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Nutraceuticals may induce doping infractions through contamination of the product itself or their ingestion might be metabolized within the body to create a positive doping control test. We tested this possibility using a commercially available, proprietary ginseng root extract (COLD-FX CV Technologies Inc., Edmonton, AB). After athletes ingested COLD-FX for 28 d at 400 mg/d, urine samples were collected and processed under strict IOC doping control guidelines and then analyzed for a full screen of IOC banned/restricted substances by an IOC-approved laboratory. There were no positive tests for any banned substances in any of the subjects. Our study demonstrates that ingestion of COLD-FX for 28 d at 400 mg/d does not represent a doping concern for athletes. Carefully controlled clinical studies like this one are necessary to provide the athlete, the nutraceutical industry and IOC regulatory bodies with information to avoid inadvertent exposure to banned/restricted or potentially unhealthy substances. [ABSTRACT FROM AUTHOR]

Epidemiological evidence has associated dietary trans fatty acids (TFA) with heart disease. TFA are primarily from hydrogenated fats rich in elaidic acid, but dairy products also contain naturally occurring TFA such as vaccenic acid. Our purpose in this study was to compare the effects of consuming a commercially hydrogenated vegetable shortening rich in elaidic TFA (18:1t9) or a butter rich in vaccenic TFA (18:1t11) in the absence and presence of dietary cholesterol on atherosclerosis. LDL receptor deficient (LDLr(-/-)) mice were fed 1 of 8 experimental diets for 14 wk with the fat content replaced by: regular (pork/soy) fat (RG), elaidic shortening (ES), regular butter (RB), vaccenic butter (VB), or an atherogenic diet containing 2% cholesterol with RG (CH+RG), ES (CH+ES), RB (CH+RB), or VB (CH+VB). Serum cholesterol levels were elevated with cholesterol feeding (P < 0.001), whereas serum triglyceride levels were higher only in the CH+RB (P < 0.001) and CH+VB (P < 0.001) groups compared with the other 6 groups. Serum cholesterol and triglyceride levels were significantly lower in the CH+VB group than in the CH+RB group (P < 0.001). Atherosclerosis was stimulated by dietary ES compared with RG (P = 0.021), but CH+ES did not stimulate atherosclerosis beyond CH+RG alone. In contrast, VB did not induce an increase in atherosclerotic plaque formation compared with the RG and RB diets and the CH+VB diet reduced atherosclerosis compared with the other diets containing cholesterol (P < 0.01). In summary, consuming a hydrogenated elaidic acid-rich diet stimulates atherosclerosis, whereas a vaccenic acid-rich butter protects against atherosclerosis in this animal model. [ABSTRACT FROM AUTHOR]

Hypertension contributes to the increase in health care spending in Canada through two primary mechanisms. First, it directly increases costs, as individuals with hypertension require medical care to manage the condition. Second, it indirectly raises expenses by serving as a risk factor for numerous chronic diseases, leading to increased health care utilization among those affected. Therefore, reducing hypertension prevalence could alleviate its resulting strain on the Canadian health care system. Clinical trials have demonstrated that daily flaxseed consumption effectively lowers both systolic and diastolic blood pressure. This study employs a four-step cost-of-illness analysis to estimate the potential health care cost-savings from a flaxseed-based treatment for hypertension. The analysis begins by assessing the proportion of individuals with hypertension likely to adopt the flaxseed regimen. It then evaluates the impact of flaxseed consumption on systolic and diastolic blood pressure. Next, data from the Canadian Health Measures Survey, Cycles 5 and 6, are used to estimate the prevalence of hypertension and the expected reduction in prevalence due to the flaxseed treatment. Finally, the potential reduction in health care spending is calculated. To incorporate uncertainty, partial sensitivity analysis and Monte Carlo simulations were utilized, varying the intake success rate and other model parameters, respectively. The most conservative estimate suggests a potential health care cost-savings of CAD 96,284,344 in Canada for the year 2020.

Non-alcoholic fatty liver disease (NAFLD), a significant cause of chronic liver disease, presents a considerable public health concern. Despite this, there is currently no treatment available. This study aimed to investigate dietary flaxseed in the JCR:LA-corpulent rat strain model of NAFLD. Both obese male and female rats were studied along with their lean counterparts after 12 weeks of ingestion of a control diet, or control diet with flaxseed, or high fat, high sucrose (HFHS), or HFHS plus flaxseed. Obese rats showed higher liver weight and increased levels of cholesterol, triglyceride, and saturated fatty acid, which were further elevated in rats on the HFHS diet. The HFHS diet induced a significant two-fold elevation in the plasma levels of both aspartate aminotransferase and alanine aminotransferase in the obese male and female rats. Including flaxseed in the HFHS diet significantly lowered liver weight, depressed the plasma levels of both enzymes in the obese male rats, and reduced hepatic cholesterol and triglyceride content as well as improving the fatty acid profile. In summary, including flaxseed in the diet of male and female obese rats led to an improved lipid composition in the liver and significantly reduced biomarkers of tissue injury despite consuming a HFHS chow.

The decision to use the optimal animal model to mimic the various types of cardiovascular disease is a critical one for a basic scientist. Clinical cardiovascular disease can be complex and presents itself as atherosclerosis, hypertension, ischemia/reperfusion injury, myocardial infarcts, and cardiomyopathies, amongst others. This may be further complicated by the simultaneous presence of two or more cardiovascular lesions (for example, atherosclerosis and hypertension) and co-morbidities (i.e., diabetes, infectious disease, obesity, etc). This variety and merging of disease states creates an unusually difficult situation for the researcher who needs to identify the optimal animal model that is available to best represent all of the characteristics of the clinical cardiovascular disease. The present manuscript reviews the characteristics of the various animal models of cardiovascular disease available today, their advantages and disadvantages, with the goal to allow the reader access to the most recent data available for optimal choices prior to the initiation of the study. The animal species that can be chosen, the methods of generating these models of cardiovascular disease, as well as the specific cardiovascular lesions involved in each of these models are reviewed. A particular focus on the JCR:LA- cp rat as a model of cardiovascular disease is discussed., Competing Interests: There are no competing interests that are financial or non-financial or any other relationship that might bias or be seen to bias our work.

