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In mammalian cells, reactive oxygen species (ROS) are produced via a variety of cellular oxidative processes, including the activity of NADPH oxidases (NOX), the activity of xanthine oxidases, the metabolism of arachidonic acid (AA) by lipoxygenases (LOX) and cyclooxygenases (COX), and the mitochondrial respiratory chain. Although NOX-generated ROS are the best characterized examples of ROS in mammalian cells, ROS are also generated by the oxidative metabolism (e.g., via LOX and COX) of AA that is released from the membrane phospholipids via the activity of cytosolic phospholipase A₂ (cPLA₂). Recently, growing evidence suggests that LOX- and COX-generated AA metabolites can induce ROS generation by stimulating NOX and that a potential signaling connection exits between the LOX/COX metabolites and NOX. In this review, we discuss the results of recent studies that report the generation of ROS by LOX metabolites, especially 5-LOX metabolites, via NOX stimulation. In particular, we have focused on the contribution of leukotriene B₄ (LTB₄), a potent bioactive eicosanoid that is derived from 5-LOX, and its receptors, BLT1 and BLT2, to NOX stimulation through a signaling mechanism that leads to ROS generation.

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-delta(12,14)-prostaglandin J2 have been shown to bind to PPARgamma, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated G2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 us a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARalpha and PPARgamma at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-delta(12,14)-prostaglandin J2 can function as subtype-selective ligands for PPARalpha and PPARgamma, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis

Oxidative stress and inflammation are supposed to be the key players of several acute and chronic diseases, and also for progressive aging process. Eicosanoids, especially prostaglandin F∧2α (PGF∧2α) and F₂-isoprostanes are endogenous compounds that are involved both in physiology and the above mentioned pathologies. These compounds are biosynthesized mainly from esterified arachidonic acid through both enzymatic and non-enzymatic free radical-catalysed reactions in vivo, respectively. They have shown to possess potent biological activities in addition to their application as biomarkers of oxidative stress and inflammation. Recent advancement of methodologies has made it possible to quantify these compounds more reliably and apply them in various in vivo studies successfully. Today, experimental and clinical studies have revealed that both PGF∧2α and F₂-isoprostanes are involved in severe acute or chronic inflammatory conditions such as rheumatic diseases, asthma, risk factors of atherosclerosis, diabetes, ischemia-reperfusion, septic shock and many others. These evidences promote that assessment of bioactive PGF∧2α and F₂-isoprostanes simultaneously in body fluids offers unique non-invasive analytical opportunity to study the function of these eicosanoids in physiology, oxidative stress-related and inflammatory diseases, and also in the determination of potency of various radical scavengers, anti-inflammatory compounds, drugs, antioxidants and diet.

Calder describes the effects of the amount and type of fat in the diet on lymphocyte proliferation, lumphocyte-mediated cytotoxicity, antigen presentation and cytokine production.

An entomopathogenic fungus, Nomuraea rileyi, was isolated and its identity was confirmed by its internal transcribed spacer DNA sequence. The isolated N. rileyi exhibited a specific pathogenicity to lepidopteran species. This study was focused on enhancing the fungal pathogenicity by using immunosuppressive agents. In response to infection of N. rileyi, Spodoptera exigua larvae significantly induced catalytic activity of phospholipase A₂ (PLA₂) in three immune-associated tissues, namely hemocytes, fat body, and hemolymph plasma. Furthermore, the infected S. exigua larvae induced transcription of several antimicrobial peptide (AMP) genes. Two entomopathogenic bacteria, Xenorhabdus nematophila (Xn) and Photorhabdus temperata subsp. temperata (Ptt), possessed specific PLA₂-inhibitory activities and their culture broths significantly inhibited the enzyme activities in hemocytes, fat body, and plasma of S. exigua. In addition, the bacterial metabolites inhibited transcription of AMP genes in S. exigua that would normally respond to the immune challenge by N. rileyi. The immunosuppressive effect of Xn or Ptt bacterial broth resulted in significant enhancement of the fungal pathogenicity against late instar larvae of S. exigua and Plutella xylostella. The effect of such a mixture was confirmed by field assay against two lepidopteran species. These results suggest that the bacterial and fungal mixture can be applied to develop a novel biopesticide to control lepidopteran species.

A pathogenic (biological or chemical) stimulus is the earliest information received by a cell that can result in the disruption of homeostasis with consequent development of disease. Chronic inflammation involves many cell types with numerous cytokines and signaling pathways, the release of different components by the cells, and the crosstalk provoked by such stimuli involving subclinical chronic inflammation and is mechanistically manifold. Exosomes secrete chemicals that trigger the epithelium to produce exosome-like nanoparticles promoting chronic inflammation. Small molecules, together with various cytokines, selectively target signaling pathways inducing crosstalk that suppress apoptosis. 16S rRNA gene sequencing has become routine to provide information on the composition and abundance of bacteria found in human tissues and in reservoirs. The deregulation of autophagy with chronic stimulation of inflammation is an early phenomenon in carcinogenesis. The disruption of cell–cell integrity enables transcellular CagA migration and triggers deregulation of autophagy with the net result being chronic inflammation. The complex and insidious nature of chronic inflammation can be seen both inside and outside the cell and even with intracellular nuclear fragments such as chromatin, which itself can elicit a chronic inflammatory response within the cytoplasm and affect autophagy. The ultimate result of unresolved chronic inflammation is fibrosis, a step before tissue remodeling results in the formation of a precancerous niche (PCN). Various pathogenic stimuli associated with different neoplasms result in persistent inflammation. This ongoing disruption of homeostasis in the micromilieu of cells, tissues, and organs is an essential preamble to carcinogenesis and occurs early in that process.

