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Competition with polyunsaturated fatty acids (PUFA) and an impact on eicosanoid biosynthesis may be one of mechanisms of conjugated linolenic acids (CLnA) action. The aim of this study was to investigate the influence of diet supplementation with pomegranate seed oil, containing punicic acid (PA)—one of CLnA isomers, and an aqueous extract of dried bitter melon fruits, administered separately or together, on PUFA and their lipoxygenase metabolites’ concentration in serum of rats. Percentage share of fatty acids was diversified in relation to applied supplementation. PA was only detected in serum of pomegranate seed oil supplemented group, where it was about 1%. Cis -9, trans -11 conjugated linoleic acid (rumenic acid, RA) level tended to increase in group supplemented simultaneously with both dietary supplements whereas its highest share in total fatty acids pool was detected in group receiving solely bitter melon dried fruits aqueous extract. This indicates that consumption of bitter melon tea significantly increased RA content in fatty acids pool in serum. However, pomegranate seed oil elevated procarcinogenic 12-hydroxyeicosatetraenoic acid concentration. Taking into account that pomegranate seed oil and bitter melon dried fruits are dietary supplements accessible worldwide and willingly consumed, the biological significance of this phenomenon should be further investigated. We presume, that there may be a need for some precautions concerning the simultaneous use of these products. [ABSTRACT FROM AUTHOR]

Modern analytical techniques allow for the measurement of oxylipins derived from linoleic acid in biological samples. Most validatory work has concerned extraction techniques, repeated analysis of aliquots from the same biological sample, and the influence of external factors such as diet and heparin treatment upon their levels, whereas less is known about the relative and absolute reliability of measurements undertaken on different days. A cohort of nineteen healthy males were used, where samples were taken at the same time of day on two occasions, at least 7 days apart. Relative reliability was assessed using Lin’s concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC). Absolute reliability was assessed by Bland–Altman analyses. Nine linoleic acid oxylipins were investigated. ICC and CCC values ranged from acceptable (0.56 [13-HODE]) to poor (near zero [9(10)- and 12(13)-EpOME]). Bland–Altman limits of agreement were in general quite wide, ranging from ±0.5 (12,13-DiHOME) to ±2 (9(10)-EpOME; log 10 scale). It is concluded that relative reliability of linoleic acid-derived oxylipins varies between lipids with compounds such as the HODEs showing better relative reliability than compounds such as the EpOMEs. These differences should be kept in mind when designing and interpreting experiments correlating plasma levels of these lipids with factors such as age, body mass index, rating scales etc. [ABSTRACT FROM AUTHOR]

Conjugated linoleic acids (CLA), which are a group of naturally occurring in food isomers of linoleic acid, seem to be active in each step of cancer development. There are many possible mechanisms of this action, and interactions with polyunsaturated fatty acids (PUFA) in lipoxygenase (LOX) and cyclooxygenase (COX) pathways are among the most likely ones. The aim of this study was to assess the influence of diet supplementation with CLA of pregnant and breastfeeding Sprague-Dawley female rats on selected polyunsaturated fatty acids and their LOX metabolites concentrations in serum of the progeny with chemically induced mammary tumors. We confirmed that higher supply of CLA in the diet of female rats corresponded with the lower susceptibility to chemically induced mammary tumors in their female offspring. It also influenced the polyunsaturated n-3 and n-6 fatty acid concentrations in serum, as well as the concentrations of their LOX metabolites. The significant negative correlation between the concentrations of two CLA isomers in serum and linoleic acid ( p = 0.0144, p = 0.0098), eicosapentaenoic acid ( p = 0.0158, p = 0.0124), and 5-HEPE ( p = 0.0014, p = 0.01690) and between cis-9, trans-11 CLA and 15-HEPE was detected, whereas arachidonic acid concentration positively correlated with CLA concentration in serum ( p = 0.0150, p = 0.0231). Our results indicate that CLA can compete with PUFA and influence serum concentration of PUFA and their LOX metabolites, which could partly explain the anticancerogenic action of CLA. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), i.e., 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), play an important role in the regulation of renal tubular and vascular function. The present study for the first time profiled HETEs and epoxygenase derived dihydroxyeicosatetraenoic acid diHETEs levels in spot urines and plasma in 262 African American patients from the University of Mississippi Chronic Kidney Disease Clinic and 31 African American controls. Significant correlations in eGFR and urinary 20-HETE/creatinine and 19-HETE/creatinine levels were observed. The eGFR increased by 17.47 [ p = 0.001] and 60.68 [( p = 0.005] ml/min/for each ng/mg increase in 20-HETE and 19-HETE levels, respectively. Similar significant positive associations were found between the other urinary eicosanoids and eGFR and also with 19-HETE/urine creatinine concentration and proteinuria. We found that approximately 80% of plasma HETEs and 30% diHETEs were glucuronidated and the fractional excretion of 20-HETE was less than 1%. These results suggest that there is a significant hepatic source of urinary 20-HETE glucuronide and EETs with extensive renal biotransformation to metabolites which may play a role in the pathogenesis of CKD. [ABSTRACT FROM AUTHOR]