The inclusion of flaxseed in the diet may have a great number of potential benefits for the well-being of both healthy individuals and those challenged by disease conditions as well. With an increase in the number and quality of studies focused on the physiological and pathophysiological effects of dietary flaxseed, our knowledge concerning the rationale for the inclusion of flaxseed in our diet has become more convincing and stronger. The purpose of this review is threefold. First, the review will comprehensively document the evidence supporting the value of dietary flaxseed to improve bodily health in both normal and disease conditions. Second, this review will identify the mechanisms of action responsible for these effects. Finally, this article will review practical aspects relevant to the inclusion of flaxseed in the diet. Briefly, supplementing the diet with flaxseed has beneficial effects on the treatment and/or prevention of different kinds of cardiovascular disease (hypertension, ischemic heart disease, myocardial infarcts, atherosclerosis), non-alcoholic fatty liver disease, breast cancer, bone strength, menopause, diabetes, and wound healing. Although some controversy exists on the component within flaxseed that provides these beneficial actions, it is likely that the rich content of the omega-3 fatty acid, alpha linolenic acid, is primarily responsible for the majority of these biological effects. It is concluded that the constantly expanding evidence in support of the inclusion of flaxseed in our daily diet to provide significant health benefits strongly encourages the initiation of additional work on dietary flaxseed in order to both confirm past findings as well as to further advance our knowledge regarding the important biological actions of dietary flaxseed., Competing Interests: The author declares no conflict of interest. Grant N. Pierce is serving as one of the Editorial Board members and Guest editors of this journal. We declare that Grant N. Pierce had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gary David Lopaschuk., (Copyright: © 2023 The Author(s). Published by IMR Press.)

The mammalian Na + /H + exchanger (NHE) is a family of ubiquitous membrane proteins present in humans. Isoform one (NHE1) is present on the plasma membrane and regulates intracellular pH by removal of one intracellular proton in exchange for one extracellular sodium thus functioning as an electroneutral process. Human NHE1 has a 500 amino acid membrane domain plus a C-terminal 315 amino acid, regulatory cytosolic tail. It is regulated through a cytosolic regulatory C-terminal tail which is subject to phosphorylation and is modulated by proteins and lipids. Substantial evidence has implicated NHE1 activity in both myocardial ischemia and reperfusion damage and myocardial remodeling resulting in heart failure. Experimental data show excellent cardioprotection with NHE1 inhibitors although results from clinical results have been mixed. In cardiac surgery patients receiving the NHE1 inhibitor cariporide, subgroups showed beneficial effects of treatment. However, in one trial this was associated with a significantly increased incidence of ischemic strokes. This likely reflected both inappropriate dosing regimens as well as overly high drug doses. We suggest that further progress towards NHE1 inhibition as a treatment for cardiovascular disease is warranted through the development of novel compounds to inhibit NHE1 that are structurally different than those previously used in compromised clinical trials. Some novel pyrazinoyl guanidine inhibitors of NHE1 are already in development and the recent elucidation of the three-dimensional structure of the NHE1 protein and identity of the inhibitor binding site may facilitate development. An alternative approach may also be to control the endogenous regulation of activity of NHE1, which is activated in disease., Competing Interests: The authors declare no conflict of interest. Morris Karmazyn and Grant N. Pierce are serving as the Guest editors of this journal. Grant N. Pierce is serving as one of the Editorial Board members of this journal. We declare that Morris Karmazyn and Grant N. Pierce had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Fabian Sanchis-Gomar., (Copyright: © 2022 The Author(s). Published by IMR Press.)

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.

Invasive cardiovascular procedures which include heart transplantations, congenital heart surgery, coronary artery bypass grafts, cardiac valve repair and replacement, and interventional cardiac electrophysiology procedures represent common mechanisms to treat a variety of cardiovascular diseases across the globe. The majority of these invasive approaches employ antibiotics as a regular and obligatory feature of the invasive procedure. Although the growing incidence of bacterial resistance to currently used antibiotics threatens to curtail the use of all interventional surgical techniques, it remains an underappreciated threat within the arsenal of cardiovascular therapies. It is reasonable to expect that the continued overuse of antibiotics and the frequent management of coronavirus disease 2019 (COVID-19) infected patients with high doses of antibiotics will inevitably accentuate the rise of multidrug resistance. The purpose of this article is to heighten awareness of the role of bacterial infections in cardiovascular disease, the use of antibiotics in today's cardiovascular surgical theaters, the threat facing cardiovascular surgery should multidrug resistance continue to rise unabated, and the development of new antibiotic platforms to solve this problem., Competing Interests: PD is the Chief Scientific Advisor for Viotika Life Sciences, Inc. The authors declare no conflict of interest. Grant N. Pierce is serving as one of the Editorial Board members of this journal. We declare that Grant N. Pierce had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Morris Karmazyn and Victor L. Serebruany., (© 2022 The Author(s). Published by IMR Press.)

