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1.
J Immunol ; 210(3): 221-227, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36649580

RESUMO

Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase pathway of arachidonate metabolism. Though best known for their role in asthma, they have broad actions that touch on virtually every aspect of mammalian biology. In a Brief Review published in the journal in 2005, we presented the existing evidence supporting a role for LTs in host defense. In this updated Brief Review, we focus on selected advances since then. We detail new insights into mechanisms and regulation of LT biosynthesis; the protective roles of LTs in the host response to diverse classes of pathogens, with an emphasis on viruses, including SARS-CoV-2; the phagocyte signal transduction mechanisms by which LTs exert their antimicrobial actions; the capacity for overexuberant LT production to promote tissue damage; and roles of LTs in the noninfectious immune-relevant conditions neuroinflammation and cancer.


Assuntos
COVID-19 , Animais , Humanos , Araquidonato 5-Lipoxigenase/metabolismo , Eicosanoides , Imunidade Inata , Leucotrienos , Mamíferos/metabolismo , SARS-CoV-2/metabolismo
3.
J Am Soc Mass Spectrom ; 34(1): 75-81, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36507839

RESUMO

We developed a structural identification method for eicosanoids with various ring structures using mass spectrometry. We discovered that an electron beam with a kinetic energy of 10 eV, which is in the Electron Impact Excitation of Ions from Organics (EIEIO) regime, cleaved the fatty acids enough to distinguish constitutional and cis/trans isomers. In addition to EIEIO, a comparison to authentic standards using differential mobility spectrometry (DMS) can identify diastereomers, which was difficult by EIEIO. The combination of EIEIO and DMS can provide a high-throughput method to identify complete structures of eicosanoids in mixed samples, which is not allowed with conventional analytical methods though eicosanoids are important signaling molecules in biosystems.


Assuntos
Eicosanoides , Elétrons , Espectrometria de Massas/métodos , Análise Espectral , Íons/química
4.
Biochem Pharmacol ; 207: 115375, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36481345
5.
Am J Physiol Renal Physiol ; 324(2): F138-F151, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36475868

RESUMO

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including antiapoptotic, anti-inflammatory, and antifibrotic functions. Soluble epoxide hydrolase (sEH)-mediated hydrolysis of EETs to dihydroxyeicosatrienoic acids (DHETs) attenuates these effects. Recent studies have demonstrated that inhibition of sEH prevents renal tubulointerstitial fibrosis and inflammation in the chronic kidney disease model. Given the pathophysiological role of the EET pathway in chronic kidney disease, we investigated if administration of EET regioisomers and/or sEH inhibition will promote antifibrotic and renoprotective effects in renal fibrosis following unilateral ureteral obstruction (UUO). EETs administration abolished tubulointerstitial fibrogenesis, as demonstrated by reduced fibroblast activation and collagen deposition after UUO. The inflammatory response was prevented as demonstrated by decreased neutrophil and macrophage infiltration and expression of cytokines in EET-administered UUO kidneys. EET administration and/or sEH inhibition significantly reduced M1 macrophage markers, whereas M2 macrophage markers were highly upregulated. Furthermore, UUO-induced oxidative stress, tubular injury, and apoptosis were all downregulated following EET administration. Combined EET administration and sEH inhibition, however, had no additive effect in attenuating inflammation and renal interstitial fibrogenesis after UUO. Taken together, our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest EET treatment as a potential therapeutic strategy to treat fibrotic diseases.NEW & NOTEWORTHY Epoxyeicosatrienoic acids (EETs) are cytochrome P-450-dependent antihypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered renoprotective. We found that EET administration and/or soluble epoxide hydrolase inhibition significantly attenuates oxidative stress, renal cell death, inflammation, macrophage differentiation, and fibrogenesis following unilateral ureteral obstruction. Our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest that EET treatment may be a potential therapeutic strategy to treat fibrotic diseases.


