Genome-Wide Analysis Indicates a Complete Prostaglandin Pathway from Synthesis to Inactivation in Pacific White Shrimp, Litopenaeus vannamei.

Prostaglandins (PGs) play many essential roles in the development, immunity, metabolism, and reproduction of animals. In vertebrates, arachidonic acid (ARA) is generally converted to prostaglandin G2 (PGG2) and H2 (PGH2) by cyclooxygenase (COX); then, various biologically active PGs are produced through different downstream prostaglandin synthases (PGSs), while PGs are inactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). However, there is very limited knowledge of the PG biochemical pathways in invertebrates, particularly for crustaceans. In this study, nine genes involved in the prostaglandin pathway, including a COX, seven PGSs (PGES, PGES2, PGDS1/2, PGFS, AKR1C3, and TXA2S), and a PGDH were identified based on the Pacific white shrimp (Litopenaeus vannamei) genome, indicating a more complete PG pathway from synthesis to inactivation in crustaceans than in insects and mollusks. The homologous genes are conserved in amino acid sequences and structural domains, similar to those of related species. The expression patterns of these genes were further analyzed in a variety of tissues and developmental processes by RNA sequencing and quantitative real-time PCR. The mRNA expression of PGES was relatively stable in various tissues, while other genes were specifically expressed in distant tissues. During embryo development to post-larvae, COX, PGDS1, GDS2, and AKR1C3 expressions increased significantly, and increasing trends were also observed on PGES, PGDS2, and AKR1C3 at the post-molting stage. During the ovarian maturation, decreasing trends were found on PGES1, PGDS2, and PGDH in the hepatopancreas, but all gene expressions remained relatively stable in ovaries. In conclusion, this study provides basic knowledge for the synthesis and inactivation pathway of PG in crustaceans, which may contribute to the understanding of their regulatory mechanism in ontogenetic development and reproduction.

Arachidonic Acid Derivatives and Neuroinflammation.

Neuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset of several neurodegenerative disorders and is considered a typical feature of these disorders. Microglia perform primary immune surveillance and macrophage-like activities within the central nervous system. Activated microglia are predominant players in the central nervous system response to damage related to stroke, trauma, and infection. Moreover, microglial activation per se leads to a proinflammatory response and oxidative stress. During the release of cytokines and chemokines, cyclooxygenases and phospholipase A2 are stimulated. Elevated levels of these compounds play a significant role in immune cell recruitment into the brain. Cyclic phospholipase A2 plays a fundamental role in the production of prostaglandins by releasing arachidonic acid. In turn, arachidonic acid is biotransformed through different routes into several mediators that are endowed with pivotal roles in the regulation of inflammatory processes. Some experimental models of neuroinflammation exhibit an increase in cyclic phospholipase A2, leukotrienes, and prostaglandins such as prostaglandin E2, prostaglandin D2, or prostacyclin. However, findings on the role of the prostacyclin receptors have revealed that their signalling suppresses Th2-mediated inflammatory responses. In addition, other in vitro evidence suggests that prostaglandin E2 may inhibit the production of some inflammatory cytokines, attenuating inflammatory events such as mast cell degranulation or inflammatory leukotriene production. Based on these conflicting experimental data, the role of arachidonic acid derivatives in neuroinflammation remains a challenging issue.

Effects of an ω3 fatty acid-biased diet on luteolysis, parturition, and uterine prostanoid synthesis in pregnant mice.

