The Influence of Supplementation with Zinc in Micro and Nano Forms on the Metabolism of Fatty Acids in Livers of Rats with Breast Cancer.

The aim of this study was to investigate the effect of zinc supplementation (in the form of nano or microparticles) on the profile and metabolism of fatty acids in the liver microsomes of rats with induced breast cancer. The activity of desaturases (Δ5, Δ6, Δ9) and the level of cholesterol and its oxidized derivatives were measured. The aim of this study was also to determine the effect of various forms of zinc supplements on rats that were on 5-, 12- and 15-hydroxyeicosatetraenoic (5-, 12- and 15-HETE) and hydroxyoctadecadienoic (HODE) acids, and the level of prostaglandin E2 (PGE2). Female Spraque-Dawley rats (n = 24) were divided into 2 groups that were supplemented with zinc in the micro form (342 nm) or nano form (99 nm) particles, respectively, and a group with a standard diet (control group). All animals received 7,12-dimethylbenz[a]anthracene twice for the induction of breast cancer. Dietary nano-Zn supplementation increased vaccenic acid content (p = 0.032) and decreased Δ6-desaturase activity (p = 0.006), whereas micro-Zn increased cholesterol (p = 0.006), ∑COPs (total cholesterol-oxidation products) (p = 0.019) and PGE2 (p = 0.028) content. Dietary enrichment with Zn microparticles resulted in lower concentrations of the metabolites 15-, 12- and 5-HETE and HODE. Our study indicates that the effect of zinc supplementation on the metabolism of fatty acids in the liver microsomes under neoplastic conditions depends on the form in which it is administered.

Influence of Lipoxygenase Inhibition on Glioblastoma Cell Biology.

BACKGROUND: The relationship between glioblastoma (GBM) and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-lipoxygenase-1 (15-LOX), a linolenic acid and arachidonic acid metabolizing enzyme, induces both pro- and antitumorigenic effects in different cancer types. Its role in glioma activity has not yet been clearly described. The objective of this study was to identify the influence of 15-LOX and its metabolites on glioblastoma cell activity. METHODS: GBM cell lines were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify 15-LOX metabolites. GBM cells treated with 15-LOX metabolites, 13-hydroxyoctadecadeinoic acid (HODE) and 9-HODE, and two 15-LOX inhibitors (luteolin and nordihydroguaiaretic acid) were also examined. Dose response/viability curves, RT-PCRs, flow cytometry, migration assays, and zymograms were performed to analyze GBM growth, migration, and invasion. RESULTS: Higher quantities of 13-HODE were observed in five GBM cell lines compared to other lipids analyzed. Both 13-HODE and 9-HODE increased cell count in U87MG. 15-LOX inhibition decreased migration and increased cell cycle arrest in the G2/M phase. CONCLUSION: 15-LOX and its linoleic acid (LA)-derived metabolites exercise a protumorigenic influence on GBM cells in vitro. Elevated endogenous levels of 13-HODE called attention to the relationship between linoleic acid metabolism and GBM cell activity.

Fatty acid binding protein 7 mediates linoleic acid-induced cell death in triple negative breast cancer cells by modulating 13-HODE.

Different fatty acids have distinct effects on the survival of breast cancer cells, which could be mediated by fatty acid binding proteins (FABPs), a family of lipid chaperones. Due to the diverse structures of the members of FABP family, each FABP demonstrates distinct binding affinities to different fatty acids. Of note, FABP7 is predominantly expressed in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Yet, the role of FABP7 in modulating the effects of fatty acids on TNBC survival was unclear. In contrast to the high expression of FABP7 in human TNBC tumours, FABP7 protein was undetectable in TNBC cell lines. Hence, a FABP7 overexpression model was used for this study, in which the transduced TNBC cell lines (MDA-MB-231 and Hs578T) were treated with various mono- and polyunsaturated fatty acids. Oleic acid (OA), docosahexaenoic acid (DHA) and arachidonic acid (AA) inhibited TNBC cell growth at high concentrations, with no differences resulted from FABP7 overexpression. Interestingly, overexpression of FABP7 augmented linoleic acid-induced cell death in MDA-MB-231 cells. The increased cell death may be explained by a decrease in 13-HODE, a pro-tumorigenic oxidation product of linoleic acid. The phenotype was, however, attenuated with a rescue treatment using 25 nM 13-HODE. The decrease in 13-HODE was potentially due to fatty acid partitioning modulated by FABP7, as demonstrated by a 3-fold increase in fatty acid oxidation. Our findings suggest that linoleic acid could be a potential therapeutic strategy for FABP7-overexpressing TNBC patients.