Assuntos
Insuficiência Renal Crônica , Obstrução Ureteral , Humanos , Epóxido Hidrolases , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Rim/metabolismo , Eicosanoides/metabolismo , Inflamação , Ácidos Araquidônicos , Ácido 8,11,14-Eicosatrienoico
6.
Free Radic Biol Med ; 194: 308-315, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36509313

RESUMO

Proinflammatory bioactive lipid mediators and oxidative stress are increased in coronavirus disease 2019 (COVID-19). The randomized controlled single-blind trial COVID-Omega-F showed that intravenous omega-3 polyunsaturated fatty acids (n-3 PUFA) shifted the plasma lipid signature of COVID-19 towards increased proresolving precursor levels and decreased leukotoxin diols, associated with a beneficial immunodulatory response. The present study aimed to determine the effects of n-3 PUFA on the urinary oxylipidome and oxidative stress in COVID-19. From the COVID-Omega-F trial, 20 patients hospitalized for COVID-19 had available serial urinary samples collected at baseline, after 24-48 h, and after completing 5 days treatment with one daily intravenous infusion (2 mL/kg) of either placebo (NaCl; n = 10) or a lipid emulsion containing 10 g of n-3 PUFA per 100 mL (n = 10). Urinary eicosanoids and isoprostanes were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Erythrocytes obtained at the different time-points from n = 10 patients (n = 5 placebo and n = 5 n-3 PUFA) were used for determination of reactive oxygen species. Intravenous n-3 PUFA emulsion administration altered eicosanoid metabolites towards decreased levels for mediators of inflammation and thrombosis, and increased levels of the endothelial function mediator prostacyclin. Furthermore, non-enzymatic metabolism was skewed towards n-3 PUFA-derived metabolites with potential anti-inflammatory and pro-resolving effects. The oxidative stress marker 15-F2t-isoprostane was significantly lower in patients receiving n-3 PUFA treatment, who also exhibited significantly decreased erythrocyte oxidative stress compared with placebo-treated patients. These findings point to additional beneficial effects of intravenous n-3 PUFA emulsion treatment through a beneficial oxylipin profile and decreased oxidative stress in COVID-19.


Assuntos
COVID-19 , Ácidos Graxos Ômega-3 , Humanos , Emulsões , Cromatografia Líquida , Método Simples-Cego , Espectrometria de Massas em Tandem , Eicosanoides/metabolismo , Estresse Oxidativo
7.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36555666

RESUMO

Eicosanoids and related compounds are pleiotropic lipid mediators, which are biosynthesized in mammals via three distinct metabolic pathways (cyclooxygenase pathway, lipoxygenase pathway, epoxygenase pathway). These mediators have been implicated in the pathogenesis of inflammatory diseases and drugs interfering with eicosanoid signaling are currently available as antiphlogistics. Eicosanoid biosynthesis has well been explored in mammals including men, but much less detailed information is currently available on eicosanoid biosynthesis in other vertebrates including bony fish. There are a few reports in the literature describing the expression of arachidonic acid lipoxygenases (ALOX isoforms) in several bony fish species but except for two zebrafish ALOX-isoforms (zfALOX1 and zfALOX2) bony fish eicosanoid biosynthesizing enzymes have not been characterized. To fill this gap and to explore the possible roles of ALOX15 orthologs in bony fish inflammation we cloned and expressed putative ALOX15 orthologs from three different bony fish species (N. furzeri, P. nyererei, S. formosus) as recombinant N-terminal his-tag fusion proteins and characterized the corresponding enzymes with respect to their catalytic properties (temperature-dependence, activation energy, pH-dependence, substrate affinity and substrate specificity with different polyenoic fatty acids). Furthermore, we identified the chemical structure of the dominant oxygenation products formed by the recombinant enzymes from different free fatty acids and from more complex lipid substrates. Taken together, our data indicate that functional ALOX isoforms occur in bony fish but that their catalytic properties are different from those of mammalian enzymes. The possible roles of these ALOX-isoforms in bony fish inflammation are discussed.


