Eicosapentaenoic acid (EPA)-induced inhibitory effects on porcine coronary and cerebral arteries involve inhibition of prostanoid TP receptors.
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ABSTRACT:
SUBMITTER: Yoshioka K
PROVIDER: S-EPMC9329469 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND AND PURPOSE: Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E? (DX-DM PGE?) on pig cerebral artery when used as a selective EP? receptor agonist. This study investigated the selectivity profile of DX-DM PGE?, focusing on the interaction between its EP? and TP (thromboxane A?-like) agonist activities. EXPERIMENTAL APPROACH: Contraction of guinea-pig trachea (EP? system) and aorta (EP? and TP systems) was measured in conventional organ baths. KEY RESULTS: Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE? (EP? agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE? induced strong contraction, which on the basis of treatment with (DG)-3ap (EP? antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP? and TP receptors. EP?/TP self-synergism also accounted for contraction induced by PGF(2?) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE? also showed significant EP? agonism on guinea-pig trachea as defined by the EP? antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations ?3 µM. CONCLUSIONS AND IMPLICATIONS: EP?/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP? agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP? system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed.
| S-EPMC3031070 | biostudies-literature
Project description:Retort sterilization is cost-effective for small-scale production of specialized nutrition products. However, the sensory properties and stability of active ingredients after sterilization remain undetermined. This study aimed to investigate the effect of retort on the existence of functional compounds and the sensory satisfaction of a fortified complete nutrition formula with branched-chain amino acids (BCAAs), and fish oil providing eicosapentaenoic acid (EPA). Changes in EPA and BCAA contents after retort were determined by using LC-MS/MS. Nutrient values, osmolality, rheology and sensory acceptance of the processed fortified and control formulas were compared. After retort, the fortified formula had an increase in all types of BCAAs but 30% loss of EPA (p = 0.001). The fortified formula had slightly higher protein and fiber contents, along with increased osmolality. It had higher viscosity and shear stress, but similar IDDSI level at 0. Among flavors tested, the fortified formula with Japanese rice flavor received the highest satisfaction scores with over 80% sensory acceptance. In conclusion, retort sterilization preserved BCAAs of the functional drink, but the addition of 30% fish oil was required to compensate for the EPA loss. The sterilized fortified formula with Japanese rice flavor was sensory acceptable.
| S-EPMC9320311 | biostudies-literature
Project description:The omega-3 fatty acid eicosapentaenoic acid (EPA) has multiple actions potentially conferring cardiovascular benefit, including lowering serum triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) levels and potentially reducing key steps in atherogenesis. Dietary supplements are a common source of omega-3 fatty acids in the US, but virtually all contain docosahexaenoic acid (DHA) in addition to EPA, and lipid effects differ between DHA and EPA. Contrary to popular belief, no over-the-counter omega-3 products are available in the US, only prescription products and dietary supplements. Among the US prescription omega-3 products, only one contains EPA exclusively (Vascepa); another closely related prescription omega-3 product also contains highly purified EPA, but is approved only in Japan and is provided in different capsule sizes. These high-purity EPA products do not raise low-density lipoprotein cholesterol (LDL-C) levels, even in patients with TG levels >500 mg/dL, in contrast to the increase in LDL-C levels with prescription omega-3 products that also contain DHA. The Japanese prescription EPA product was shown to significantly reduce major coronary events in hypercholesterolemic patients when added to statin therapy in the Japan EPA Lipid Intervention Study (JELIS). The effects of Vascepa on cardiovascular outcomes are being investigated in statin-treated patients with high TG levels in the Reduction of Cardiovascular Events With EPA-Intervention Trial (REDUCE-IT).