Suppression of Membranous LRP5 Recycling, Wnt/ß-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P.

APC mutation activation of Wnt/ß-catenin drives initiation of colorectal carcinogenesis (CRC). Additional factors potentiate ß-catenin activation to promote CRC. Western diets are enriched in linoleic acid (LA); LA-enriched diets promote chemically induced CRC in rodents. 15-Lipoxygenase-1 (15-LOX-1), the main LA-metabolizing enzyme, is transcriptionally silenced during CRC. Whether LA and 15-LOX-1 affect Wnt/ß-catenin signaling is unclear. We report that high dietary LA promotes CRC in mice treated with azoxymethane or with an intestinally targeted Apc mutation (ApcΔ580) by upregulating Wnt receptor LRP5 protein expression and ß-catenin activation. 15-LOX-1 transgenic expression in mouse intestinal epithelial cells suppresses LRP5 protein expression, ß-catenin activation, and CRC. 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) leads to PI3P_13-HODE formation, which decreases PI3P binding to SNX17 and LRP5 and inhibits LRP5 recycling from endosomes to the plasma membrane, thereby increasing LRP5 lysosomal degradation. This regulatory mechanism of LRP5/Wnt/ß-catenin signaling could be therapeutically targeted to suppress CRC.

The Lipid Receptor G2A (GPR132) Mediates Macrophage Migration in Nerve Injury-Induced Neuropathic Pain.

Nerve injury-induced neuropathic pain is difficult to treat and mechanistically characterized by strong neuroimmune interactions, involving signaling lipids that act via specific G-protein coupled receptors. Here, we investigated the role of the signaling lipid receptor G2A (GPR132) in nerve injury-induced neuropathic pain using the robust spared nerve injury (SNI) mouse model. We found that the concentrations of the G2A agonist 9-HODE (9-Hydroxyoctadecadienoic acid) are strongly increased at the site of nerve injury during neuropathic pain. Moreover, G2A-deficient mice show a strong reduction of mechanical hypersensitivity after nerve injury. This phenotype is accompanied by a massive reduction of invading macrophages and neutrophils in G2A-deficient mice and a strongly reduced release of the proalgesic mediators TNFα, IL-6 and VEGF at the site of injury. Using a global proteome analysis to identify the underlying signaling pathways, we found that G2A activation in macrophages initiates MyD88-PI3K-AKT signaling and transient MMP9 release to trigger cytoskeleton remodeling and migration. We conclude that G2A-deficiency reduces inflammatory responses by decreasing the number of immune cells and the release of proinflammatory cytokines and growth factors at the site of nerve injury. Inhibiting the G2A receptor after nerve injury may reduce immune cell-mediated peripheral sensitization and may thus ameliorate neuropathic pain.

Inflammation with the participation of arachidonic (AA) and linoleic acid (LA) derivatives (HETEs and HODEs) is necessary in the course of a normal reproductive cycle and pregnancy.