Assuntos
Lipoxigenase , Peixe-Zebra , Animais , Lipoxigenase/genética , Lipoxigenase/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Mamíferos/metabolismo , Eicosanoides/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inflamação/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo
8.
Sci Rep ; 12(1): 20218, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36418854

RESUMO

Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR < 0.05 were considered significant. In total, 2676 AF-free individuals (mean age 66 ± 9 years, 56% females) were followed for mean 10.8 ± 3.4 years; 351 participants developed incident AF. Six eicosanoids were associated with incident AF after adjusting for multiple testing (FDR < 0.05). A joint score was built from the top eicosanoids weighted by their effect sizes, which was associated with incident AF (HR = 2.72, CI = 1.71-4.31, P = 2.1 × 10-5). In conclusion, six eicosanoids were associated with incident AF after adjusting for clinical risk factors for AF.


Assuntos
Fibrilação Atrial , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Masculino , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Estudos Longitudinais , Modelos de Riscos Proporcionais , Anti-Hipertensivos/uso terapêutico , Eicosanoides
9.
PLoS One ; 17(11): e0265854, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36395179

RESUMO

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder which induces endothelial dysfunction and platelet activation. Eicosanoids produced from arachidonic acid regulate cellular and vascular functions. Sigma-1 receptors (S1R) are expressed in platelets and endothelial cells and S1R expression is protective in diabetes. OBJECTIVES: Our aim was to examine the influence of sub-chronic, in vivo administered S1R ligands PRE-084, (S)-L1 (a new compound) and NE-100 on the ex vivo arachidonic acid metabolism of platelets and aorta in streptozotocin-induced diabetic rats. METHODS: The serum level of the S1R ligands was detected by LC-MS/MS before the ex vivo analysis. Sigma-1 receptor and cyclooxygenase gene expression in platelets were determined by RT-qPCR. The eicosanoid synthesis was examined with a radiolabelled arachidonic acid substrate and ELISA. RESULTS: One month after the onset of STZ-induced diabetes, in vehicle-treated, diabetic rat platelet TxB2 and aortic 6-k-PGF1α production dropped. Sub-chronic in vivo treatment of STZ-induced diabetes in rats for one week with PRE-084 enhanced vasoconstrictor and platelet aggregator and reduced vasodilator and anti-aggregator cyclooxygenase product formation. (S)-L1 reduced the synthesis of vasodilator and anti-aggregator cyclooxygenase metabolites and promoted the recovery of physiological platelet function in diabetic rats. The S1R antagonist NE-100 produced no significant changes in platelet arachidonic acid metabolism. (S)-L1 decreased the synthesis of vasoconstrictor and platelet aggregator cyclooxygenase metabolites, whereas NE-100 increased the quantity of aortic vasodilator and anti-aggregator cyclooxygenase products and promoted the recovery of diabetic endothelial dysfunction in the aorta. The novel S1R ligand, (S)-L1 had similar effects on eicosanoid synthesis in platelets as the agonist PRE-084 and in aortas as the antagonist NE-100. CONCLUSIONS: S1R ligands regulate cellular functions and local blood circulation by influencing arachidonic acid metabolism. In diabetes mellitus, the cell-specific effects of S1R ligands have a compensatory role and aid in restoring physiological balance between the platelet and vessel.