Abstract: Alcoholic liver disease (ALD) begins with the accumulation of lipid droplets in the liver. Lipids which accumulate in the liver can stimulate inflammation, and the fatty acid derivatives, hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs), may play an important role in this process. We evaluated the concentrations of linoleic and arachidonic acid derivatives in the plasma of patients with ALD, non-alcoholic fatty liver disease (NAFLD) and healthy individuals. The groups consisted of 173 subjects: 63 patients with ALD, 90 with NAFLD and 20 healthy volunteers. Plasma 12-, 15-, and 5-HETE as well as 9- and 13-HODE were assessed using HPLC and isoprostane 8-epi-PGF 2α III was evaluated with an ELISA. In addition the mRNA expression of lipoxygenases (5-LOX, 15-LOX-1, 15-LOX-2) in the liver samples of patients with ALD cirrhosis was measured. A significant difference between the plasma concentrations of the analyzed derivatives was found when divided according to gender. The most significant differences were found between healthy individuals and ALD patients, as well as ALD and NAFLD individuals regardless of gender. The increased plasma HODEs and HETEs concentrations were in line with the increase in 5- and 15-LOX-1 and 15-LOX-2 mRNA in liver samples from ALD cirrhosis patients. LOXs expression and peroxidation of polyunsaturated fatty acids by free radical-propagated chemical oxidation may be contributing factors in liver necroinflammatory injury in ALD. [Copyright &y& Elsevier]

Abstract: Bioactive lipids derived from polyunsaturated fatty acids constitute an important set of lipid mediators with diverse homeostatic and pathophysiological activities. The role of bioactive lipids in inflammation, active resolution of inflammation, reproduction, cardiovascular biology, chronic diseases such as cancer and metabolic disorders is an active area of research. Other than the few clinically used eicosanoids such as prostaglandin F2α, prostacyclin, and prostaglandin E2, little is known about the stability of a majority of the bioactive lipids in aqueous solutions despite their extensive use under in vitro experimental conditions. The present study evaluated the stability of eicosanoids and docosanoids as well as their parent polyunsaturated fatty acids in tissue culture media with respect to incubation time, temperature, and composition of the media using multiple reaction monitoring (MRM) LC–MS. The results provide a comprehensive and valuable data set on the stability of these bioactive lipid mediators to guide in vitro experimentation. [Copyright &y& Elsevier]

