Involvement Of Eicosanoids Research Articles

An adaptable in silico ensemble model of the arachidonic acid cascade.

Eicosanoids are a family of bioactive lipids, including derivatives of the ubiquitous fatty acid arachidonic acid (AA). The intimate involvement of eicosanoids in inflammation motivates the development of predictive in silico models for a systems-level exploration of disease mechanisms, drug development and replacement of animal models. Using an ensemble modelling strategy, we developed a computational model of the AA cascade. This approach allows the visualisation of plausible and thermodynamically feasible predictions, overcoming the limitations of fixed-parameter modelling. A quality scoring method was developed to quantify the accuracy of ensemble predictions relative to experimental data, measuring the overall uncertainty of the process. Monte Carlo ensemble modelling was used to quantify the prediction confidence levels. Model applicability was demonstrated using mass spectrometry mediator lipidomics to measure eicosanoids produced by HaCaT epidermal keratinocytes and 46BR.1N dermal fibroblasts, treated with stimuli (calcium ionophore A23187), (ultraviolet radiation, adenosine triphosphate) and a cyclooxygenase inhibitor (indomethacin). Experimentation and predictions were in good qualitative agreement, demonstrating the ability of the model to be adapted to cell types exhibiting differences in AA release and enzyme concentration profiles. The quantitative agreement between experimental and predicted outputs could be improved by expanding network topology to include additional reactions. Overall, our approach generated an adaptable, tuneable ensemble model of the AA cascade that can be tailored to represent different cell types and demonstrated that the integration of in silico and in vitro methods can facilitate a greater understanding of complex biological networks such as the AA cascade.

Eicosanoids Signals in SARS-CoV-2 Infection: A Foe or Friend.

SARS-CoV-2 mediated infection instigated a scary pandemic state since 2019. They created havoc comprising death, imbalanced social structures, and a wrecked global economy. During infection, the inflammation and associated cytokine storm generate a critical pathological situation in the human body, especially in the lungs. By the passage of time of infection, inflammatory disorders, and multiple organ damage happen which might lead to death, if not treated properly. Until now, many pathological parameters have been used to understand the progress of the severity of COVID-19 but with limited success. Bioactive lipid mediators have the potential of initiating and resolving inflammation in any disease. The connection between lipid storm and inflammatory states of SARS-CoV-2 infection has surfaced and got importance to understand and mitigate the pathological states of COVID-19. As the role of eicosanoids in COVID-19 infection is not well defined, available information regarding this issue has been accumulated to address the possible network of eicosanoids related to the initiation of inflammation, promotion of cytokine storm, and resolution of inflammation, and highlight possible strategies for treatment and drug discovery related to SARS-CoV-2 infection in this study. Understanding the involvement of eicosanoids in exploration of cellular events provoked by SARS-CoV-2 infection has been summarized as an important factor to deescalate any upcoming catastrophe imposed by the lethal variants of this micro-monster. Additionally, this study also recognized the eicosanoid based drug discovery, treatment, and strategies for managing the severity of SARS-COV-2 infection.

Understanding modulations of lipid mediators in cancer using a murine model of carcinomatous peritonitis.

BackgroundNumerous studies have investigated the possible involvement of eicosanoids, lysophospholipids, and sphingolipids in cancer. We considered that comprehensive measurement of these lipid mediators might provide a better understanding of their involvement in the pathogenesis of cancer. In the present study, we attempted to elucidate the modulations of sphingolipids, lysophospholipids, diacyl‐phospholipids, eicosanoids, and related mediators in cancer by measuring their levels simultaneously by a liquid chromatography‐mass spectrometry method in a mouse model of carcinomatous peritonitis.MethodsWe investigated the modulations of these lipids in both ascitic fluid and plasma specimens obtained from Balb/c mice injected intraperitoneally with Colon‐26 cells, as well as the modulations of the lipid contents in the cancer cells obtained from the tumor xenografts.ResultsThe results were as follows: the levels of sphingosine 1‐phosphate were increased, while those of lysophosphatidic acid (LysoPA), especially unsaturated long‐chain LysoPA, tended to be increased, in the ascitic fluid. Our findings suggested that ceramides, sphingomyelin, and phosphatidylcholine, their precursors, were supplied by both de novo synthesis and from elsewhere in the body. The levels of lysophosphatidylserine (LysoPS), lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidylethanolamine were also increased in the ascitic fluid, while those of phosphatidylserine (PS), a precursor of LysoPS, were markedly decreased. The levels of arachidonic acid derivatives, especially PGE2‐related metabolites, were increased, while the plasma levels of eicosanoids and related mediators were decreased. Comprehensive statistical analyses mainly identified PS in the ascitic fluid and eicosanoids in the plasma as having highly negative predictive values for cancer.ConclusionsThe results proposed many unknown associations of lipid mediators with cancer, underscoring the need for further studies. In particular, the PS/LysoPS pathway could be a novel therapeutic target, and plasma eicosanoids could be useful biomarkers for cancer.

