important shift in hypertension management.

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

UNLABELLED: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781950.

Dietary restriction in moderately obese rats improves body size and glucose handling without the renal and hepatic alterations observed with a high-protein diet.

Obesity is increasing worldwide, and high-protein (HP) diets are widely used for weight loss. However, the overall safety of HP diets is not well established in obese individuals, who make up a significant proportion of the population. To evaluate the health effects of an HP diet in obesity, obesity-prone (OP) Sprague-Dawley rats were given high-fat diets for 12 weeks to induce obesity. Following this, for 8 more weeks, these rats were given either a normal-protein (NP) (15% of energy) or an HP (35% of energy) diet ad libitum, or the NP diet at a restricted level to achieve body weights similar to those of the HP group (pair-weighted (PW) group). Obesity-resistant (OR) control rats were also given the NP diet throughout the feeding period. The HP-OP group had higher food intake but lower body weight, improved glucose handling, and lowered serum haptoglobin compared with the NP-OP group. These benefits were also observed in PW-OP rats. In addition, PW-OP rats had less fat accumulation when compared with NP-OP rats, and an improved Lee index, lower liver size, and lower serum alanine aminotransferase when compared with HP-OP rats. On the other hand, kidney size, proteinuria, and serum homocysteine were increased in HP-OP rats compared with NP-OP rats, whereas PW-OP rats did not experience these effects. These results indicate that in obese rats, more benefits are obtained via dietary restriction with an NP diet and without some of the potentially detrimental effects of an HP diet.

Trans-10,cis-12-conjugated linoleic acid worsens renal pathology and alters cyclooxygenase derived oxylipins in obesity-associated nephropathy.

Dietary conjugated linoleic acid (CLA) reduces indicators of early renal disease progression and the associated elevated cyclooxygenase (COX) levels in young obese rats with obesity-associated nephropathy (OAN). Therefore, renal function and injury and COX and its metabolites were assessed in obese fa/fa Zucker rats with more advanced renal disease. Obese rats at 16 weeks of age were provided with either cis(c)9, trans(t)11 (fa/fa-9,11) or t10,c12 (fa/fa-10,12) CLA for 8 weeks, and compared to lean (lean-CTL) and obese (fa/fa-CTL) rats provided the control diet without CLA. Obese rats displayed significantly reduced renal function and increased renal injury compared to lean rats. In the obese rat groups, glomerular hypertrophy was reduced in both CLA-supplemented groups. While all other measures of renal function or injury were not different in fa/fa-9,11 compared to fa/fa-CTL rats, the fa/fa-10,12 rats had greater renal hypertrophy, glomerular fibrosis, fibrosis, tubular casts and macrophage infiltration compared to the fa/fa-CTL and fa/fa-9,11 groups. The fa/fa-10,12 group also had elevated levels of renal COX1, which was associated with increased levels of two oxylipins produced by this enzyme, 6-keto-prostaglandin F(1α), and thromboxane B2. Renal linoleic acid and its lipoxygenase products also were lower in obese compared to lean rats, but CLA supplementation had no effect on these or any other lipoxygenase oxylipins. In summary, supplementation with c9,t11 CLA did not improve more advanced OAN and t10,c12 CLA worsened the renal pathology. Altered production of select COX1 derived oxylipins was associated with the detrimental effect of the t10,c12 isomer.

Flaxseed for hypertension: implications for blood pressure regulation.

Hypertension is the single largest risk factor attributed to mortality in the world. Medications are the primary treatment for hypertension; however, adherence to drug regimens is low (~50 %). Low adherence may be a contributing factor leading to uncontrolled blood pressure in patients. An effective alternative or complement to medications in managing hypertension is through lifestyle modifications. Adopting a healthy diet is a valuable strategy. A recent, randomized controlled year-long trial observed impressive reductions in blood pressure in patients with hypertension consuming flaxseed daily. Therefore, attention has been garnered for flaxseed as a potentially valuable strategy for the management of hypertension. This review will highlight the recent data for flaxseed and its extracts in blood pressure regulation in both animal models and clinical trials. Insight into the proposed anti-hypertensive mechanism of flaxseed and the implications of flaxseed as a potential global anti-hypertensive therapy will be discussed.

Evidence for the use of glomerulomegaly as a surrogate marker of glomerular damage and for alpha-linolenic acid-rich oils in the treatment of early obesity-related glomerulopathy in a diet-induced rodent model of obesity.

Obesity-related glomerulopathy (ORG) is a unique and emerging condition that can lead to renal failure. Early detection, aided by an earlier diagnostic marker, would improve patient outcomes; this could be facilitated by an accurate model. Such a model would be useful to examine interventions like dietary fatty acids, which are known to influence renal diseases in later stages. In this study, obese-prone rats were provided high-fat (55% of energy) diets for 12 weeks to generate a model of diet-induced obesity. The rats were subsequently provided dietary oils with various levels of alpha-linolenic acid (ALA) and linoleic acid (LA) for 8 weeks, as follows: (g ALA:LA per 100 g oil): canola/flax (20:18), canola (8:18), soy (9:53), high-oleic canola/canola (5:16), high-oleic canola (2:15), lard/soy (1:8), and safflower (0.2:73). The model developed obesity, glomerulomegaly, proteinuria, and scarce glomerular damage with an indolent course. Morphometry and histology revealed glomerulomegaly as the first renal structural alteration. The utility of this marker as a predictor for the presence of ORG and renal injury was evidenced by its correlation to visceral adiposity (p < 0.0001, r = 0.44), proteinuria (p < 0.0001, ρ = 0.55), change in proteinuria (p = 0.0092, ρ = 0.42), and glomerular damage (p < 0.0001, ρ = 0.48). Renal triglyceride ALA:LA was strongly correlated with dietary ALA:LA (p < 0.0005, ρ = 0.96), and inversely associated with mean glomerular volume (p = 0.02, ρ = -0.82). The diet-induced obese model accurately represents early ORG, and implicates glomerulomegaly as an early surrogate diagnostic marker. Early intervention with ALA-rich dietary oils slowed glomerular enlargement; these findings warrant further clinical investigation to promote optimal patient outcomes.