| S-EPMC5282870 | biostudies-literature
Project description:Receptors for purines and pyrimidines are expressed throughout the cardiovascular system. This study investigated their functional expression in porcine isolated pancreatic arteries. Pancreatic arteries (endothelium intact or denuded) were prepared for isometric tension recording and preconstricted with U46619, a thromboxane A(2) mimetic; adenosine-5'-diphosphate (ADP), uridine-5'-triphosphate (UTP) and MRS2768, a selective P2Y(2) agonist, were applied cumulatively, while adenosine-5'-triphosphate (ATP) and αβ-methylene-ATP (αβ-meATP) response curves were generated from single concentrations per tissue segment. Antagonists/enzyme inhibitors were applied prior to U46619 addition. ATP, αβ-meATP, UTP and MRS2768 induced vasoconstriction, with a potency order of αβ-meATP > MRS2768 > ATP ≥ UTP. Contractions to ATP and αβ-meATP were blocked by NF449, a selective P2X(1) receptor antagonist. The contraction induced by ATP, but not UTP, was followed by vasorelaxation. Endothelium removal and DUP 697, a cyclooxygenase-2 inhibitor, had no significant effect on contraction to ATP but attenuated that to UTP, indicating actions at distinct receptors. MRS2578, a selective P2Y(6) receptor antagonist, had no effect on contractions to UTP. ADP induced endothelium-dependent vasorelaxation which was inhibited by MRS2179, a selective P2Y(1) receptor antagonist, or SCH58261, a selective adenosine A(2A) receptor antagonist. The contractions to ATP and αβ-meATP were attributed to actions at P2X(1) receptors on the vascular smooth muscle, whereas it was shown for the first time that UTP induced an endothelium-dependent vasoconstriction which may involve P2Y(2) and/or P2Y(4) receptors. The relaxation induced by ADP is mediated by P2Y(1) and A(2A) adenosine receptors. Porcine pancreatic arteries appear to lack vasorelaxant P2Y(2) and P2Y(4) receptors.
| S-EPMC4040170 | biostudies-literature
Project description:EPA, an omega-3 polyunsaturated fatty acid, exerts beneficial effects on human health. However, the molecular mechanisms underlying EPA function are poorly understood. The object was to illuminate molecular mechanism underlying EPA's role. Here, 1H-NMR-based metabolic analysis showed enhanced branched-chain amino acids (BCAAs) and lactate following EPA treatment in skeletal muscle cells. EPA regulated mitochondrial oxygen consumption rate. Furthermore, EPA induced calcium/calmodulin-dependent protein kinase kinase (CaMKK) through the generation of intracellular calcium. This induced the phosphorylation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK) that led to glucose uptake, and the translocation of glucose transporter type 4 (GLUT4) in muscles. In conclusion, EPA exerts benign effects on glucose through the activation of AMPK-p38 MAPK signaling pathways in skeletal muscles.
| S-EPMC6801536 | biostudies-literature
Project description:We hypothesize that whole microalga biomass is a natural rumen-protected source of eicosapentaenoic acid (EPA, 20:5n-3) for ruminants. To test our hypothesis, we studied the ruminal biohydrogenation of EPA from two microalgae, Nannochloropsis oceanica and Phaeodactylum tricornutum using in vitro incubations with rumen fluid. A total mixed ration was incubated with: no EPA (control), EPA as free-fatty acid, N. oceanica spray-dried (SD), N. oceanica freeze-dried (FD), or P. tricornutum FD. The kinetics of EPA disappearance and of products formed during the 24 hours of incubation were evaluated, and complemented by deuterated-EPA incubation. Results showed that EPA metabolism from the N. oceanica was remarkably reduced compared with the P. tricornutum and free-EPA, and this reduction was even more effective with the N. oceanica FD. Our data also indicates that neither feed dry matter disappearance nor rumen microbial markers (branched-chain fatty acids and dimethyl acetals) were affected by EPA-sources. We reported for the first time the kinetics of EPA biohydrogenation class products and the unequivocal formation of 20:0 from EPA. Overall, N. oceanica shows a strong potential to be used as a natural dietary source of EPA to ruminants, nevertheless further studies are needed to verify its protection in vivo.
| S-EPMC6035222 | biostudies-literature
Project description:Background and purposeLubiprostone, a prostaglandin E? derivative, is reported to activate ClC-2 chloride channels located in the apical membranes of a number of transporting epithelia. Lack of functioning CFTR chloride channels in epithelia is responsible for the genetic disease cystic fibrosis, therefore, surrogate channels that can operate independently of CFTR are of interest. This study explores the target receptor(s) for lubiprostone in airway epithelium.Experimental approachAll experiments were performed on the ventral tracheal epithelium of sheep. Epithelia were used to measure anion secretion from the apical surface as short circuit current or as fluid secretion from individual airway submucosal glands, using an optical method.Key resultsThe EP? antagonists L-161982 and GW627368 inhibited short circuit current responses to lubiprostone, while EP?(,)?(&)? receptor antagonists were without effect. Similarly, lubiprostone induced secretion in airway submucosal glands was inhibited by L-161982. L-161982 effectively competed with lubiprostone with a K(d) value of 0.058 µM, close to its value for binding to human EP? receptors (0.024 µM). The selective EP? agonist L-902688 and lubiprostone behaved similarly with respect to EP? receptor antagonists. Results of experiments with H89, a protein kinase A inhibitor, were consistent with lubiprostone acting through a G(s) -protein coupled EP? receptor/cAMP cascade.Conclusions and implicationsLubiprostone-induced short-circuit currents and submucosal gland secretions were inhibited by selective EP? receptor antagonists. The results suggest EP? receptor activation by lubiprostone triggers cAMP production necessary for CFTR activation and the secretory responses, a possibility precluded in CF tissues.