Trisomy 21 impairs PGE2 production in dermal fibroblasts

The triplication of human chromosome 21 results in Down syndrome (DS), the most common genetic form of intellectual disability. This aneuploid condition also results in an enhanced risk of a spectrum of comorbid conditions, such as leukemia, early onset Alzheimer’s disease, and diabetes. Individuals with DS also display an increased incidence of wound healing complications and resistance to solid tumor development. Due to this unique phenotype and the involvement of eicosanoids in key comorbidities like poor healing and tumor development, we hypothesized that cells from DS individuals would display altered eicosanoid production. Using age- and sex-matched dermal fibroblasts we interrogated this hypothesis. Briefly, assessment of over 90 metabolites derived from cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome p450 systems revealed a possible deficiency in the COX system. Basal gene expression and Western blotting experiments showed significantly decreased gene expression of COX1 and 2, and COX2 protein abundance in DS fibroblasts compared to euploid controls. Further, using two different stressors, scratch wound or LPS, we found that DS fibroblasts could not upregulate COX2 abundance and prostaglandin E2 production. Together, these findings show that dermal fibroblasts from DS individuals have a deficient COX2 response, which may contribute to wound healing complications and tumor resistance in DS.

Eicosanoids and Oxidative Stress in Diabetic Retinopathy.

Oxidative stress is an important factor to cause the pathogenesis of diabetic retinopathy (DR) because the retina has high vascularization and long-time light exposition. Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes can convert arachidonic acid (AA) into eicosanoids, which are important lipid mediators to regulate DR development. COX-derived metabolites appear to be significant factors causative to oxidative stress and retinal microvascular dysfunction. Several elegant studies have unraveled the importance of LOX-derived eicosanoids, including LTs and HETEs, to oxidative stress and retinal microvascular dysfunction. The role of CYP eicosanoids in DR is yet to be explored. There is clear evidence that CYP-derived epoxyeicosatrienoic acids (EETs) have detrimental effects on the retina. Our recent study showed that the renin-angiotensin system (RAS) activation augments retinal soluble epoxide hydrolase (sEH), a crucial enzyme degrading EETs. Our findings suggest that EETs blockade can enhance the ability of RAS blockade to prevent or mitigate microvascular damage in DR. This review will focus on the critical information related the function of these eicosanoids in the retina, the interaction between eicosanoids and reactive oxygen species (ROS), and the involvement of eicosanoids in DR. We also identify potential targets for the treatment of DR.

Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4

BackgroundSuccinate is a Krebs cycle intermediate whose formation is enhanced under metabolic stress, and for which a selective sensor GPR91 has been identified on various cell types including platelets. Platelet‐derived eicosanoids play pivotal roles in platelet activation/aggregation, which is key to thrombus formation and progression of atherothrombosis. ObjectivesThis study aims to decipher the molecular mechanism(s) and potential involvement of eicosanoids in succinate enhanced platelet activation/aggregation. MethodsWe used liquid chromatography‐mass spectrometry (LC‐MS)/MS‐based lipid mediator profiling to identify eicosanoids regulated by succinate. We ran light transmittance aggregometry and flow cytometry to assess platelet aggregation, P‐selectin expression, and platelet‐polymorphonuclear leukocyte (PMN) adherence. Various pharmacological tools were used to assess the contributions of GPR91 signalling and eicosanoids in platelet aggregation. ResultsSuccinate and two types of synthetic non‐metabolite GPR91 agonists—cis‐epoxysuccinate (cES) and Cmpd131—potentiated platelet aggregation, which was partially blocked by a selective GPR91 antagonist XT1. GPR91 activation increased production of 12‐hydroxy‐eicosatetraenoic acid (12‐HETE), thromboxane (TX) A2, and 12‐hydroxy‐heptadecatrienoic acid (12‐HHT) in human platelets, associated with phosphorylation of cytosolic phospholipase A2 (cPLA2), suggesting increased availability of free arachidonic acid. Blocking 12‐HETE and TXA2 synthesis, or antagonism of the TXA2 receptor, significantly reduced platelet aggregation enhanced by GPR91 signalling. Moreover, platelet‐PMN suspensions challenged with succinate exhibited enhanced transcellular biosynthesis of leukotriene C4 (LTC4), a powerful proinflammatory vascular spasmogen. ConclusionSuccinate signals through GPR91 to promote biosynthesis of eicosanoids, which contribute to platelet aggregation/activation and potentially vascular inflammation. Hence, GPR91 may be a suitable target for pharmacological intervention in atherothrombotic conditions.

Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury.

Ischemia, lack of blood flow, and reperfusion, return of blood flow, are a common phenomenon affecting millions of Americans each year. Roughly 30,000 Americans per year experience intestinal ischemia-reperfusion (IR), which is associated with a high mortality rate. Previous studies of the intestine established a role for neutrophils, eicosanoids, the complement system and naturally occurring antibodies in IR-induced pathology. Furthermore, data indicate involvement of a lipid or lipid-like moiety in mediating IR-induced damage. It has been proposed that antibodies recognize exposure of neo-antigens, triggering action of the complement cascade. While it is evident that the pathophysiology of IR-induced injury is complex and multi-factorial, we focus this review on the involvement of eicosanoids, phospholipids and neo-antigens in the early pathogenesis. Lipid changes occurring in response to IR, neo-antigens exposed and the role of a phospholipid transporter, phospholipid scramblase 1 will be discussed.

Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase.

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

Mechanisms of Involvement of Eicosanoids and their Precursors in the Pathophysiology and Treatment of Schizophrenia

The pathophysiology of schizophrenia has not been fully elucidated but there are converging leads to understanding this complex psychiatric disorder. One family of molecules that may play a crucial role in the development of schizophrenia is the eicosanoids. Review of the literature on eicosanoids in patients with schizophrenia points to findings in three areas: precursor molecules such as polyunsaturated fatty acids (PUFAs) and specifically arachidonic acid (AA), the actions of specific eicosanoids such as thromboxane A2 (TxA2), thromboxane B2 (TxB2) and prostaglandin E2 (PGE2), and enzymes with important functions in eicosanoid metabolism such as cyclooxygenase 2 (COX-2). It has also been found that classical as well as second generation antipsychotics, drugs used to treat schizophrenia, influence eicosanoid metabolism. For example, clozapine and its metabolite N-desmethylclozapine (NDMC) decreased TxB2 production in vitro. Eicosanoids and the enzymes involved in their metabolism may provide novel future drug targets. Therapeutic response to COX-2 inhibitors has already been demonstrated in patients at an early stage of schizophrenia. COX-2 inhibitors may exert this therapeutic action through their effects in reducing PGE2, type-2 cytokine and kynurenic acid production and strengthening glutamatergic neurotransmission.

Effects of the Experimental Subarachnoid Hemorrhage on the Eicosanoid Receptors in Nicotine-induced Contraction of the Rat Basilar Artery

Smoking is one of the most important risk factors for subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the influence of experimental SAH and arachidonic acid metabolites on nicotine-induced contraction in the rat basilar artery. Rats were killed at 1 hour and 1 week after SAH, and the basilar artery was isolated and cut into a spiral strip. The effects of various eicosanoid receptor antagonists on nicotine-induced contraction in the rat basilar artery were investigated. Antagonists of thromboxane A2 (TXA2) and cysteinyl leukotriene (CysLT) receptors did not affect nicotine-induced contraction. In contrast, the antagonists of leukotriene B4 (LTB4) receptors (BLT1 and BLT2) attenuated the nicotine-induced contraction in the rat basilar artery. We also observed that SAH did not influence the effect of TXA2, LTB4, and CysLTs receptor antagonists on the nicotine-induced contraction. These results suggest that TXA2 and CysLTs are not involved in nicotine-induced contraction, while LTB4 potentates this contraction in rat basilar artery. BLT2 receptor seemed to be more involved in the nicotine-induced contraction than the BLT1 receptor. SAH did not affect the involvement of eicosanoids in the nicotine-induced contraction of the rat basilar artery. The present study shows the involvement of some of the arachidonic acid metabolites into signaling pathways of nicotine-induced contraction. It will serve to improve therapeutic interventions of SAH and suggests a promising approach to protect the cerebral vasculature of cigarette smokers.