The Na + -translocating NADH:quinone oxidoreductase (Na + -NQR) is the major Na + pump in aerobic pathogens such as Vibrio cholerae. The interface between two of the NQR subunits, NqrB and NqrD, has been proposed to harbor a binding site for inhibitors of Na + -NQR. While the mechanisms underlying Na + -NQR function and inhibition remain underinvestigated, their clarification would facilitate the design of compounds suitable for clinical use against pathogens containing Na + -NQR. An in silico model of the NqrB-D interface suitable for use in molecular dynamics simulations was successfully constructed. A combination of algorithmic and manual methods was used to reconstruct portions of the two subunits unresolved in the published crystal structure and validate the resulting structure. Hardware and software optimizations that improved the efficiency of the simulation were considered and tested. The geometry of the reconstructed complex compared favorably to the published V. cholerae Na + -NQR crystal structure. Results from one 1 µs, three 150 ns and two 50 ns molecular dynamics simulations illustrated the stability of the system and defined the limitations of this model. When placed in a lipid bilayer under periodic boundary conditions, the reconstructed complex was completely stable for at least 1 µs. However, the NqrB-D interface underwent a non-physiological transition after 350 ns., (© 2021. The Author(s).)

Previous work has shown that dietary flaxseed can significantly reduce cardiac damage from a coronary artery ligation-induced myocardial infarction. However, this model uses healthy animals and the ligation creates the infarct in an artificial manner. The purpose of this study was to determine if dietary flaxseed can protect the hearts of JCR:LA-cp rats, a model of genetic obesity and metabolic syndrome, from naturally occurring myocardial ischemic lesions. Male and female obese rats were randomized into four groups (n = 8 each) to receive, for 12 weeks, either a) control diet (Con), b) control diet supplemented with 10% ground flaxseed (CFlax), c) a high-fat, high sucrose (HFHS) diet, or d) HFHS supplemented with 10% ground flaxseed (HFlax). Male and female JCR:LA-cp lean rats served as genetic controls and received similar dietary interventions. In male obese rats, serum total cholesterol and LDL-C were significantly lower in CFlax compared to Con.  Obese rats on HFHS exhibited increased myocardial ischemic lesions and diastolic dysfunction regardless of sex. HFlax significantly lowered the frequency of cardiac lesions and improved diastolic function in male and female obese rats compared to HFHS. Blood pressures were similar in obese and lean rats. No aortic atherosclerotic lesions were detectable in any group. Collectively, this study shows that a HFHS diet increased myocardial ischemic lesion frequency and abolished the protective effect of female sex on cardiac function. More importantly, the data demonstrates dietary flaxseed protected against the development of small spontaneous cardiac infarcts despite the ingestion of a HFHS diet and the presence of morbid obesity., Competing Interests: Declaration of competing interests The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has had significant morbidity, mortality, social and financial implications for the global population. Despite this knowledge, we still know very little about how COVID-19 infection affects quality of life resulting from changes in nutritional behaviour and, conversely, how nutrition could modulate the epidemiology of COVID-19. In addition, the social isolation most have experienced due to the regulations imposed by governments during the COVID-19 pandemic may have also had effects on our nutritional behaviour. It is possible that nutritional interventions may have effects on the incidence of COVID-19 infection and mortality rates. The purpose of this review is to evaluate the current status of research on the topic of nutrition as it relates to the COVID-19 pandemic.

There is an increased interest in the gut microbiota as it relates to health and obesity. The impact of diet and sex on the gut microbiota in conjunction with obesity also demands extensive systemic investigation. Thus, the influence of sex, diet, and flaxseed supplementation on the gut microbiota was examined in the JCR:LA- cp rat model of genetic obesity. Male and female obese rats were randomized into four groups ( n = 8) to receive, for 12 weeks, either (a) control diet (Con), (b) control diet supplemented with 10% ground flaxseed (CFlax), (c) a high-fat, high sucrose (HFHS) diet, or (d) HFHS supplemented with 10% ground flaxseed (HFlax). Male and female JCR:LA- cp lean rats served as genetic controls and received similar dietary interventions. Illumine MiSeq sequencing revealed a richer microbiota in rats fed control diets rather than HFHS diets. Obese female rats had lower alpha-diversity than lean female; however, both sexes of obese and lean JCR rats differed significantly in β-diversity, as their gut microbiota was composed of different abundances of bacterial types. The feeding of an HFHS diet affected the diversity by increasing the phylum Bacteroidetes and reducing bacterial species from phylum Firmicutes. Fecal short-chain fatty acids such as acetate, propionate, and butyrate-producing bacterial species were correspondingly impacted by the HFHS diet. Flax supplementation improved the gut microbiota by decreasing the abundance of Blautia and Eubacterium dolichum . Collectively, our data show that an HFHS diet results in gut microbiota dysbiosis in a sex-dependent manner. Flaxseed supplementation to the diet had a significant impact on gut microbiota diversity under both flax control and HFHS dietary conditions.

Despite advances in diagnostic, prognostic, and treatment modalities, myocardial infarction (MI) remains a leading cause of morbidity and mortality. Impaired cellular signaling after an MI causes maladaptive changes resulting in cardiac remodeling. MicroRNAs (miRNAs/miR) along with other molecular components have been investigated for their involvement in cellular signaling in the pathogenesis of various cardiac conditions like MI. miRNAs are small non-coding RNAs that negatively regulate gene expression. They bind to complementary mRNAs and regulate the rate of protein synthesis by altering the stability of their targeted mRNAs. A single miRNA can modulate several cellular signaling pathways by targeting hundreds of mRNAs. This review focuses on the biogenesis and beneficial effects of cellular and circulating (exosomal) miRNAs on cardiac remodeling after an MI. Particularly, miR-1, -133, 135, and -29 that play an essential role in cardiac remodeling after an MI are described in detail. The limitations that will need to be addressed in the future for the further development of miRNA-based therapeutics for cardiovascular conditions will also be discussed.