Data on the effect of dietary arachidonic acid (AA) (20∶4n‐6) on the synthesis of thromboxane and prostacyclin (PGI2) in humans are lacking. We measured the effect of 1.5 g/d (ca. 0.5 en%) of 20∶4n‐6 added isocalorically to a stabilization (low‐AA) diet on the excretion of 11‐dehydrothromboxane B2 (11‐DTXB2) and 2,3‐dinor‐6‐oxo‐PGF1α (PGI2‐M). In a crossover design, 10 healthy men, living in a metabolic unit, were fed a diet (low‐AA) containing 210 mg/d of 20∶4n‐6 for 65 d and an identical diet (high‐AA) that contained 1.5 g/d of additional 20∶4n‐6 for 50 d. Three‐day urine pools were collected at the end of each dietary period and analyzed for eicosanoids by gas chromatography‐electron capture negative ion‐tandem mass spectrometry. Mean excretion of 11‐dehydrothromboxane B2 was 515±76, 493±154, and 696±144 ng/d (SD; n=10) during the acclimation (15 d) low‐AA diet and high‐AA diet periods, respectively (41% increase from low‐AA to high‐AA diet, P=0.0037); mean excretion of PGI2‐M was 125±40, 151±36, and 192±55 ng/d (SD; n=10) during acclimation (15 d) low‐AA and high‐AA diets, respectively (27% increase from low‐AA to high‐AA diets; P=0.0143). Thus, both the metabolites of thromboxane and PGI2 increase on the high‐AA diet. Furthermore, both indicated changes in metabolite excretion may be associated with measurable effects on several physiologically significant cellular functions, such as platelet aggregation in vivo and inflammation in response to immune challenges.

The effect of tea polyphenols on the release of chemical mediators, histamine and leukotriene B₄ (LTB₄), from rat peritoneal exudate cells (PEC) was studied. Among polyphenols, (-)-epigallocatechin gallate (EGCG) most strongly inhibited the histamine release from the cells stimulated with a calcium ionophore, A23187 or compound 48/80. Though (+)-catechin (C) and (-)-epicatechin (EC) had no effect, (-)-epigallocatechin (EGC) and (-)-epicatechin gallate (ECG) moderately inhibited the histamine release. Similarly, EGCG, ECG, and EGC inhibited LTB₄ release from PEC, whereas C and EC were not effective. The magnitude of the inhibitory effect on the release of these mediators of tea polyphenols was in the order of EGCG > ECG > EGC. These results indicated an important role of the triphenol structure in the inhibitory activity. Therefore, the possible antiallergic effect of tea polyphenols can be expected.

6,9,12,15,18‐Heneicosapentaenoic acid (21:5n‐3) (HPA), present in small amounts in fish oils, has been prepared by chemical elongation of eicosapentaenoic acid (EPA) and its biological properties compared with EPA and docosahexaenoic acid (DHA). All the double bonds of HPA are displaced one carbon away from the carboxyl group when compared to EPA. HPA is incorporated into phospholipids and into triacylglycerol in cell culture to a similar extent as EPA and DHA. HPA is a stronger inhibitor of the conversion of α‐linoleic acid and dihomo‐γ‐linolenic acid to arachidonic acid (AA) in hepatoma cells than are EPA, DHA, and AA. HPA is a poor substrate for prostaglandin H synthase and for 5‐lipoxygenase, but it inactivates prostaglandin H synthase as rapidly as do AA, EPA, and DHA. HPA inhibits thromboxane synthesis in isolated platelets as efficiently as EPA. EPA, HPA, and DHA are all weak inducers of acyl‐CoA oxidase in hepatoma cells. Therefore, since fish oils contain only small amounts of HPA, it is unlikely that this fatty acid is of particular significance for the biological effects of these oils, possibly with the exception that it is a strong inhibitor of AA synthesis.

The boreoarctic barnacle, Semibalanus balanoides (= Balanus balanoides) (L.), has the ability to synchronize the release of its nauplii with the spring phytoplankton bloom, thereby ensuring that the larvae can start their planktotrophic development successfully. Hatching is induced by an egg-hatching pheromone (an hydroxy fatty acid) released by the adult. Here, the possibility that the pheromone is an excretory metabolite of dietary eicosapentaenoic acid (EPA) is examined. Egg hatching could be induced by feeding gravid adult barnacles on Skeletonema costatum, but neither a concentrated culture of this diatom nor cell-free culture medium induced egg hatching in vitro. Following a 15-min incubation of EPA in seawater, a product with egg hatching activity was obtained, presumably by autooxidation. Egg hatching was not induced by feeding barnacles with lecithin liposomes containing EPA. Likewise, radiolabeled egg-hatching pheromone was not released by adult barnacles that had been fed with [14C]EPA liposomes. Egg-hatching pheromone was not released by barnacles that were actively feeding on S. costatum prior to egg-hatching. The production of egg-hatching pheromone was inhibited in vitro and in vivo by lipoxygenase inhibitors. Taken together, the results suggest that egg-hatching pheromone is not an excretory metabolite but is derived from EPA released from membrane phospholipid and acted upon by a lipoxygenase. The nature of the stimulus to precursor fatty acid release has yet to be established, but a link with molting appears tenuous