Clotting Factors and Eicosanoids Protect against Nematode Infections

We show that hemolymph clotting protects Drosophila melanogaster against infections with an entomopathogenic nematode and its symbiotic bacterium. We also provide biochemical and genetic evidence for an involvement of eicosanoids in the same infection model. Taken together, our results confirm the conserved nature of the immune function of clot formation.

Lipidomic Analysis of Dynamic Eicosanoid Responses during the Induction and Resolution of Lyme Arthritis

Eicosanoids and other bioactive lipid mediators are indispensable regulators of biological processes, as demonstrated by the numerous inflammatory diseases resulting from their dysregulation, including cancer, hyperalgesia, atherosclerosis, and arthritis. Despite their importance, a robust strategy comparable with gene or protein array technology for comprehensively analyzing the eicosanoid metabolome has not been forthcoming. We have developed liquid chromatography-tandem mass spectrometry methodology that quantitatively and comprehensively analyzes the eicosanoid metabolome and utilized this approach to characterize eicosanoid production during experimental Lyme arthritis in mice infected with the bacterium Borrelia burgdorferi. Eicosanoids were extracted throughout infection from the joints of Lyme arthritis-resistant and -susceptible mice and subjected to lipidomic profiling. We identified temporal and quantitative differences between these mouse strains in the production of eicosanoids, which correlated with differences in arthritis development. The eicosanoid biosynthetic enzyme cyclooxygenase (COX)-2 has been implicated in the regulation of Lyme arthritis pathology, and subsequent lipidomic profiling of B. burgdorferi-infected COX-2(-/-) mice identified reductions not only in COX-2 products but, surprisingly, also significant off-target reductions in 5-lipoxygenase metabolites. Our results demonstrate the utility of a comprehensive lipidomic approach for identifying potential contributors to disease pathology and may facilitate the development of more precisely targeted treatment strategies.

Fibroblast Growth Factor-2 Is a Downstream Mediator of Phosphatidylinositol 3-Kinase-Akt Signaling in 14,15-Epoxyeicosatrienoic Acid-induced Angiogenesis

To determine the efficacy of cytochrome P450 2C9 metabolites of arachidonic acid, viz. 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), in inducing angiogenesis, we have studied their effects on human dermal microvascular endothelial cell (HDMVEC) tube formation and migration. All four EETs stimulated HDMVEC tube formation and migration in a dose-dependent manner. Because 14,15-EET was found to be slightly more efficacious than 5,6-, 8,9-, and 11,12-EETs in stimulating HDMVEC tube formation and migration, we next focused on elucidation of the signaling mechanisms underlying its angiogenic activity. 14,15-EET stimulated Akt and S6K1 phosphorylation in Src- and phosphatidylinositol 3-kinase (PI3K)-dependent manner in HDMVECs. Inhibition of Src and PI3K-Akt-mTOR signaling by both pharmacological and dominant-negative mutant approaches suppressed 14,15-EET-induced HDMVEC tube formation and migration in vitro and Matrigel plug angiogenesis in vivo. In addition, 14,15-EET induced the expression of fibroblast growth factor-2 (FGF-2) in Src- and PI3K-Akt-dependent and mTOR-independent manner in HDMVECs. Neutralizing anti-FGF-2 antibodies completely suppressed 14,15-EET-induced HDMVEC tube formation and migration in vitro and Matrigel plug angiogenesis in vivo. Together, these results show for the first time that Src and PI3K-Akt signaling via targeting in parallel with FGF-2 expression and mTOR-S6K1 activation plays an indispensable role in 14,15-EET-induced angiogenesis.