The ω3 polyunsaturated fatty acids (PUFAs) are known to have beneficial effects on health and diseases, and hence their intake is encouraged. However, it remains unknown as to how ω3 PUFAs affect female reproduction processes, in which ω6 PUFA-derived prostaglandin (PG) E2 and PGF2α play crucial roles. We therefore compared female reproductive performance between ω3 PUFA-biased linseed oil diet-fed (Lin) mice and ω6 PUFA-biased soybean oil diet-fed (Soy) mice. In Lin mice, the uterine levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) were 0.42 fold and 16 fold of those in Soy mice, respectively, with the EPA/AA ratio being 0.7 (vs 0.02 in Soy mice). Lin mice showed no alterations in any of the fertility indexes, including luteolysis and parturition. The uterine PG synthesis profiles of Lin mice were similar to those of Soy mice, but the levels of PGF2α and PGE2 were 50% of those in Soy mice, as a result of the increased EPA/AA ratio. PGF3α and PGE3 were undetectable in the uterine tissues of Soy and Lin mice. Interestingly, in Lin mice, 'luteolytic' PGF2α synthesis was considerably maintained even in the ω6 PUFA-reduced condition. These results suggest the existence of an elaborate mechanism securing PGF2α synthesis to a level that is sufficient for triggering luteolysis and parturition, even under ω6 PUFA-reduced conditions.

Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells.

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)-mutations in which are associated with autoinflammatory disorders and Alzheimer's disease-serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.

Limitations of drug concentrations used in cell culture studies for understanding clinical responses of NSAIDs.

In this review, the in vitro cellular effects of six nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate, ibuprofen, naproxen, indomethacin, celecoxib and diclofenac, are examined. Inhibition of prostanoid synthesis in vitro generally occurs within the therapeutic range of plasma concentrations that are observed in vivo, consistent with the major action of NSAIDs being inhibition of prostanoid production. An additional probable cellular action of NSAIDs has been discovered recently, viz. decreased oxidation of the endocannabinoids, 2-arachidonoyl glycerol and arachidonyl ethanolamide. Many effects of NSAIDs, other than decreased oxidation of arachidonic acid and endocannabinoids, have been put forward but almost all of these additional processes are observed at supratherapeutic concentrations when the concentration of albumin, the major protein that binds NSAIDs, is taken into account. However, one exception is salicylate, a very potent inhibitor of the neutrophilic enzyme, myeloperoxidase, the inhibition of which leads to reduced production of the inflammatory mediator, hypochlorous acid, and inhibition of the inflammation associated with rheumatoid arthritis.

Peripheral leucocyte molecular indicators of inflammation and oxidative stress are altered in dairy cows with embryonic loss.

Objective of experiment was to determine whether oxidative stress (OS) and inflammation altered embryonic loss in dairy cows. Blood samples were collected at days 0, 16, 32 and 60 after timed (AI) from 200 Holstein cows to determine embryonic loss based on interferon-stimulated gene-15 (ISG15) mRNA expression (day 16) and ultrasound at day 32 and day 60. Leucocyte expressions of mRNA TLR2, TLR4, TNF-α, IL1B, IL10, STAT3 (inflammation), PTGS2, PTGES (prostaglandin synthesis), and PLA2G4A and ALOX5AP (eicosanoid metabolism) at days 0 and 16 were determined. Plasma redox status for antioxidant enzymatic activities of glutathione peroxidase (GPX), superoxide dismutase (SOD), total antioxidant capacity (TAC), and concentrations of malondialdehyde (MDA) were determined at days 0, 16, 32 and 60. All antioxidant-redox responses were beneficially significant in pregnant cows diagnosed pregnant at day16 and sustained pregnancy to day 60 compared to non-pregnant cows at day16 or pregnant at day16 and lost embryos by days 32 or 60. The leucocyte mRNA expressions of TLR2, TLR4, STAT 3, IL1B, PTGS2, PLA2G4A and ALOX5AP were greater and PTGES was lower at day16 in pregnant cows that lost embryos early (P < 0.05). In conclusion peripheral leucocyte molecular indicators of inflammation and plasma indicators of OS were altered in pregnant cows undergoing embryonic losses compared to cows with a sustained pregnancy.

Role of 2­series prostaglandins in the pathogenesis of type 2 diabetes mellitus and non­alcoholic fatty liver disease (Review).