The HYPERFlax trial for determining the anti-HYPERtensive effects of dietary flaxseed in newly diagnosed stage 1 hypertensive patients: study protocol for a randomized, double-blinded, controlled clinical trial.

BACKGROUND: In 2013 the World Health Organization deemed hypertension as a global crisis as it is the leading risk factor attributed to global mortality. Therefore, there is a great need for effective alternative treatment strategies to combat a condition that affects 40% of adults worldwide. Recently, the FlaxPAD Trial observed a significant reduction in systolic and diastolic blood pressure in hypertensive patients with peripheral arterial disease that consumed 30 g of milled flaxseed per day for one year. However, these patients were already on anti-hypertensive medication. Therefore, there is a need to assess if dietary flaxseed can effectively reduce blood pressure in the absence of peripheral arterial disease and anti-hypertensive medication in newly diagnosed hypertensive patients. METHODS/DESIGN: The HYPERFlax Trial is a parallel, superiority, phase II/III, randomized, double-blinded, controlled clinical trial. St. Boniface Hospital and the Health Sciences Centre of Winnipeg, Canada, will recruit 100 participants newly diagnosed with stage 1 hypertension who have yet to be administered anti-hypertensive medication. Participants will be randomly allocated with a 1:1 ratio into a flaxseed or control group and provided food products to consume daily for six months. At baseline, two, four, and six months, participant assessments will include the primary outcome measure, averaged automated blood pressure, and secondary measures: 24-hour food recall, international physical activity questionnaire, anthropometrics, and blood and urine sampling for biochemical analysis. Plasma will be assessed for lipids, metabolomics profiling, and molecules that regulate vascular tone. Urine will be collected for metabolomics profiling. With an estimated dropout rate of 20%, the trial will have a power of 0.80 to detect differences between groups and across time, out of an effect size of 0.7 (SD) at an α level of 0.05. DISCUSSION: This trial will determine if dietary flaxseed is efficacious over six months as an anti-hypertensive therapy in subjects newly diagnosed with hypertension. If flaxseed can effectively reduce blood pressure as a monotherapy, then flaxseed will provide individuals on a global basis with a cost-effective food-based strategy to control hypertension. TRIAL REGISTRATION: NCT01952340, Registered 24 September 2013.

Flaxseed consumption reduces blood pressure in patients with hypertension by altering circulating oxylipins via an α-linolenic acid-induced inhibition of soluble epoxide hydrolase.

UNLABELLED: In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (-10 mm Hg) and diastolic (-7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid. Plasma α-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography-mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10- and 12,13-dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase-derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [95% confidence interval], -7.97 [-14.4 to -1.50] mm Hg) versus those who exhibited increased plasma soluble epoxide hydrolase-derived oxylipins (+3.17 [-4.78 to 11.13] mm Hg). These data suggest that a flaxseed bioactive may have decreased blood pressure via soluble epoxide hydrolase inhibition. Using a soluble epoxide hydrolase inhibitor screening assay, increasing concentrations of α-linolenic acid decreased soluble epoxide hydrolase activity (P=0.0048; ρ=-0.94). In conclusion, α-linolenic acid in flaxseed may have inhibited soluble epoxide hydrolase, which altered oxylipin concentrations that contributed to the antihypertensive effects in patients with peripheral arterial disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781950.

Elevated levels of pro-inflammatory oxylipins in older subjects are normalized by flaxseed consumption.

BACKGROUND AND AIMS: Oxylipins, including eicosanoids, are highly bioactive molecules endogenously produced from polyunsaturated fatty acids. Oxylipins play a key role in chronic disease progression. It is possible, but unknown, if oxylipin concentrations change with the consumption of functional foods or differ with subject age. METHODS: Therefore, in a parallel comparator trial, 20 healthy individuals were recruited into a younger (19-28years) or older (45-64years) age group (n=10/group). Participants ingested one muffin/day containing 30g of milled flaxseed (6g alpha-linolenic acid) for 4weeks. Plasma oxylipins were isolated through solid phase extraction, analyzed with HPLC-MS/MS targeted lipidomics, and quantified with the stable isotope dilution method. RESULTS: At baseline, the older group exhibited 13 oxylipins ≥2-fold the concentration of the younger group. Specifically, pro-inflammatory oxylipins 5-hydroxyeicosatetraenoic acid, 9,10,13-trihydroxyoctadecenoic acid, and 9,12,13-trihydroxyoctadecenoic acid were significantly greater in the older (1.1±0.23nM, 5.6±0.84nM, and 4.5±0.58nM, respectively) versus the younger group (0.34±0.12nM, 3.5±0.33nM, and 3.0±0.24nM, respectively) (p<0.05). After 4weeks of flaxseed consumption the number of oxylipins that were ≥2-fold higher in the older versus the younger group was reduced to 3. 5-Hydroxyeicosatetraenoic acid, 9,10,13-trihydroxyoctadecenoic acid, and 9,12,13-trihydroxyoctadecenoic acid decreased in the older group to concentrations equivalent to the younger group after flaxseed consumption. CONCLUSION: These data suggest a potential role for oxylipins in the aging process and how nutritional interventions like flaxseed can beneficially disrupt these biological changes associated with inflammation and aging.