Assuntos
Diabetes Mellitus Experimental , Animais , Ratos , Estreptozocina , Ácido Araquidônico/farmacologia , Diabetes Mellitus Experimental/metabolismo , Ligantes , Células Endoteliais/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ácidos Araquidônicos/metabolismo , Aorta/metabolismo , Eicosanoides , Ciclo-Oxigenase 2 , Vasodilatadores , Vasoconstritores
10.
Anal Bioanal Chem ; 414(29-30): 8233-8244, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36344666

RESUMO

The eicosanoid metabolic pathway is responsible for mediating the production of various inflammatory factors that are closely related to the development and resolution of inflammation. In biological matrices, the major quantifying obstacles were shown to be the oxidation and low quantities of eicosanoids and their metabolites. This study aimed to develop a reliable, sensitive ultrahigh-performance liquid chromatography coupled to a tandem mass spectrometry (UPLC-MS/MS) method to quantify eicosanoids in human serum. Solid-phase extraction (SPE) was used for sample preparation. The approach employed continuous ionization polarity switching. The target eicosanoids showed good linearity over the investigated concentration range (r2 > 0.99). The recovery rates were over 64.5%, and the matrix effects ranged from 73.0 to 128.0%. The limits of quantification were 0.048 ~ 0.44 ng/mL. For the broad concentration range, the CV % for accuracy and precision were less than ± 20%. We successfully applied this method to rapidly analyse 74 serum samples from severe influenza pneumonia, severe bacterial pneumonia and healthy individuals. Eicosanoid-related metabolite concentrations were quantified within a range similar to those of previously published articles. Compared to healthy individuals, our application found that 20-HETE, 14,15-EET and 11,12-EET were upregulated in severe influenza pneumonia patients, while LTB4 was downregulated. 8-HETE and 5-HETE were upregulated in severe bacterial pneumonia patients, while LTE4 was downregulated. This approach provides a means for monitoring the low quantities of eicosanoids in biological matrices, and our finding that different characteristic metabolite profiles may help discriminate the induction of severe pneumonia patients.


Assuntos
Influenza Humana , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Cromatografia Líquida de Alta Pressão/métodos , Eicosanoides/metabolismo , Extração em Fase Sólida
11.
Front Immunol ; 13: 994626, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439105

RESUMO

Various microbiota including beneficial symbionts reside in the insect gut. Infections of pathogens cause dysregulation of the microflora and threaten insect survival. Reactive oxygen species (ROS) have been used in the gut immune responses, in which its production is tightly regulated by controlling dual oxidase (Duox) activity via Ca2+ signal to protect beneficial microflora and gut epithelium due to its high cytotoxicity. However, it was not clear how the insects discriminate the pathogens from the various microbes in the gut lumen to trigger ROS production. An entomopathogenic nematode (Steinernema feltiae) infection elevated ROS level in the gut lumen of a lepidopteran insect, Spodoptera exigua. Dorsal switch protein 1 (DSP1) localized in the nucleus in the midgut epithelium was released into plasma upon the nematode infection and activated phospholipase A2 (PLA2). The activated PLA2 led to an increase of PGE2 level in the midgut epithelium, in which rising Ca2+ signal up-regulated ROS production. Inhibiting DSP1 release by its specific RNA interference (RNAi) or specific inhibitor, 3-ethoxy-4-methoxyphenol, treatment failed to increase the intracellular Ca2+ level and subsequently prevented ROS production upon the nematode infection. A specific PLA2 inhibitor treatment also prevented the up-regulation of Ca2+ and subsequent ROS production upon the nematode infection. However, the addition of PGE2 to the inhibitor treatment rescued the gut immunity. DSP1 release was not observed at infection with non-pathogenic pathogens but detected in plasma with pathogenic infections that would lead to damage to the gut epithelium. These results indicate that DSP1 acts as a damage-associated molecular pattern in gut immunity through DSP1/PLA2/Ca2+/Duox.


Assuntos
Dinoprostona , Insetos , Animais , Oxidases Duais , Espécies Reativas de Oxigênio/metabolismo , Insetos/metabolismo , Eicosanoides , Triptofano Oxigenase , Proteínas Fúngicas
12.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361847

RESUMO

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia.