Arachidonic acid (AA) can undergo monooxygenation or epoxidation by enzymes in the cytochrome P450 (CYP) family in the brain, kidney, lung, vasculature, and the liver. CYP-AA metabolites, 19- and 20-hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) and diHETEs have different biological properties based on sites of production and can be stored in tissue lipids and released in response to hormonal stimuli. 20-HETE is a vasoconstrictor, causing blockade of Ca++-activated K+ (KCa) channels. Inhibition of the formation of nitric oxide (NO) by 20-HETE mediates most of the cGMP-independent component of the vasodilator response to NO. 20-HETE elicits a potent dilator response in human and rabbit pulmonary vascular and bronchiole rings that is dependent on an intact endothelium and COX. 20-HETE is also a vascular oxygen sensor, inhibits Na+/K+-ATPase activity, is an endogenous inhibitor of the Na+–K+–2Cl−cotransporter, mediates the mitogenic actions of vasoactive agents and growth factors in many tissues and plays a significant role in angiogenesis. EETs, produced by the vascular endothelium, are potent dilators. EETs hyperpolarize VSM cells by activating KCa channels. Several investigators have proposed that one or more EETs may serve as endothelial-derived hyperpolarizing factors (EDHF). EETs constrict human and rabbit bronchioles, are potent mediators of insulin and glucagon release in isolated rat pancreatic islets, and have anti-inflammatory activity.Compared with other organs, the liver has the highest total CYP content and contains the highest levels of individual CYP enzymes involved in the metabolism of fatty acids. In humans, 50–75% of CYP-dependent AA metabolites formed by liver microsomes are ω/ω-OH-AA, mainly w-OH-AA, i.e. 20HETE, and 13–28% are EETs. Very little information is available on the role of 19- and 20-HETE and EETs in liver function. EETs are involved in vasopressin-induced glycogenolysis, probably via the activation of phosphorylase. In the portal vein, inhibition of EETs exerts profound effects on a variety of K-channel activities in smooth muscles of this vessel. 20-HETE is a weak, COX-dependent, vasoconstrictor of the portal circulation. EETs, particularly 11,12-EET, cause vasoconstriction of the porto-sinusoidal circulation. Increased synthesis of EETs in portal vessels and/or sinusoids or increased levels in blood from the meseneric circulation may participate in the pathophysiology of portal hypertension of cirrhosis. CYP-dependent AA metabolites are involved in the pathophysiology of portal hypertension, not only by increasing resistance in the porto-sinusoidal circulation, but also by increasing portal inflow through mesenteric vasodilatation. In patients with cirrhosis, urinary 20-HETE is several-fold higher than PGs and TxB2, whereas in normal subjects, 20-HETE and PGs are excreted at similar rates. Thus, 20-HETE is probably produced in increased amounts in the preglomerular microcirculation accounting for the functional decrease of flow and increase in sodium reabsorption.In conclusion, CYP-AA metabolites represent a group of compounds that participate in the regulation of liver metabolic activity and hemodynamics. They appear to be deeply involved in abnormalities related to liver diseases, particularly cirrhosis, and play a key role in the pathophysiology of portal hypertension and renal failure. [Copyright &y& Elsevier]

• EETs have anti-inflammatory effects. • ETs inhibit bone resorption and osteoclastogenesis. • 20-HETE is a pro-inflammatory mediator. • sEHI can be used to treat rheumatoid arthritis. • Multiple ligands targeting CYP 450-derived eicosanoids are promising targets in rheumatoid arthritis treatment. Today the role of cytochrome P450 metabolites in inflammatory rheumatic disease, such as rheumatoid arthritis (RA) is still poorly understood. In this review we survey the current knowledge on cytochrome P450 metabolites in rheumatoid arthritis. The balance between CYP epoxygenase- and CYP ω- hydroxylase is correlated to the regulation of NF-κB. In RA patients synovial fluid there are higher levels of IL-6, which suppresses activities of CYP enzymes, such as CYP3A, CYP2C19, CYP2C9, and CYP1A2. EETs have anti-inflammatory effects, probably attributed to the PPARγ activation. EETs inhibit bone resorption and osteoclastogenesis, and can be considered as an innovative therapeutic strategy for rheumatoid arthritis. In reference to the CYP ɷ-hydroxylase pathway, 20-HETE is a pro-inflammatory mediator. While there is scarce information on the role of 20-HETE inhibitors and its antagonists in rheumatoid arthritis, the elevation of EETs levels by sEH inhibitors is a promising therapeutic strategy for rheumatoid arthritis patients. In addition, hybrid compounds, such as sEH inhibitors/FLAP inhibitors, or sEHI combined with NSAIDs/COXIBs are also important therapeutic target. However, studies investigating the effects of inflammation and rheumatic disease on CYP-mediated eicosanoid metabolism are necessary. Obtaining a better understanding of the complex role of CYP-derived eicosanoids in inflammatory rheumatic disease, such as rheumatoid arthritis will provide valuable insight for basic and clinical researchers investigation. [ABSTRACT FROM AUTHOR]