Data on arachidonic (AA) and linoleic (LA) acid derivatives and their role in the reproductive cycle are limited. In order to systematize these reports, 54 scientific investigations were analyzed, which revealed the important role of AA and LA in the planning and course of pregnancy. Ovulation, menstruation, pregnancy, and childbirth are strongly related to the occurrence of physiological inflammatory reactions. Ovulation and menstruation are cyclic tissue remodeling processes that cause changes in the synthesis of inflammation mediators, such as prostaglandins and leukotrienes. Thus, the cyclooxygenase (COX) and lipoxygenase-5 (5-LOX) pathway for AA transformation is activated. Only the absence of neutrophils during this process differentiates an embryo implantation from a standard inflammatory response. It has been found that in COX-2 deficiency conditions, incorrect embryo implantation and decidual reaction occur; therefore, the mechanism associated with the activation of the nuclear factor (NF)-κB pathway seems to play an important role in the course of embryo implantation. In addition, 12/15-LOX may be key modulators of uterine activity during the implantation process. According to the current state of knowledge, AA derivatives synthesized throughout the cytochrome P450 (CYP) and LOX pathways play a special role in the late pregnancy period. Decreased 5-HETE levels have been related to slowing down the progression of labor, while 11-HETE and 15-HETrE to its acceleration. It has been also proven that renal 20-HETE contents undergo significant changes in the late pregnancy period, which are caused by an increase in their adrenal medulla and vascular synthesis, leading to decrease of blood pressure and an increase of sodium excretion, finally conditioning a normal course of labor.

The Effect of Diet Supplementation with Pomegranate and Bitter Melon on Lipidomic Profile of Serum and Cancerous Tissues of Rats with Mammary Tumours.

The aim of this study was to present overall lipid profile of organisms with ongoing neoplastic process and applied diet supplementation with pomegranate seed oil (PSO) and bitter melon extract (BME). The following were quantified in serum and cancerous tissues of rats suffering from mammary tumours: fatty acids, conjugated fatty acids and sterols, their oxidised metabolites (malondialdehyde and oxysterols) and lipoxygenase (LOX) metabolites of polyunsaturated fatty acids. The obtained results indicate that abnormalities in lipid metabolism accompany neoplastic process. These differences concern all classes of lipids and most pathways of their transformation, with the special emphasis on lipid peroxidation and LOX-mediated metabolism. Cancer process appears to be so detrimental that it may conceal positive influence of dietary modifications. The lack of anticarcinogenic properties of PSO and BME in this model may be due to their antioxidant properties or elevated levels of conjugated linoleic acids (CLA), which change CLA isomer activity from anti- to pro-tumorigenic. As CLA are the product of conjugated linolenic acids (CLnA) endogenous metabolism, high CLA levels may be explained by applied diet enrichment.

Discovery of aspirin-triggered eicosanoid-like mediators in a Drosophila metainflammation blood tumor model.

Epidemiologic studies have linked the use of aspirin to a decline in chronic inflammation that underlies many human diseases, including some cancers. Aspirin reduces the levels of cyclooxygenase-mediated pro-inflammatory prostaglandins, promotes the production of pro-resolution molecules, and triggers the production of anti-inflammatory electrophilic mono-oxygenated (EFOX) lipid mediators. We investigated the effects of aspirin in fruit fly models of chronic inflammation. Ectopic Toll/NF-κB and JAK/STAT signaling in mutant D. melanogaster results in overproliferation of hematopoietic blood progenitors resulting in the formation of granuloma-like tumors. Ectopic JAK-STAT signaling also leads to metabolic inflammation. We report that aspirin-treated mutant flies experience reduction in metabolic inflammation, mitosis, ectopic immune signaling, and macrophage infiltration. Moreover, these flies synthesize 13-HODE, and aspirin triggers 13-oxoODE (13-EFOX-L2) production. Providing the precursor of 13-HODE, linoleic acid, or performing targeted knockdown of the transcription factor STAT in inflammatory blood cells, boosts 13-EFOX-L2 levels while decreasing metabolic inflammation. Thus, hematopoietic cells regulate metabolic inflammation in flies, and their effects can be reversed by pharmaceutical or dietary intervention, suggesting deep phylogenetic conservation in the ability of animals to resolve inflammation and repair tissue damage. These findings can help identify novel treatment targets in humans.

Up-regulation of 15-lipoxygenase enzymes and products in functional and non-functional pituitary adenomas.