Myocardial ischemia-reperfusion (I/R) injury increases the generation of oxidized phosphatidylcholines (OxPCs), which results in cell death. However, the mechanism by which OxPCs mediate cell death and cardiac dysfunction is largely unknown. The aim of this study was to determine the mechanisms by which OxPC triggers cardiomyocyte cell death during reperfusion injury. Adult rat ventricular cardiomyocytes were treated with increasing concentrations of various purified fragmented OxPCs. Cardiomyocyte viability, bioenergetic response, and calcium transients were determined in the presence of OxPCs. Five different fragmented OxPCs resulted in a decrease in cell viability, with 1-palmitoyl-2-(5'-oxo-valeroyl)- sn -glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC) having the most potent cardiotoxic effect in both a concentration and time dependent manner ( P < 0.05). POVPC and PONPC also caused a significant decrease in Ca 2+ transients and net contraction in isolated cardiomyocytes compared to vehicle treated control cells ( P < 0.05). PONPC depressed maximal respiration rate ( P < 0.01; 54%) and spare respiratory capacity ( P < 0.01; 54.5%). Notably, neither caspase 3 activation or TUNEL staining was observed in cells treated with either POVPC or PONPC. Further, cardiac myocytes treated with OxPCs were indistinguishable from vehicle-treated control cells with respect to nuclear high-mobility group box protein 1 (HMGBP1) activity. However, glutathione peroxidase 4 activity was markedly suppressed in cardiomyocytes treated with POVPC and PONPC coincident with increased ferroptosis. Importantly, cell death induced by OxPCs could be suppressed by E06 Ab, directed against OxPCs or by ferrostatin-1, which bound the sn-2 aldehyde of POVPC during I/R. The findings of the present study demonstrate that oxidation of phosphatidylcholines during I/R generate bioactive phospholipid intermediates that disrupt mitochondrial bioenergetics and calcium transients and provoke wide spread cell death through ferroptosis. Neutralization of OxPC with E06 or with ferrostatin-1 prevents cell death during reperfusion. Our study demonstrates a novel signaling pathway that operationally links generation of OxPC during cardiac I/R to ferroptosis. Interventions designed to target OxPCs may prove beneficial in mitigating ferroptosis during I/R injury in individuals with ischemic heart disease. NEW & NOTEWORTHY Oxidized phosphatidylcholines (OxPC) generated during reperfusion injury are potent inducers of cardiomyocyte death. Our studies have shown that OxPCs exert this effect through a ferroptotic process that can be attenuated. A better understanding of the OxPC cell death pathway can prove a novel strategy for prevention of cell death during myocardial reperfusion injury.

One of the primary purposes of the studies that life science researchers carry out is to translate their findings into demonstrable impacts in the lives of the general population. If we study the mechanism of heart disease, for example, it is our hope that new therapies or preventative strategies can be created from these mechanistic data. In the field of nutrition, it is the ultimate goal to translate research findings on the health benefits of functional foods and nutraceuticals into products consumed by the public that will benefit their health, improve quality of life, prevent disease, and prolong life. However, the pathway from research on the health benefits of specific foods or food products into industry applications is often a pathway with multiple, unexpected roadblocks for the unsuspecting scientist. The purpose of this article, therefore, is to identify these obstacles that have confronted industry translation in the past by using flaxseed research as an example. The ultimate goal of the review is to alert those in research and in the food industry of these translational hindrances to avoid them in the future and promote a more rapid and effective translation of food/health research into marketing success.

Background: The shortage of single-use N95 respirator masks (NRMs) during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted consideration of NRM recycling to extend limited stocks by healthcare providers and facilities., Aim: To assess potential reuse via autoclaving of NRMs worn daily in a major urban Canadian hospital., Methods: NRM reusability was assessed following collection from volunteer staff after 2-8 h use, sterilization by autoclaving and PortaCount fit testing. A workflow was developed for reprocessing hundreds of NRMs daily., Findings: Used NRMs passed fit testing after autoclaving once, with 86% passing a second reuse/autoclave cycle. A separate cohort of used masks pre-warmed before autoclaving passed fit testing. To recycle 200-1000 NRMs daily, procedures for collection, sterilization and re-distribution were developed to minimize particle aerosolization risk during NRM handling, to reject NRM showing obvious wear, and to promote adoption by staff. NRM recovery ranged from 49% to 80% across 12 collection cycles., Conclusion: Reuse of NRMs is feasible in major hospitals and other healthcare facilities. In sharp contrast to studies of unused NRMs passing fit testing after 10 autoclave cycles, we show that daily wear substantially reduces NRM fit, limiting reuse to a single cycle, but still increasing NRM stocks by ∼66%. Such reuse requires development of a comprehensive plan that includes communication across staffing levels, from front-line workers to hospital administration, to increase the collection, acceptance of and adherence to sterilization processes for NRM recovery., (Copyright © 2020 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs/miRs) such as miR-1, miR-133a, miR-133b, miR-135a, and miR-29b play a key role in many cardiac pathological remodeling processes, including apoptosis, fibrosis, and arrhythmias, after a myocardial infarction (MI). Dietary flaxseed has demonstrated a protective effect against an MI. The present study was carried out to test the hypothesis that dietary flaxseed supplementation before and after an MI regulates the expression of above-mentioned miRNAs to produce its cardioprotective effect. Animals were randomized after inducing MI by coronary artery ligation into: (a) sham MI with normal chow, (b) MI with normal chow, and (c-e) MI supplemented with either 10% milled flaxseed, or 4.4% flax oil enriched in alpha-linolenic acid (ALA), or 0.44% flax lignan secoisolariciresinol diglucoside. The feeding protocol consisted of 2 weeks before and 8 weeks after the surgery. Dietary flax oil supplementation selectively upregulated the cardiac expression of miR-133a, miR-135a, and miR-29b. The levels of collagen I expression were reduced in the flax oil group. We conclude that miR-133a, miR-135a, and miR-29b are sensitive to dietary flax oil, likely due to its rich ALA content. The cardioprotective effect of flaxseed in an MI could be due to modulation of these miRNAs.