| S-EPMC3031069 | biostudies-literature
Project description:BackgroundAmong extremophiles, halophiles are defined as microorganisms adapted to live and thrive in diverse extreme saline environments. These extremophilic microorganisms constitute the source of a number of hydrolases with great biotechnological applications. The interest to use extremozymes from halophiles in industrial applications is their resistance to organic solvents and extreme temperatures. Marinobacter lipolyticus SM19 is a moderately halophilic bacterium, isolated previously from a saline habitat in South Spain, showing lipolytic activity.Methods and findingsA lipolytic enzyme from the halophilic bacterium Marinobacter lipolyticus SM19 was isolated. This enzyme, designated LipBL, was expressed in Escherichia coli. LipBL is a protein of 404 amino acids with a molecular mass of 45.3 kDa and high identity to class C β-lactamases. LipBL was purified and biochemically characterized. The temperature for its maximal activity was 80°C and the pH optimum determined at 25°C was 7.0, showing optimal activity without sodium chloride, while maintaining 20% activity in a wide range of NaCl concentrations. This enzyme exhibited high activity against short-medium length acyl chain substrates, although it also hydrolyzes olive oil and fish oil. The fish oil hydrolysis using LipBL results in an enrichment of free eicosapentaenoic acid (EPA), but not docosahexaenoic acid (DHA), relative to its levels present in fish oil. For improving the stability and to be used in industrial processes LipBL was immobilized in different supports. The immobilized derivatives CNBr-activated Sepharose were highly selective towards the release of EPA versus DHA. The enzyme is also active towards different chiral and prochiral esters. Exposure of LipBL to buffer-solvent mixtures showed that the enzyme had remarkable activity and stability in all organic solvents tested.ConclusionsIn this study we isolated, purified, biochemically characterized and immobilized a lipolytic enzyme from a halophilic bacterium M. lipolyticus, which constitutes an enzyme with excellent properties to be used in the food industry, in the enrichment in omega-3 PUFAs.
| S-EPMC3154438 | biostudies-literature
Project description:A hallmark pathological feature of the Alzheimer's disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD.
| S-EPMC3503350 | biostudies-other
Project description:No studies have examined the relationship between endogenous polyunsaturated fatty acids (PUFAs) levels and treatment response to PUFAs. We conducted a 12-week, double-blind, placebo-controlled trial comparing the effects of high-dose eicosapentaenoic acid (EPA, 1.2 g) and placebo on cognitive function (continuous performance test) in n = 92 youth (age 6-18-years-old) with Attention Deficit Hyperactivity Disorder (ADHD). Blood erythrocytes PUFAs were measured before and after treatment, to examine the effects of baseline endogenous EPA levels on treatment response and the effects of EPA treatment on PUFAs levels. Secondary measures included other ADHD symptoms, emotional symptoms, and levels of plasma high-sensitivity c-reactive protein (hs-CRP) and brain-derived neurotrophic factor (BDNF). Overall, EPA group improved more than placebo group on focused attention (variability, Effect size (ES) = 0.38, p = 0.041); moreover, within youth with the lowest baseline endogenous EPA levels, EPA group improved more than placebo group in another measure of focused attention (hit reaction time, HRT, ES = 0.89, p = 0.015) and in vigilance (HRT interstimulus interval changes, HRTISIC, ES = 0.83, p = 0.036). Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. EPA increased blood erythrocytes EPA by 1.6-fold but not DHA levels, and did not affect hs-CRP and BDNF plasma levels. In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.
| S-EPMC6864068 | biostudies-literature