Assuntos
Eicosanoides , Epóxido Hidrolases , Animais , Camundongos , Feminino , Epóxido Hidrolases/metabolismo , Eicosanoides/metabolismo , Encéfalo/metabolismo , Microvasos/metabolismo
13.
Nutrients ; 14(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36296994

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a wide spectrum condition characterized by excessive liver fat accumulation in people who do not abuse alcohol. There is no effective medical treatment for NAFLD; therefore, most important recommendations to reduce liver steatosis are diet and lifestyle, including proper physical activity. The aim of our study was to analyze the fatty acids and eicosanoids changes in the serum of patients who consumed high-fiber rolls for 8 weeks. MATERIALS AND METHODS: The group of 28 Caucasian participants was randomly divided into two groups, those who received 24 g of fiber/day-from 2 buns of 12 g each (n = 14), and those who received 12 g of fiber/day-from 2 buns of 6 g (n = 14). At the beginning and on the last visit of the 8-week intervention, all patients underwent NAFLD evaluation, biochemical parameter measurements, and fatty acids and eicosanoids evaluation. RESULTS: Patients who received 12 g of fiber had significantly reduced liver steatosis and body mass index. In the group who received 24 g of fiber/day, we observed a trend to liver steatosis reduction (p = 0.07) and significant decrease in aspartate aminotransferase (p = 0.03) and total cholesterol (p = 0.03). All changes in fatty acid and eicosanoids profile were similar. Fatty acids analysis revealed that extra fiber intake was associated with a significant increase in monounsaturated fatty acids and decrease in saturated fatty acids. Moreover, both groups showed increased concentration of gamma linoleic acid and docosahexaenoic acid. We also observed reduction in prostaglandin E2. CONCLUSIONS: Our study revealed that a high amount of fiber in the diet is associated with a reduction in fatty liver, although this effect was more pronounced in patients in the lower fiber group. However, regardless of the amount of fiber consumed, we observed significant changes in the profile of FAs, which may reflect the positive changes in the lipids liver metabolism. Regardless of the amount of fiber consumed, patients decreased the amount of PGE2, which may indicate the lack of disease progression associated with the development of inflammation.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácidos Graxos/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Fígado/metabolismo , Dieta , Aspartato Aminotransferases/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Fibras na Dieta/metabolismo , Eicosanoides/metabolismo , Ácidos Linoleicos/metabolismo , Prostaglandinas E/metabolismo , Prostaglandinas/metabolismo , Colesterol/metabolismo
14.
Int J Mol Sci ; 23(20)2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36293289

RESUMO

CYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to cis-epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by EPHX2) or re-esterified back to the membrane. EETs have several cardioprotective properties and higher levels are usually associated with better cardiac outcomes/prognosis. This study investigates how cardiovascular disease (CVD) can influence total EET levels by altering protein expression and activity of enzymes involved in their biosynthesis and degradation. Diseased ventricular cardiac tissues were collected from patients receiving Left Ventricular Assist Device (LVAD) or heart transplants and compared to ventricular tissue from controls free of CVD. EETs, and enzymes involved in EETs biosynthesis and degradation, were measured using mass spectrometric assays. Terfenadine hydroxylation was used to probe CYP2J2 activity. Significantly higher cis- and trans-EET levels were observed in control cardiac tissue (n = 17) relative to diseased tissue (n = 24). Control cardiac tissue had higher CYP2J2 protein levels, which resulted in higher rate of terfenadine hydroxylation, compared to diseased cardiac tissues. In addition, levels of both NADPH-Cytochrome P450 oxidoreductase (POR) and sEH proteins were significantly higher in control versus diseased cardiac tissue. Overall, alterations in protein and activity of enzymes involved in the biosynthesis and degradation of EETs provide a mechanistic understanding for decreased EET levels in diseased tissues.