Involvement of eicosanoids and surfactant protein D in extrinsic allergic alveolitis

The pathophysiology of extrinsic allergic alveolitis (EAA) involves oxidative lung damage as well as interstitial and alveolar inflammation. Macrophages and mast cells are inflammatory components of EAA that produce both leukotrienes (LTs) and prostaglandin D2 (PGD2). In addition, PGD2 is also produced by the free-radical-catalysed peroxidation of arachidonic acid during oxidative stress. Urinary 8-iso prostaglandin F2alpha (8-isoPGF2alpha) and serum surfactant protein D (SP-D) are considered appropriate biomarkers of oxidative stress and interstitial lung disease activity, respectively. The present study aimed to assess the association of these biomarkers with the pathophysiology of EAA. Two cases of acute EAA caused by the inhalation of fungi spores were reported. Eight asthmatic patients and six healthy control subjects were also enrolled in the current study. The serum SP-D and urinary eicosanoid (LTE4, PGD2 metabolite (9alpha,11betaPGF2), 8-isoPGF2alpha) concentrations markedly increased during the acute exacerbation phase. These concentrations decreased following corticosteroid therapy in the EAA patients. There was a significant correlation between serum SP-D and urinary 9alpha,11betaPGF2 concentrations in the EAA patients. In conclusion, although the present study proposes that serum surfactant protein-D and urinary eicosanoids are new biomarkers involved in the various immunological responses in extrinsic allergic alveolitis, further large-scale studies are needed to investigate the role of these compounds, not just as biomarkers, but also as biological potentiators of extrinsic allergic alveolitis.

Ecdysis of Oesophagostomum: possible involvement of eicosanoids and development of a bioassay

Bioassays were developed and applied to test the role of eicosanoids and pH changes in ecdysis of Oesophagostomum dentatum. Exsheathment (80-100%) was achieved by subjecting third-stage larvae (L3) either to chlorine (hypochlorite assay) for 5 min or by incubating them in HCl followed by addition of NaHCO3 (pH-change assay) with subsequent cultivation at 38.5 degrees C/10% CO2 for 1 week. Addition of the lipoxygenase (LOX) inhibitor diethylcarbamacine (DEC) to the larvae resulted in a reduction of the exsheathment rates which could be restored by the addition of leukotrienes (LT)B4, LTC4, LTD4 and LTE4. Addition of the cyclooxygenase (COX) inhibitor acetylsalicylic acid (ASA) also resulted in decreased exsheathment rates both in the hypochlorite and in the pH-change assays in a dose-dependent manner. However, the primary COX products (prostaglandins) were not able to reverse this effect, in contrast to LTC4. It was concluded that: (1) both tests are suitable for bioassaying the effect of substances on exsheathment, and (2) eicosanoids involved in the control of exsheathment of L3 of O. dentatum are primarily LT.

Eicosanoid regulation of angiogenesis in tumors.

Tumor angiogenesis, the formation of new capillary blood vessels in tumors from pre-existing vasculature, is required for tumor growth and progression. Eicosanoids, the bioactive lipids derived from arachidonic acid, possess potent and diverse biological activities. In response to stimuli, arachidonic acid is mobilized from phospholipid pools and metabolized by cyclooxygenases (COX), lipoxygenases (LOX), and p450 epoxygenases (EOX) to form a variety of eicosanoids. The involvement of eicosanoids in tumor angiogenesis and progression is implicated by the observations that nonsteroidal anti-inflammation drugs (NSAIDs) reduce tumor growth and angiogenesis. Subsequently, it is found that the levels of COX-2 and/or 12-LOX are frequently increased in various cancers. Further studies using molecular and pharmacological approaches have found that COX-2 and 12-LOX, when overexpressed in carcinoma cells, enhance their angiogenic potential and stimulate tumor growth. In this article, we discuss how COX and LOX in cancer cells modulate tumor angiogenesis and present the possibility of using NSAIDs and LOX inhibitors as antiangiogenesis agents.

Involvement of eicosanoids in the hypothermic response to lipopolysaccharide during endotoxemia in rats

Hypothermia is one of the prominent features of the acute phase response to endotoxin (LPS). This study was undertaken to elucidate the effects of the COX-inhibitor Indomethacin (INDO) and the selective FLAP inhibitor MK-886 on LPS-induced hypothermia, mortality and increase in production of hypothalamic prostaglandin E 2 (PGE 2) and leukotriene during endotoxemia. It has been demonstrated that INDO and MK-886 significantly attenuate the hypothermia induced by LPS, but MK-886 has a lesser (protective) effect than INDO. Only INDO was found to attenuate significantly the hyperthermic response to LPS. Furthermore, INDO significantly reduced the elevation in hypothalamic PGE 2 levels. MK-886 significantly reduced the elevation in hypothalamic leukotriene production only when LPS was given in a dose of 1 mg/kg. Both drugs failed to reduce the elevation in plasma TNF- α and mortality induced by LPS. We conclude that in rats, febrile response to endotoxin involves many inflammatory mediators. However, it seems that PGE 2 and leukotrienes do not have a pivotal role in the mechanism of LPS-induced mortality.