Nowadays, metabolic syndromes are emerging as global epidemics, whose incidence are increasing annually. However, the efficacy of therapy does not increase proportionately with the increased morbidity. Type 2 diabetes mellitus (T2DM) and non­alcoholic fatty liver disease (NAFLD) are two common metabolic syndromes that are closely associated. The pathogenic mechanisms of T2DM and NAFLD have been studied, and it was revealed that insulin resistance, hyperglycemia, hepatic lipid accumulation and inflammation markedly contribute to the development of these two diseases. The 2­series prostaglandins (PGs), a subgroup of eicosanoids, including PGD2, PGE2, PGF2α and PGI2, are converted from arachidonic acid catalyzed by the rate­limiting enzymes cyclooxygenases (COXs). Considering their wide distribution in almost every tissue, 2­series PG pathways exert complex and interlinked effects in mediating pancreatic ß­cell function and proliferation, insulin sensitivity, fat accumulation and lipolysis, as well as inflammatory processes. Previous studies have revealed that metabolic disturbances, such as hyperglycemia and hyperlipidemia, can be improved by treatment with COX inhibitors. At present, an accumulating number of studies have focused on the roles of 2­series PGs and their metabolites in the pathogenesis of metabolic syndromes, particularly T2DM and NAFLD. In the present review, the role of 2­series PGs in the highly intertwined pathogenic mechanisms of T2DM and NAFLD was discussed, and important therapeutic strategies based on targeting 2­series PG pathways in T2DM and NAFLD treatment were provided.

Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism.

The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.

Prostaglandin production by the microalga with heterologous expression of cyclooxygenase.

Prostaglandins (PGs) are the physiologically active compounds synthesized from C20 polyunsaturated fatty acids (PUFAs) by cyclooxygenase (COX) and a series of PG synthases, and are utilized as pharmaceuticals. Currently, commercialized PGs are mainly produced by chemical synthesis under harsh conditions. By contrast, bioproduction of PGs can be an alternative, environmental-friendly, and inexpensive process with genetic engineering of model plants, although these conventional host organisms contain a limited quantity of PG precursors. In this study, we established an efficient PG production process using the genetically engineered microalga Fistulifera solaris which is rich in C20 PUFAs. A cox gene derived from the red alga Agarophyton vermiculophyllum was introduced into F. solaris. As a result, a transformant clone with high cox expression produced PGs (i.e., PGD2 , PGE2 , PGF2α , and 15-ketoPGF2α derived from arachidonic acid, and PGD3 , PGE3 , and PGF3α derived from eicosapentaenoic acid) as revealed by liquid chromatography/mass spectrometry. The total content of PGs was 1290.4 ng/g of dry cell weight, which was higher than that produced in the transgenic plant reported previously. The results obtained in this study indicate that the C20 PUFA-rich microalga functionally expressing COX is a promising host for PG bioproduction.

Mechanisms of TGFß in prostaglandin synthesis and sperm guidance in Caenorhabditis elegans.

BACKGROUND: The transparent epidermis of Caenorhabditis elegans makes it an attractive model to study sperm motility and migration within an intact reproductive tract. C elegans synthesize specific F-series prostaglandins (PGFs) that are important for guiding sperm toward the spermatheca. These PGFs are synthesized from polyunsaturated fatty acid (PUFA) precursors, such as arachidonic acid (AA), via a novel pathway, independent of the classical cyclooxygenases (Cox) responsible for most PG synthesis. While the enzyme(s) responsible for PG synthesis has yet to be identified, the DAF-7 TGFß pathway has been implicated in modulating PG levels and sperm guidance. RESULTS: We find that the reduced PGF levels in daf-1 type I receptor mutants are responsible for the sperm guidance defect. The lower level of PGs in daf-1 mutants is due in part to the inaccessibility of AA. Finally, lipid analysis and assessment of sperm guidance in daf-1;daf-3 double mutants suggest DAF-3 suppresses PG production and sperm accumulation at the spermatheca. Our data suggest that DAF-3 functions in the nervous system, and possibly the germline, to affect sperm guidance. CONCLUSION: The C elegans TGFß pathway regulates many pathways to modulate PG metabolism and sperm guidance. These pathways likely function in the nervous system and possibly the germline.