Background: Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects., Objective: We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ-mediated cardiotoxicity in a chronic in vivo female murine model., Methods: Wild-type C57BL/6 female mice (10-12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures., Results: In the RC + DOX + TRZ-treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P < 0.05). However, the prophylactic administration of the FLX, ALA, or SDG diet was partially cardioprotective, with mice in these treatment groups showing an ∼68% increase in LVEF compared with the RC + DOX + TRZ-treated group at week 6 (P < 0.05). Although markers of inflammation (nuclear transcription factor κB), apoptosis [poly (ADP-ribose) polymerase-1 and the ratio of BCL2-associated X protein to B-cell lymphoma-extra large], and mitochondrial dysfunction (BCL2-interacting protein 3) were significantly elevated by approximately 2-fold following treatment with RC + DOX + TRZ compared with treatment with RC + saline at week 6, prophylactic administration of FLX, ALA, or SDG partially downregulated these signaling pathways., Conclusion: In a chronic in vivo female C57BL/6 mouse model of DOX + TRZ-mediated cardiotoxicity, FLX, ALA, and SDG were partially cardioprotective., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been associated with a lower incidence of cardiovascular events and sudden cardiac death. Flaxseed is a rich plant source of n-3 PUFAs and can retard the progression and accelerate the regression of atherosclerotic plaques. The aim of the study was to examine the preventive and therapeutic effects of dietary flaxseed on arrhythmias and heart dysfunction that develops after a myocardial infarction (MI). The left anterior descending coronary artery was ligated in rats to induce the MI. Rats were randomized into five groups: sham MI with normal chow, MI with normal chow, MI with 10% milled flaxseed supplementation (flax), MI with 4.4% supplemented flax oil enriched in alpha-linolenic acid (ALA) and MI with flax lignan secoisolariciresinol diglucoside (SDG) supplementation (0.44%). Animals were fed with their respective diets for 2 weeks before and for 8 weeks after the surgery. Echocardiography and continuous electrocardiographic recordings were obtained after ligation to confirm the induction of the MI, to check for arrhythmias and to assess cardiac function. Histological examination was also performed to evaluate cardiac fibrosis. Dietary supplementation with flaxseed, ALA or SDG before and after the induction of the MI significantly reduced the incidence of arrhythmias and resulted in significantly smaller infarct size, less left ventricle dilation, and decreased myocardial fibrosis and tumor necrosis factor-α levels compared to the control MI group. Together, this study supports a beneficial effect of dietary flaxseed in patients for the prevention and treatment of arrhythmias and ventricular remodeling post-MI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cell death is an important component of the pathophysiology of any disease. Myocardial disease is no exception. Understanding how and why cells die, particularly in the heart where cardiomyocyte regeneration is limited at best, becomes a critical area of study. Ferroptosis is a recently described form of nonapoptotic cell death. It is an iron-mediated form of cell death that occurs because of accumulation of lipid peroxidation products. Reactive oxygen species and iron-mediated phospholipid peroxidation is a hallmark of ferroptosis. To date, ferroptosis has been shown to be involved in cell death associated with Alzheimer's disease, Huntington's disease, cancer, Parkinson's disease, and kidney degradation. Myocardial reperfusion injury is characterized by iron deposition as well as reactive oxygen species production. These conditions, therefore, favor the induction of ferroptosis. Currently there is no available treatment for reperfusion injury, which accounts for up to 50% of the final infarct size. This review will summarize the evidence that ferroptosis can induce cardiomyocyte death following reperfusion injury and the potential for this knowledge to open new therapeutic approaches for myocardial ischemia-reperfusion injury.

Over the past decade, there has been intense investigation in trying to understand the pathological role that oxidized phospholipids play in cardiovascular disease. Phospholipids are targets for oxidation, particularly during conditions of excess free radical generation. Once oxidized, they acquire novel roles uncharacteristic of their precursors. Oxidized phosphatidylcholines have an important role in multiple physiological and pathophysiological conditions including atherosclerosis, neurodegenerative diseases, lung disease, inflammation, and chronic alcohol consumption. Circulating oxidized phosphatidylcholine may also serve as a clinical biomarker. The focus of this review, therefore, will be to summarize existing evidence that oxidized phosphatidylcholine molecules play an important role in cardiovascular pathology.

Patients with peripheral artery disease (PAD) are at increased risk for cardiovascular events, and higher susceptibility for cardiac arrhythmias may be involved. The objectives of this double-blinded randomized controlled FLAX-PAD trial were to determine whether daily consumption of a diet supplemented with 30 g of milled flaxseed (or placebo) over 1 year by PAD patients has effects on the prevalence of cardiac arrhythmias and exercise capacity. Cardiac arrhythmias were assessed on a cardiac stress test and at rest. At baseline, the PAD patients had a high incidence of cardiac arrhythmias (48% in the flaxseed group and 32% in the placebo group). After 1 year, the presence of cardiac arrhythmias in the flaxseed group decreased by 2% and increased by 12% in the placebo group ( P > 0.05). Electrocardiographic variables (P, PR, QRS, QT, and QTc) did not change in either group during the trial. Patients from both groups improved initial and absolute claudication distances but the intergroup difference was also not statistically significant. In summary, the prevalence of cardiac arrhythmias and physical capacity trended in a positive direction for patients ingesting flaxseed but either a larger sample size or a longer intervention with flaxseed may be required to show statistically significant differences.