BACKGROUND: Pituitary adenoma accounts as a complex and multifactorial intracranial neoplasm with wide range of clinical symptoms which its underlying molecular mechanism has yet to be determined. The bioactive lipid mediators received attentions toward their contribution in cancer cell proliferation, progression and death. Amongst, 15-Lipoxygense (15-Lox) enzymes and products display appealing role in cancer pathogenesis which their possible effect in pituitary adenoma tumor genesis is perused in the current study. METHODS: The 15-Lipoxygenses isoforms expression level was evaluated in tumor tissues of prevalent functional and non-functional pituitary adenomas and normal pituitary tissues via Real-Time PCR. The circulating levels of 15(S) HETE and 13(S) HODE as 15-Lox main products were assessed in serum of patients and healthy subjects using enzyme immunoassay kits. RESULTS: Our results revealed that 15-Lox-1 and 15-Lox-2 expression levels were elevated in tumor tissues of pituitary adenomas comparing to normal pituitary tissues. The elevated levels of both isoforms were accompanied with 15(S) HETE and 13(S) HODE elevation in the serum of patients. The 15-Lox-1 expression and activity was higher in invasive tumors as well as tumors with bigger size indicating the possible pro-tumorigenic role of 15-Lox-1, more than 15-Lox-2 in pituitary adenomas. The diagnostic value of 15-Lipoxygense isoforms and products were considerable between patients and healthy groups. CONCLUSION: The possible involvement of 15-Lipoxygense pathway especially 15-Lox-1 in the regulation of pituitary tumor growth and progression may open up new molecular mechanism regarding pituitary adenoma pathogenesis and might shed light on its new therapeutic strategies.

Microalgae-derived oxylipins decrease inflammatory mediators by regulating the subcellular location of NFκB and PPAR-γ.

Oxylipins (OXLs) are bioactive molecules generated by the oxidation of fatty acids that promote the resolution of acute inflammation and prevent chronic inflammatory processes through molecular mechanisms that are not well known. We have previously reported the anti-inflammatory activity of microalgae-derived OXLs and OXL-containing biomass in two inflammatory bowel disease (IBD) models: 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis and TNBS-induced recurrent colitis. In this study, we examined the in vitro anti-inflammatory mechanism of action of the most abundant OXLs isolated from Chlamydomonas debaryana (13S-HOTE and 13S-HODE) and Nannochloropsis gaditana (15S-HEPE). These OXLs decreased IL-1ß and IL-6 pro-inflammatory cytokines production as well as iNOS and COX-2 expression levels in THP-1 macrophages. In addition, OXLs decreased IL-8 production in HT-29 colon cells, the major chemokine produced by these cells. The interaction of OXLs with NFκB and PPAR-γ signaling pathways was studied by confocal microscopy. In THP-1 macrophages and HT-29 colon cells, stimulated by LPS and TNFα respectively, a pre-treatment with 13S-HOTE, 13S-HODE and 15S-HEPE (100µM) resulted in a lower nuclear presence of NFκB in both cell lines. The study of the subcellular localization of PPAR-γ showed that the treatment of THP-1 and HT-29 cells with these OXLs caused the migration of PPAR-γ into the nucleus. Colocalization analysis of both transcription factors in LPS-stimulated THP-1 macrophages showed that the pre-treatment with 13S-HOTE, 13S-HODE or 15S-HEPE lowered nuclear colocalization similar to control value, and increased cytosolic localization above control level. These results indicate that these OXLs could act as agonist of PPAR-γ and consequently inhibit NFκB signaling pathway activation, thus lowering the production of inflammatory markers, highlighting the therapeutic potential of these OXLs in inflammatory diseases such as IBD.

Impact of conjugated linoleic acid administered to rats prior and after carcinogenic agent on arachidonic and linoleic acid metabolites in serum and tumors.

The objective of the study was to assess the influence of conjugated linoleic acid (CLA) daily supplementation prior and after carcinogenic agent on the concentrations of eicosanoids - metabolites of arachidonic acid (15-, 12- or 5-hydroxyeicosatetraenoic acids (15-, 12-, 5-HETE), prostaglandin E2 (PGE2)) and linoleic acid (13- or 9-hydroxyoctadecadienoic acids (13-, 9-HODE)) in rat serum and 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumors. Female rats were randomised into six groups, receiving 1% or 2% Bio-C.L.A or plant oil since the 37th day of life throughout the whole experiment. Some rats (50-day-old) were administered DMBA to induce tumors. Eicosanoids were analyzed with LC-MS/MS. The study indicated that CLA supplemented daily to rats prior and after carcinogen administration affected concentrations of arachidonic and linoleic acid metabolites in rat serum and induced tumors. However, ratios of eicosanoids exerting opposite activities (e.g. 12-HETE/15-HETE) appear to act as more precise factors reflecting pathological changes in an organism than individual compounds.