Protective activities of distinct omega-3 enriched oils are linked to their ability to upregulate specialized pro-resolving mediators.

Clinical studies using a range of omega-3 supplements have yielded conflicting results on their efficacy to control inflammation. Omega-3 fatty acids are substrate for the formation of potent immune-protective mediators, termed as specialized pro-resolving mediators (SPM). Herein, we investigated whether observed differences in the potencies of distinct omega-3 supplements were linked with their ability to upregulate SPM formation. Using lipid mediator profiling we found that four commercially available supplements conferred a unique SPM signature profile to human macrophages, with the overall increases in SPM concentrations being different between the four supplements. These increases in SPM concentrations were linked with an upregulation of macrophage phagocytosis and a decreased uptake of oxidized low-density lipoproteins. Pharmacological inhibition of two key SPM biosynthetic enzymes 5-Lipoxygenase or 15-Lipoxygenase reversed the macrophage-directed actions of each of the omega-3 supplements. Furthermore, administration of the two supplements that most potently upregulated macrophage SPM formation and reprogrammed their responses in vitro, to APOE-/- mice fed a western diet, increased plasma SPM concentrations and reduced vascular inflammation. Together these findings support the utility of SPM as potential prognostic markers in determining the utility of a given supplement to regulate macrophage responses and inflammation.

Role and Regulation of Mechanotransductive HIF-1α Stabilisation in Periodontal Ligament Fibroblasts.

Orthodontic tooth movement (OTM) creates compressive and tensile strain in the periodontal ligament, causing circulation disorders. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be primarily stabilised by compression, but not hypoxia in periodontal ligament fibroblasts (PDLF) during mechanical strain, which are key regulators of OTM. This study aimed to elucidate the role of heparan sulfate integrin interaction and downstream kinase phosphorylation for HIF-1α stabilisation under compressive and tensile strain and to which extent downstream synthesis of VEGF and prostaglandins is HIF-1α-dependent in a model of simulated OTM in PDLF. PDLF were subjected to compressive or tensile strain for 48 h. In various setups HIF-1α was experimentally stabilised (DMOG) or destabilised (YC-1) and mechanotransduction was inhibited by surfen and genistein. We found that HIF-1α was not stabilised by tensile, but rather by compressive strain. HIF-1α stabilisation had an inductive effect on prostaglandin and VEGF synthesis. As expected, HIF-1α destabilisation reduced VEGF expression, whereas prostaglandin synthesis was increased. Inhibition of integrin mechanotransduction via surfen or genistein prevented stabilisation of HIF-1α. A decrease in VEGF expression was observed, but not in prostaglandin synthesis. Stabilisation of HIF-1α via integrin mechanotransduction and downstream phosphorylation of kinases seems to be essential for the induction of VEGF, but not prostaglandin synthesis by PDLF during compressive (but not tensile) orthodontic strain.

A paracrine effect of 15 (S)-hydroxyeicosatetraenoic acid revealed in prostaglandin production by human follicular dendritic cell-like cells.

Lipid mediators play active roles in each stage of inflammation under physiological and pathologic conditions. We have investigated the cellular source and functions of several prostanoids in the immune inflammatory responses using follicular dendritic cell (FDC)-like cells. In this study, we report a novel finding on the role of 15(S)- hydroxyeicosatetraenoic acid (HETE). Our observation of 15(S)-HETE uptake by FDC-like cells prompted to hypothesize that 15(S)-HETE might have a regulatory role in the other branch of eicosanoid production. The effects of 15(S)-HETE on COX-2 expression and prostaglandin (PG) production were analyzed by immunoblotting and specific enzyme immunoassays. The addition of 15(S)-HETE resulted in elevated levels of COX-2 expression and PG production. The enhanced PG production was not due to growth stimulation of FDC-like cells since 15(S)-HETE did not modulate FDC-like cell proliferation by the culture period of PG measurement. Peroxisome proliferator-activated receptor gamma (PPARγ) seems to mediate the augmenting activity as the antagonist GW9662 dose- dependently prevented 15(S)-HETE from increasing PG production. In addition, PPARγ protein expression was readily detected in FDC-like cells. These effects of 15(S)-HETE were displayed in the combined addition with IL-1ß. Based on these results, we suggest that 15(S)-HETE is an inflammatory costimulator of FDC acting in a paracrine fashion.