Fatty acids come in a variety of structures and, because of this, create a variety of functions for these lipids. Some fatty acids have a role to play in energy metabolism, some help in lipid storage, cell structure, the physical state of the lipid, and even in food stability. Fatty acid metabolism plays a particularly important role in meeting the energy demands of the heart. It is the primary source of myocardial energy in control conditions. Its role changes dramatically in disease states in the heart, but the pathologic role these fatty acids play depends upon the type of cardiovascular disease and the type of fatty acid. However, no matter how good a food is for one's health, its taste will ultimately become a deciding factor in its influence on human health. No food will provide health benefits if it is not ingested. This review discusses the taste characteristics of culinary oils that contain fatty acids and how these fatty acids affect the performance of the heart during healthy and diseased conditions. The contrasting contributions that different fatty acid molecules have in either promoting cardiac pathologies or protecting the heart from cardiovascular disease is also highlighted in this article.

Flaxseed is a rich source of the omega-3 fatty acid, alpha linolenic acid, the lignan secoisolariciresinol diglucoside and fiber. These compounds provide bioactivity of value to the health of animals and humans through their anti-inflammatory action, anti-oxidative capacity and lipid modulating properties. The characteristics of ingesting flaxseed or its bioactive components are discussed in this article. The benefits of administering flaxseed or the individual bioactive components on health and disease are also discussed in this review. Specifically, the current evidence on the benefits or limitations of dietary flaxseed in a variety of cardiovascular diseases, cancer, gastro-intestinal health and brain development and function, as well as hormonal status in menopausal women, are comprehensive topics for discussion.

Food quality and nutritional habits strongly influence human health status. Extensive research has been conducted to confirm that foods rich in biologically active nutrients have a positive impact on the onset and development of different pathological processes, including cardiovascular diseases. However, the underlying mechanisms by which dietary compounds regulate cardiovascular function have not yet been fully clarified. A growing number of studies confirm that bioactive food components modulate various signaling pathways which are involved in heart physiology and pathology. Recent evidence indicates that microRNAs (miRNAs), small single-stranded RNA chains with a powerful ability to influence protein expression in the whole organism, have a significant role in the regulation of cardiovascular-related pathways. This review summarizes recent studies dealing with the impact of some biologically active nutrients like polyunsaturated fatty acids (PUFAs), vitamins E and D, dietary fiber, or selenium on the expression of many miRNAs, which are connected with cardiovascular diseases. Current research indicates that the expression levels of many cardiovascular-related miRNAs like miRNA-21, -30 family, -34, -155, or -199 can be altered by foods and dietary supplements in various animal and human disease models. Understanding the dietary modulation of miRNAs represents, therefore, an important field for further research. The acquired knowledge may be used in personalized nutritional prevention of cardiovascular disease or the treatment of cardiovascular disorders.

The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague⁻Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-α were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-α in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-α levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease.

Food constituents can either promote cardiovascular health or serve in its demise. In view of the lack of more effective pharmacological interventions in cardiovascular disease (CVDs), attention has focused on the potential protective effects of diet. Food components and their metabolites are emerging as major regulators of the human epigenome, which is being linked to CVDs. In this review, we summarize data from studies that suggest an important role for bioactive food compounds in cardioprotection and the potential for harnessing the epigenome as a nutrient sensor target in CVDs. While clinical data strongly support a role for effective diet intervention in CVDs protection, studies linking changes to human epigenome are now warranted for mechanistic insight and development of personalized care., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Flaxseed (Linum usitatissimum) is composed of a unique combination of bioactive components that appear to generate, through either an isolated or a synergistic action, a significant beneficial effect on the cardiovascular system. With a significant increase in the generation of data on the dietary impact of flaxseed on the cardiovascular system, a review of where we stand - what we know and what we still need to understand about these effects on the heart and the vasculature - was thought to be of value and the rationale for this paper. For example, although we now know how to deliver the bioactives most efficiently (oil versus ground seed versus whole seed), we do not know how different foods can influence that delivery. Further, we know flaxseed has anti-arrhythmic, anti-atherogenic, anti-hypertensive, and cholesterol-lowering actions in animal studies and some selected human trials but much more needs to be learned, particularly in human trials. These results have justified further commitment of resources to the initiation of human trials. Because of the impact of nutrition on many chronic diseases, this may not only be true for the effects of flaxseed on cardiovascular disease but may be just as relevant for many other disease conditions.

The functional significance of having two nuclei in a cell is unknown. Having two stores of genetic material may be advantageous for cell growth. Nuclear protein import is at a critical juncture in the cell to modify cell growth. This study addressed the potential for differential nuclear protein import in two nuclei of the same cell. Isolated adult rat cardiomyocytes were microinjected with an exogenous fluorescent protein conjugated with nuclear localization amino acid sequences to facilitate nuclear import and its detection. Our results demonstrate the rate of nuclear protein import was not significantly different between the two nuclei in the same cell. These data demonstrate that the two nuclei are functionally similar in a binucleated cardiomyocyte, at least as far as nucleocytoplasmic transport is concerned., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size., Methods and Results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14% and with PONPC was 25.3 ± 3.4% compared to 8.0 ± 1.6% and 6.4 ± 1.0%, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9% vs. 47.7 ± 17.6%, P = 0.023)., Conclusions: OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.