Influence of pomegranate seed oil and bitter melon aqueous extract on polyunsaturated fatty acids and their lipoxygenase metabolites concentration in serum of rats.

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.

15-Lipoxygenase inhibitors: a patent review.

INTRODUCTION: 15-Lipoxygenases (15-LOXes) are a family of iron-containing proteins that have the capability for unsaturated fatty acid peroxidation in animals and plants. Two types of the enzyme, 15-LOX-1 and 15-LOX-2, have been recognized in mammals to have different abilities in the peroxidation of arachidonic acid and linoleic acid. In mammalians, the critical role of the mentioned enzymes and their metabolites, hydroxyoctadecadienoic acid (HODE), lipoxins and eoxins, in the formation of inflammation, sensitivities, atherosclerosis and some cancers has been demonstrated. AREAS COVERED: This article reviews relevant publications and patents on 15-LOX inhibitors from the points of view of synthesis and biological activities. Herein, based on the chemical structure and pharmacophore moiety, 15-LOX inhibitors are categorized into heterocyclic, phenolic, allyl and allyloxy derivatives. EXPERT OPINION: It is noteworthy that to date no pharmaceutical product from 15-LOX inhibitors has been approved for therapeutic usage. Recently, the role of 15-LOX-1 in obesity, by directly relating 15-LOX-1 expression with the proliferation and hypertrophy of adipose cells, has been reported. Based on the role 15-LOX plays in promoting cancer by amplifying PPARγ transcription activity, however, it can be claimed that 15-LOX inhibitors will be deemed suitable as chemotherapy agents in the near future.

Antineoplastic effects of 15(S)-hydroxyeicosatetraenoic acid and 13-S-hydroxyoctadecadienoic acid in non-small cell lung cancer.

BACKGROUND: Previous studies have shown that the levels of 15-lipoxygenase 1 (15-LOX-1) and 15-LOX-2 as well as their metabolites 13-S-hydroxyoctadecadienoic acid (13(S)-HODE) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) are significantly reduced in smokers with non-small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen-induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC. METHODS: NSCLC cells were treated with exogenous 13(S)-HODE and 15(S)-HETE, and then the ways in which they affected cell function were examined. 15-LOX-1 and 15-LOX-2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)-HODE and 15(S)-HETE before cell function was assessed. RESULTS: The application of exogenous 13(S)-HODE and 15(S)-HETE significantly enhanced the activity of peroxisome proliferator-activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15-LOX-1 and 15-LOX-2 obviously promoted the endogenous levels of 13(S)-HODE and 15(S)-HETE, which were demonstrated to be more effective in the inhibition of NSCLC. CONCLUSIONS: This study has demonstrated that exogenous or endogenous 13(S)-HODE and 15(S)-HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15-LOX activity to increase the production of endogenous 15(S)-HETE and 13(S)-HODE may offer a novel research direction for molecular targeting treatment of smoking-related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands.

Influence of maternal diet enrichment with conjugated linoleic acids on lipoxygenase metabolites of polyunsaturated fatty acids in serum of their offspring with 7,12-dimethylbenz[a]anthracene induced mammary tumors.

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.

Effect of conjugated linoleic acid mixture supplemented daily after carcinogen application on linoleic and arachidonic acid metabolites in rat serum and induced tumours.