Primary Dysmenorrhea: Diagnosis and Therapy.

Primary dysmenorrhea is defined as pain during the menstrual cycle in the absence of an identifiable cause. It is one of the most common causes of pelvic pain in women. Dysmenorrhea can negatively affect a woman's quality of life and interfere with daily activities. The pathophysiology of primary dysmenorrhea is likely a result of the cyclooxygenase pathway producing increased prostanoids, particularly prostaglandins (PGs). The increased PGs cause uterine contractions that restrict blood flow and lead to the production of anaerobic metabolites that stimulate pain receptors. Women with a history typical for primary dysmenorrhea can initiate empiric treatment without additional testing. Shared decision making is key to effective management of dysmenorrhea to maximize patient compliance and satisfaction. After a discussion of their risks and benefits, extremely effective empiric therapies are nonsteroidal antiinflammatory drugs and contraceptive hormonal therapy. Other treatments for primary dysmenorrhea can be employed solely or in combination with other modalities, but the literature supporting their use is not as convincing. The physician should initiate an evaluation for secondary dysmenorrhea if the patient does not report improved symptomatology after being compliant with their medical regimen.

Polychaete consumption increased prostaglandin biosynthesis in female Penaeus monodon.

The polychaete Perinereis nuntia is preferred over commercial feed pellets for boosting ovarian maturation of the female black tiger shrimp Penaeus monodon. High levels of prostaglandins in polychaetes are believed to enhance shrimp ovarian development. However, the impact of polychaete feeding on shrimp prostaglandin biosynthesis and fatty acid regulatory pathways have yet to be investigated. As polychaetes contain higher levels of arachidonic acid (ARA), eicosapentaenoic acid (EPA), prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) than feed pellets, we examined the effects of polychaete feeding alone and in combination with eyestalk ablation on shrimp hepatopancreases and ovaries. Shrimp fed with polychaetes contained higher levels of EPA, PGE2 and PGF2α in hepatopancreases than those of pellet-fed shrimp. Similarly, higher levels of ARA and higher transcription levels of cyclooxygenase (COX) and prostaglandin F synthase (PGFS) were detected in ovaries of polychaete-fed shrimp compared to those of pellet-fed shrimp. The combination of polychaete-feeding and eyestalk ablation, commonly practiced to induce ovarian development, increased levels of ARA and EPA and transcription levels of COX in hepatopancreases and ovaries of polychaete-fed shrimp compared to those of pellet-fed shrimp. In ovaries, prostaglandin biosynthesis gene transcripts were induced by polychaete feeding while transcriptional levels of fatty acid regulatory genes were regulated by shrimp feed and eyestalk ablation. Our findings not only elucidate the effects of polychaete consumption on shrimp prostaglandin biosynthesis and fatty acid regulatory pathways during larvae production, but also suggests that high levels of dietary ARA, EPA and prostaglandins are essential during P. monodon ovarian development.

What about COVID-19 and arachidonic acid pathway?