Aim: Heat shock protein 60 (Hsp60) is a mediator of stress-induced vascular smooth muscle cell (VSMC) proliferation. This study will determine, first, if the mitochondrial or cytoplasmic localization of Hsp60 is critical to VSMC proliferation and, second, the mechanism of Hsp60 induction of VSMC proliferation with a focus on modification of nucleocytoplasmic trafficking., Methods and Results: Hsp60 was overexpressed in primary rabbit VSMCs with or without a mitochondrial targeting sequence (AdHsp60 mito- ). Both interventions induced an increase in VSMC PCNA expression and proliferation. The increase in VSMC PCNA expression and growth was not observed after siRNA-mediated knockdown of Hsp60 expression. Nuclear protein import in VSMC was measured by fluorescent microscopy using a microinjected fluorescent import substrate. Nuclear protein import was stimulated by both AdHsp60 and AdHsp60 mito- treatments. AdHsp60 treatment also induced increases in nucleoporin (Nup) 62, Nup153, importin-α, importin-β and Ran expression as well as cellular ATP levels compared to control. AdHsp60 mito- treatment induced an up-regulation in importin-α, importin-β and Ran expression compared to control. Hsp60 knockdown did not change nuclear protein import nor the expression of any nuclear transport receptors or nucleoporins. Both heat shock treatment and Hsp60 overexpression promoted the interaction of Ran with Hsp60., Conclusions: VSMC proliferation can be modulated via an Hsp60 dependent, cytosol localized mechanism that in part involves a stimulation of nuclear protein import through an interaction with Ran. This novel cellular signaling role for Hsp60 may be important in growth-based vascular pathologies like atherosclerosis and hypertension., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cardiovascular disease remains the leading cause of mortality and morbidity worldwide. The inclusion of functional foods and natural health products in the diet are gaining increasing recognition as integral components of lifestyle changes in the fight against cardiovascular disease. Several preclinical and clinical studies have shown the beneficial cardiovascular effects of dietary supplementation with flaxseed. The cardiovascular effects of dietary flaxseed have included an antihypertensive action, antiatherogenic effects, a lowering of cholesterol, an anti-inflammatory action, and an inhibition of arrhythmias. Its enrichment in the ω-3 fatty acid α-linolenic acid and the antioxidant lignan secoisolariciresinol diglucoside as well as its high fiber content have been implicated primarily in these beneficial cardiovascular actions. Although not as well recognized, flaxseed is also composed of other potential bioactive compounds such as proteins, cyclolinopeptides, and cyanogenic glycosides, which may also produce biological actions. These compounds could also be responsible for the cardiovascular effects of flaxseed. This article will not only summarize the cardiovascular effects of dietary supplementation with flaxseed but also review its bioactive compounds in terms of their properties, biological effects, and proposed mechanisms of action. It will also discuss promising research directions for the future to identify additional health-related benefits of dietary flaxseed.

The omega-3 fatty acid, alpha linolenic acid (ALA) found in plant-derived foods induces significant cardiovascular benefits when ingested. ALA may be cardioprotective during ischemia; however, the mechanism(s) responsible for this effect is unknown. Isolated adult rat cardiomyocytes were exposed to medium containing ALA for 24 h and then exposed to non-ischemic (control), simulated ischemia (ISCH), or simulated ischemia/reperfusion (IR) conditions. Cardiomyocyte phospholipids were extracted and analyzed by an HPLC/electrospray ionization tandem mass spectrometry system. Pre-treatment of cells with ALA resulted in a significant incorporation of ALA within cardiomyocyte phosphatidylcholine. Cell death, DNA fragmentation and caspase-3 activity increased during ischemia and ischemia/reperfusion. Two pro-apoptotic oxidized phosphatidylcholine (OxPC) species, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) were significantly increased during both ischemia and ischemia/reperfusion. Pre-treatment of the cells with ALA resulted in a significant reduction in cell death during ischemia and ischemia/reperfusion challenge. Apoptosis was also inhibited during ischemia and ischemia/reperfusion as shown by reduced DNA fragmentation and decreased caspase activation. ALA pre-treatment significantly decreased the production of POVPC and PGPC during ischemia and ischemia/reperfusion. ALA pre-treatment also significantly increased in resting Ca 2+ during ischemia or ischemia/reperfusion but did not improve Ca 2+ transients. ALA protects the cardiomyocyte from apoptotic cell death during simulated ISCH and IR by inhibiting the production of specific pro-apoptotic OxPC species. OxPCs represent a viable interventional target to protect the heart during ischemic challenge.

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.

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., (Copyright © 2017 the American Physiological Society.)

The recent breakthrough in structural studies on Na+-translocating NADH:ubiquinone oxidoreductase (Na+-NQR) from the human pathogen Vibrio cholerae creates a perspective for the systematic design of inhibitors for this unique enzyme, which is the major Na+ pump in aerobic pathogens. Widespread distribution of Na+-NQR among pathogenic species, its key role in energy metabolism, its relation to virulence in different species as well as its absence in eukaryotic cells makes this enzyme especially attractive as a target for prospective antibiotics. In this review, the major biochemical, physiological and, especially, the pharmacological aspects of Na+-NQR are discussed to assess its 'target potential' for drug development. A comparison to other primary bacterial Na+ pumps supports the contention that NQR is a first rate prospective target for a new generation of antimicrobials. A new, narrowly targeted furanone inhibitor of NQR designed in our group is presented as a molecular platform for the development of anti-NQR remedies., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 B 2 /Prostaglandin F 1 α 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.

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.