Conjugated linoleic acid (CLA) is thought to exert anticarcinogenic, antiatherogenic, anti-inflammatory and weight loss effects. The impact on eicosanoid biosynthesis may be one of the mechanisms of its action. The aim of this study was to establish whether CLA mixture supplemented daily after administration of carcinogen (7, 12-dimethylbenz[a]anthracene, DMBA) influenced the concentration of linoleic and arachidonic acid metabolites: 13- or 9-hydroxyoctadecadienoic acids (13-, 9-HODE) and 15-, 12- or 5-hydroxyeicosatetraenoic acids (15-, 12- or 5-HETE) and prostaglandin E2 (PGE2) in rat serum and DMBA-induced tumours. The correlations between polyunsaturated fatty acids (PUFA) and HETE and HODE contents in serum were also investigated. Female Sprague-Dawley rats divided into three groups according to the diet (1% Bio-C.L.A., 2% Bio-C.L.A. and plant oil in the control group) were used in the study. On the 50th day of life some of the animals in every dietary group were administered DMBA to induce tumours. Since that day, the rats were fed one of the above-mentioned diets. After 15weeks the animals were sacrificed and blood and tumours were collected. HETE and HODE were extracted using a solid-phase extraction (SPE) method on C18 columns and analysed with LC-MS/MS. The results of our study showed that CLA daily supplementation after carcinogen administration influence LA and AA metabolite levels in serum and tumours. However, the ratios of eicosanoids having opposite effects (e.g. 12-HETE/15-HETE), not concentrations of particular compounds, appear to be better indicators of pathological processes.

Implications of chemokine receptors and inflammatory lipids in cancer.

Inflammatory lipids receive much attention due to their important biological activities. Knowledge of the chemokine system has also reached a level that makes it interesting in clinics, which prompted clinical trials into compounds manipulating chemokines or their receptors. However, little attention has been devoted to understand the relations between these two systems. Here, we will review the role of inflammatory lipids and chemokines in innate and adaptive immunity with an attempt to link the two systems and with emphasis on their importance in cancer development.

Lipidomic profiling of bioactive lipids by mass spectrometry during microbial infections.

Bioactive lipid mediators play crucial roles in promoting the induction and resolution of inflammation. Eicosanoids and other related unsaturated fatty acids have long been known to induce inflammation. These signaling molecules can modulate the circulatory system and stimulate immune cell infiltration into the site of infection. Recently, DHA- and EPA-derived metabolites have been discovered to promote the resolution of inflammation, an active process. Not only do these molecules stop the further infiltration of immune cells, they prompt non-phlogistic phagocytosis of apoptotic neutrophils, stimulating the tissue to return to homeostasis. After the rapid release of lipid precursors from the plasma membrane upon stimulation, families of enzymes in a complex network metabolize them to produce a large array of lipid metabolites. With current advances in mass spectrometry, the entire lipidome can be accurately quantified to assess the immune response upon microbial infection. In this review, we discuss the various lipid metabolism pathways in the context of the immune response to microbial pathogens, as well as their complex network interactions. With the advancement of mass spectrometry, these approaches have also been used to characterize the lipid mediator response of macrophages and neutrophils upon immune stimulation in vitro. Lastly, we describe the recent efforts to apply systems biology approaches to dissect the role of lipid mediators during bacterial and viral infections in vivo.

The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor.

5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is formed from the 5-lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). The cofactor NADP(+) is a limiting factor in the synthesis of 5-oxo-ETE because of its low concentrations in unperturbed cells. Activation of the respiratory burst in phagocytic cells, oxidative stress, and cell death all dramatically elevate both intracellular NADP(+) levels and 5-oxo-ETE synthesis. 5-HEDH is widely expressed in inflammatory, structural, and tumor cells. Cells devoid of 5-lipoxygenase can synthesize 5-oxo-ETE by transcellular biosynthesis using inflammatory cell-derived 5-HETE. 5-Oxo-ETE is a chemoattractant for neutrophils, monocytes, and basophils and promotes the proliferation of tumor cells. However, its primary target appears to be the eosinophil, for which it is a highly potent chemoattractant. The actions of 5-oxo-ETE are mediated by the highly selective OXE receptor, which signals by activating various second messenger pathways through the release of the ßγ-dimer from Gi/o proteins to which it is coupled. Because of its potent effects on eosinophils, 5-oxo-ETE may be an important mediator in asthma, and, because of its proliferative effects, may also contribute to tumor progression. Selective OXE receptor antagonists, which are currently under development, could be useful therapeutic agents in asthma and other allergic diseases.