BACKGROUND AND OBJECTIVE: COVID-19 is a highly contagious viral disease. In this study, we tried to define and discuss all the findings on the potential association between arachidonic acid (AA) pathway and COVID-19 pathophysiology. METHODS: A literature search across PubMed, Scopus, Embase, and Cochrane database was conducted. A total of 25 studies were identified. RESULTS: The data elucidated that COX-2 and prostaglandins (PGs), particularly PGE2, have pro-inflammatory action in COVID-19 pathophysiology. Arachidonic acid can act as endogenous antiviral compound. A deficiency in AA can make humans more susceptible to COVID-19. Targeting these pro-inflammatory mediators may help in decreasing the mortality and morbidity rate in COVID-19 patients. CONCLUSIONS: PGE2 levels and other PGs levels should be measured in patients with COVID-19. Lowering the PGE2 levels through inhibition of human microsomal prostaglandin E synthase-1 (mPGES-1) can enhance the host immune response against COVID-19. In addition, the hybrid compounds, such as COX-2 inhibitors/TP antagonists, can be an innovative treatment to control the overall balance between AA mediators in patients with COVID-19.

The enzymology of the human prostanoid pathway.

Prostanoids are short-lived autocrine and paracrine signaling molecules involved in a wide range of biological functions. They have been shown to be intimately involved in many different disease states when their regulation becomes dysfunctional. In order to fully understand the progression of any disease state or the biological functions of the well state, a complete evaluation of the genomics, proteomics, and metabolomics of the system is necessary. This review is focused on the enzymology for the enzymes involved in the synthesis of the prostanoids (prostaglandins, prostacyclins and thromboxanes). In particular, the isolation and purification of the enzymes, their enzymatic parameters and catalytic mechanisms are presented.

Cardiovascular Biology of Prostanoids and Drug Discovery.

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE2 critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.

Mammalian-Like Inflammatory and Pro-Resolving Oxylipins in Marine Algae.

Oxylipins constitute a family of oxidized fatty acids, that are well known as tissue hormones in mammals. They contribute to inflammation and its resolution. The major classes of these lipid mediators are inflammatory prostaglandins (PGs) and leukotrienes (LTs) as well as pro-resolving resolvins (Rvs). Understanding their biosynthetic pathways and modes of action is important for anti-inflammatory interventions. Besides mammals, marine algae also biosynthesize mammalian-like oxylipins and thus offer new opportunities for oxylipin research. They provide prolific sources for these compounds and offer unique opportunities to study alternative biosynthetic pathways to the well-known lipid mediators. Herein, we discuss recent findings on the biosynthesis of oxylipins in mammals and algae including an alternative pathway to prostaglandin E2 , a novel pathway to a precursor of leukotriene B4 , and the production of resolvins in algae. We evaluate the pharmacological potential of the algal metabolites with implications in health and disease.

Differential role of vacuolar (H+)-ATPase in the expression and activity of cyclooxygenase-2 in human monocytes.

Monocytes are professional immune cells that produce abundant levels of pro-inflammatory eicosanoids including prostaglandins and leukotrienes during inflammation. Vacuolar (H+)-ATPase (V-ATPase) is critically involved in a variety of inflammatory processes including cytokine trafficking and lipid mediator biosynthesis. However, its role in eicosanoid biosynthetic pathways in monocytes remains elusive. Here, we present a differential role of V-ATPase in the expression and in the activity of cyclooxygenase (COX)-2 in human monocytes. Pharmacological targeting of V-ATPase increased the expression of COX-2 protein in lipopolysaccharide-stimulated primary monocytes, which was paralleled by enhanced phosphorylation of p38 MAPK and ERK-1/2, without impacting the NF-κB and SAPK/JNK pathways. Targeting of both p38 MAPK and ERK-1/2 pathways showed that the kinase pathways are crucial for COX-2 expression in human monocytes. Despite increased COX-2 protein levels, however, suppression of V-ATPase activity impaired the biosynthesis of COX- and also of 5-lipoxygenase (LOX)-derived lipid mediators in monocytes without affecting 12-/15-LOX products, assessed by a metabololipidomics approach using UPLC-MS-MS analysis. Our results indicate that changes in the intracellular pH may contribute to suppression of COX-2 and 5-LOX activities. We suggest that V-ATPase on one hand limits COX-2 protein levels via restricting p38 MAPK and ERK-1/2 activation, while on the other hand it governs the cellular activity of COX-2 through appropriate adjustment of the intracellular pH.