The search for new nontraditional targets is a high priority in antibiotic design today. Bacterial membrane energetics based on sodium ion circulation offers potential alternative targets. The present work identifies the Na + -translocating NADH:ubiquinone oxidoreductase (Na + -NQR), a key respiratory enzyme in many microbial pathogens, as indispensible for the Chlamydia trachomatis infectious process. Infection by Chlamydia trachomatis significantly increased first H + and then Na + levels within the host mammalian cell. A newly designed furanone Na + -NQR inhibitor, PEG-2S, blocked the changes in both H + and Na + levels induced by Chlamydia trachomatis infection. It also inhibited intracellular proliferation of Chlamydia trachomatis with a half-minimal inhibitory concentration in the submicromolar range but did not affect the viability of mammalian cells or bacterial species representing benign intestinal microflora. At low nanomolar concentrations (IC 50 value = 1.76 nmol/L), PEG-2S inhibited the Na + -NQR activity in sub-bacterial membrane vesicles isolated from Vibrio cholerae. Taken together, these results show, for the first time, that Na + -NQR is critical for the bacterial infectious process and is susceptible to a precisely targeted bactericidal compound in situ. The obtained data have immediate relevance for many different diseases caused by pathogenic bacteria that rely on Na + -NQR activity for growth, including sexually transmitted, pulmonary, oral, gum, and ocular infections.

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., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

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., (© 2016 American Heart Association, Inc.)

Dietary trans-fats are strongly associated with heart disease. However, the capacity for the tissues of the body, and specifically the heart, to take up trans-fats is unknown. It is also unknown if different trans-fats have different uptake capacities in the heart and other tissues of the body. Diets of low-density lipoprotein receptor-deficient mice were supplemented for 14weeks with foods that contained 1.5% of the trans-fat elaidic acid or vaccenic acid. Tissues were extracted and frozen in liquid nitrogen, and then lipids were analyzed by gas chromatography for fatty acid content. Isolated cardiomyocytes were also exposed to elaidic or vaccenic acid in cell culture media for 24h. Dietary supplementation with vaccenic or elaidic acid resulted in a 20-fold higher accumulation of these TFAs in fat deposits in the body in comparison to liver. Liver tissue accumulated about twice as much per gram tissue as heart. Similar quantities of both elaidic acid and vaccenic acid were taken up by the tissues. Isolated cardiomyocytes exhibited an unusually large uptake of trans-fat, and this was dependent upon both the concentration and duration of exposure to the trans-fats but not upon the type of trans-fat. Expression levels of CD36 and FATP4 were not significantly changed during dietary interventions or exposure of cells to trans-fats. We conclude that fat, liver and heart (including cardiomyocytes) are all capable of accumulating trans-fat in response to dietary supplementation without changes in fatty acid transport protein expression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The primary endpoint was to determine the plasma concentration of alpha-linolenic acid (ALA), and its metabolites, following milled flaxseed consumption at four doses. Secondary outcomes focused on plasma enterolignan concentrations and the effects on tolerability, platelet aggregation, plasma lipids and urinary thromboxane levels., Methods: Healthy, younger adults (n = 34; 18-49 years old) were randomized into four groups consuming one muffin daily for 30 days fortified with 10, 20, 30 or 40 g of milled flaxseed. Blood and urine were collected at baseline and 4 weeks., Results: Plasma ALA concentrations increased with all flaxseed doses (P < 0.01), except the 20 g/day dose (P = 0.10), yet there was no significant dose-dependent response (P = 0.81). Only with the 30 g/day diet were n-3 polyunsaturated fatty acids (P = 0.007), and eicosapentaenoic acid (EPA) (P = 0.047) increased from baseline values. Docosapentaenoic acid and docosahexaenoic acid were not detected at any dose. Plasma total enterolignan concentrations significantly increased over time in all treatment groups, yet despite a dose-dependent tendency, no between-group differences were detected (P = 0.22). Flaxseed was well tolerated, even at the highest dose, as there were no reported adverse events, changes in cholesterol, platelet aggregation or urinary 11-dehydro-thromboxane B2., Conclusions: In healthy, younger adults, 10 g/day of milled flaxseed consumption is sufficient to significantly increase circulating ALA and total enterolignan concentrations; however, 30 g/day is required to convert ALA to EPA. Although all doses were well tolerated, 40 g/day is too low to attenuate cholesterol in this population.

Background and Aims: Elevated levels of circulating omega-3 polyunsaturated fatty acids like alpha linolenic acid (ALA) may be beneficial for cardiovascular health. Circulating ALA concentrations are elevated dramatically by a cholesterol supplemented diet which increases ALA bioavailability through enhanced micelle formation in the intestines. Conversely, it is possible that drugs which inhibit cholesterol metabolism in the intestine may also inhibit fatty acid absorption. The purpose of this study is to determine if a cholesterol absorption inhibitor, ezetimibe, will decrease circulating levels of ALA., Methods and Results: Cardiac patients (n = 34) between 44 and 80 years old, requiring statin therapy to regulate blood cholesterol levels, were randomly assigned to one of four groups for a 6 week trial: 1) placebo; 2) ezetimibe therapy; 3) a supplement of flaxseed oil (containing 1.0 g ALA in 2.0 g of flaxseed oil); or 4) ezetimibe and flaxseed oil supplementation. Ingestion of flaxseed oil resulted in a significant increase in circulating ALA levels (6 ug/dl) in patients who were not given ezetimibe. However, in the presence of ezetimibe, circulating ALA levels did not increase significantly even in the presence of flax oil supplementation (a decrease of 4 ug/dl). There were no significant differences amongst the groups in terms of circulating total cholesterol, LDL, HDL, triglyceride levels in the blood., Conclusion: Ezetimibe therapy inhibited the absorption of omega-3 fatty acids. Patients receiving ezetimibe therapy may not receive the expected cardiovascular benefits from dietary supplementation with omega-3 fatty acids., Clinical Trial Registration: NCT00955227., (Copyright © 2015 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)