Assuntos
Doenças Cardiovasculares , Cardiopatias , Humanos , Epóxido Hidrolases/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Terfenadina , NADP , Eicosanoides/metabolismo , Ácido Araquidônico/metabolismo , Citocromo P-450 CYP2J2
15.
Artigo em Inglês | MEDLINE | ID: mdl-36270150

RESUMO

Adipose tissue has been established as an endocrine organ that plays an important role in maintaining metabolic homeostasis. Adipose tissue releases several bioactive molecules called adipokines. Inflammation, dysregulation of adipokine synthesis, and secretion are observed in obesity and related diseases and cause adipose tissue dysfunction. Prostanoids, belonging to the eicosanoid family of lipid mediators, can be synthesized in adipose tissue and play a critical role in adipose tissue biology. In this review, we summarized the current knowledge regarding the interaction of prostanoids with adipokines, the expression of prostanoid receptors, and prostanoid synthase enzymes in adipose tissues in health and disease. Furthermore, the involvement of prostanoids in the physiological function or dysfunction of adipose tissue including inflammation, lipolysis, adipogenesis, thermogenesis, browning of adipocytes, and vascular tone regulation was also discussed by examining studies using pharmacological approaches or genetically modified animals for prostanoid receptors/synthase enzymes. Overall, the present review provides a perspective on the evidence from literature regarding the biological effects of prostanoids in adipose tissue. Among prostanoids, prostaglandin E2 (PGE2) is prominent in regards to its substantial role in both adipose tissue physiology and pathophysiology. Targeting prostanoids may serve as a potential therapeutic strategy for preventing or treating obesity and related diseases.


Assuntos
Tecido Adiposo , Prostaglandinas , Animais , Prostaglandinas/metabolismo , Tecido Adiposo/metabolismo , Adipocinas/metabolismo , Obesidade/metabolismo , Inflamação/metabolismo , Dinoprostona/metabolismo , Eicosanoides/metabolismo
16.
Sci Rep ; 12(1): 17832, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284115

RESUMO

Various fatty acyl lipid mediators are derived from dietary polyunsaturated fatty acids (PUFAs) and modulate nociception. The modern diet is rich in linoleic acid, which is associated with nociceptive hypersensitivities and may present a risk factor for developing pain conditions. Although recommendations about fatty acid intake exist for some diseases (e.g. cardiovascular disease), the role of dietary fatty acids in promoting pain disorders is not completely understood. To determine how dietary linoleic acid content influences the accumulation of pro- and anti-nociceptive fatty acyl lipid mediators, we created novel rodent diets using custom triglyceride blends rich in either linoleic acid or oleic acid. We quantified the fatty acyl lipidome in plasma of male and female rats fed these custom diets from the time of weaning through nine weeks of age. Dietary fatty acid composition determined circulating plasma fatty acyl lipidome content. Exposure to a diet rich in linoleic acid was associated with accumulation of linoleic and arachidonic acid-derived pro-nociceptive lipid mediators and reduction of anti-nociceptive lipid mediators derived from the omega-3 PUFAs. Our findings provide mechanistic insights into exaggerated nociceptive hypersensitivity associated with excessive dietary linoleic acid intake and highlight potential biomarkers for pain risk stratification.


Assuntos
Eicosanoides , Ácido Linoleico , Masculino , Feminino , Ratos , Animais , Ácidos Graxos Insaturados , Ácidos Graxos , Dieta , Triglicerídeos , Ácido Oleico , Ácido Araquidônico , Dor , Gorduras na Dieta , Ácidos Linoleicos
17.
Int J Mol Sci ; 23(19)2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36233111

RESUMO

As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor.


Assuntos
COVID-19 , Endocanabinoides , Ácidos Araquidônicos/metabolismo , Dinoprostona/metabolismo , Eicosanoides/metabolismo , Endocanabinoides/metabolismo , Ácidos Graxos não Esterificados , Hospitalização , Hospitais , Humanos , Ácidos Hidroxieicosatetraenoicos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Peroxidação de Lipídeos , Lipoxigenase/metabolismo , Malondialdeído , Fosfolipases A2/metabolismo , Fosfolipídeos/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , SARS-CoV-2 , Sobreviventes , Tromboxano B2 , Fator de Necrose Tumoral alfa/metabolismo
18.
Molecules ; 27(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36234768

RESUMO

Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.