Eicosanoid involvement in the regulation of behavioral fever in the desert locust, Schistocerca gregaria.

The desert locust Schistocerca gregaria behaviorally thermoregulates in order to try and maintain a favoured "set point" body temperature. Locusts infected with the deuteromycete fungal pathogen Metarhizium anisopliae var acridumchoose a significantly elevated temperature. This "behavioral fever" greatly delays the progress of mycosis. We have confirmed this phenomenon and shown that desert locusts also fever when infected with the bacterial pathogen Serratia marcescens. Elevation in the prefered environmental temperature occurs also upon injection with laminarin and lipopolysaccharide (microbial cell wall components). Since such treatments also stimulate the immune system it would appear that "behavioral fever" is probably a feature of the immune response. The eicosanoid biosynthesis inhibitor dexamethasone prevented laminarin invoked fever. This effect was reversable by arachidonic acid. Therefore in common with the febrile response in mammals behavioral fever in insects may be mediated locally by circulating eicosanoids.

COX-2, Inflammatory Secreted PLA2, and Cytoplasmic PLA2 Protein Expression in Small Bowel Adenocarcinomas Compared with Colorectal Adenocarcinomas

Cyclooxygenase-2 (COX-2), human synovial inflammatory secreted phospholipase A2 (sPLA2) and cytoplasmic phospholipase A2 (cPLA2) are involved in eicosanoid production and also seem to participate in colorectal tumorigenesis. As there are no data regarding these enzymes in human small bowel tumors, we wanted to determine whether they were involved in human small bowel tumorigenesis, and whether their expression was different in small bowel compared to colorectal adenocarcinomas, as suggested by animal studies. We studied their protein expression by immunohistochemistry in 25 small bowel adenocarcinomas and compared it to 48 colorectal adenocarcinomas. Seventy-six percent of the small bowel and 88% of the colorectal adenocarcinomas had a moderate or strong COX-2 expression. Sixty-eight percent of the small bowel and 67% of the colorectal adenocarcinomas had a moderate or strong sPLA2 expression. Forty-eight percent of the small bowel and 35% of the colorectal adenocarcinomas had a moderate or strong cPLA2 expression. In conclusion, the increased expression of COX-2, sPLA2, and sometimes cPLA2 in both small bowel and colorectal adenocarcinomas is in accordance with the likely eicosanoid involvement in tumor development. The same pattern of protein expression found in both types of adenocarcinoma contradicts experimental results in mice. Moreover, our results strengthen the similarities between these two types of human cancer.

Eicosanoids mediate Manduca sexta cellular response to the fungal pathogen Beauveria bassiana: a role for the lipoxygenase pathway.

Many studies have documented the involvement of eicosanoids in insect cellular immune responses to bacteria. The use of the fungal pathogen Beauveria bassiana as a nodulation elicitor, with inhibition of phospholipase A(2) by dexamethasone, extends the principle to fungi. This study also provides the first evidence of involvement of the lipoxygenase (LOX) pathway rather than the cyclooxygenase (COX) pathway in synthesis of the nodulation mediating eicosanoid(s). The LOX product, 5(S)-hydroperoxyeicosa-6E,8Z,11Z,14Z-tetraenoic acid (5-HPETE), substantially reversed nodulation inhibition caused by dexamethasone and the LOX inhibitors, caffeic acid and esculetin. The COX product, prostaglandin H(2) (PGH(2)), did not reverse the nodulation inhibition by dexamethasone or the COX inhibitor, ibuprofen. None of the inhibitors tested had a significant effect on the phagocytosis of B. bassiana blastospores in vitro. Hemocyte phenoloxidase activity was reduced by dexamethasone, esculetin, and the COX inhibitor, indomethacin. The rescue candidates 5-HPETE and PGH(2) did not reverse the inhibition.