Assuntos
Neoplasias , Tromboxano-A Sintase , Ácido Araquidônico , Eicosanoides , Humanos , Masculino , Neoplasias/genética , Receptores de Tromboxanos , Tromboxano A2 , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismo , Tromboxanos , Microambiente Tumoral
19.
Biomolecules ; 12(10)2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36291611

RESUMO

We previously identified that NO derived from neuronal cells acts on glial cells and causes vasodilation in the healthy rat retina via the release of epoxyeicosatrienoic acids (EETs) and prostaglandins (PGs) by activation of the arachidonic acid cascade. However, it is not clear which PG types are involved in these responses. The aim of the present study was to identify prostanoid receptors involved in glial cell-derived vasodilation induced by NO in rat retina. Male Wistar rats were used to examine the effects of intravitreal pretreatment with indomethacin, a cyclooxygenase inhibitor; PF-04418948, a prostanoid EP2 receptor antagonist; and CAY10441, a prostanoid IP receptor antagonist, on the changes in the retinal arteriolar diameter induced by intravitreal administration of NOR3, an NO donor. Retinal arteriolar diameters were measured using ocular fundus images captured with a high-resolution digital camera in vivo. The increase in the retinal arteriolar diameter induced by intravitreal injection of NOR3 was significantly suppressed by intravitreal pretreatment with indomethacin and PF-04418948, but not by CAY10441. The dose of PF-04418948 and CAY10441 injected intravitreally in the present study significantly reduced the increase in the retinal arteriolar diameter induced by prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), respectively. These results suggest that activation of the arachidonic acid cascade and subsequent stimulation of prostanoid EP2 receptors are involved in rat retinal vasodilatory responses evoked by NO-induced glial cell stimulation. Therefore, glial cell-derived PGE2, similar to EETs, may play an important role in retinal vasodilatory mechanisms.


Assuntos
Prostaglandinas , Vasodilatação , Animais , Ratos , Masculino , Óxido Nítrico/farmacologia , Epoprostenol/farmacologia , Ratos Wistar , Neuroglia , Retina , Dinoprostona , Inibidores de Ciclo-Oxigenase/farmacologia , Indometacina , Eicosanoides/farmacologia , Ácidos Araquidônicos/farmacologia
20.
Int J Mol Sci ; 23(20)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36292991

RESUMO

Psoriasis is the most common autoimmune disease, yet its pathophysiology is not fully understood. It is now believed that psoriasis is caused by the increased activation of immune cells, especially Th1 lymphocytes. However, in psoriasis, immune cells interfere with the metabolism of keratinocytes, leading to their increased activation. Therefore, the pathophysiology of psoriasis is currently associated with the overproduction of ROS, which are involved in the activation of immune cells and keratinocytes as well as the modulation of various signaling pathways within them. Nevertheless, ROS modulate the immune system by also boosting the increasing generation of various lipid mediators, such as products of lipid peroxidation as well as endocannabinoids and prostaglandins. In psoriasis, the excessive generation of ROS and lipid mediators is observed in different immune cells, such as granulocytes, dendritic cells, and lymphocytes. All of the above may be activated by ROS and lipid mediators, which leads to inflammation. Nevertheless, ROS and lipid mediators regulate lymphocyte differentiation in favor of Th1 and may also interact directly with keratinocytes, which is also observed in psoriasis. Thus, the analysis of the influence of oxidative stress and its consequences for metabolic changes, including lipidomic ones, in psoriasis may be of diagnostic and therapeutic importance.


Assuntos
Metabolismo dos Lipídeos , Psoríase , Humanos , Espécies Reativas de Oxigênio/metabolismo , Endocanabinoides/metabolismo , Psoríase/metabolismo , Queratinócitos/metabolismo , Eicosanoides/metabolismo , Prostaglandinas/metabolismo
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