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1.
Eur Rev Med Pharmacol Sci ; 25(21): 6782-6796, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34787883

RESUMO

OBJECTIVE: This study aimed to evaluate the eicosanoid and pro resolutive parameters in SARS COVID-19 patients with the severe acute respiratory syndrome. PATIENTS AND METHODS: Fourteen male patients with an acute respiratory syndrome caused by SARS COVID-19 and four healthy controls were evaluated by measuring the following parameters in plasma: Polyunsaturated fatty acids: EPA, DHA, ARA, and DPA. Specialized Pro-resolving mediators (SPMs) (including monohydroxy-containing precursors 17-HDHA, 18-HEPE, 14-HDHA) resolvins, maresins, protectins, and lipoxins. The eicosanoids group included prostaglandins, thromboxanes, and leukotrienes. RESULTS: Plasma from COVID-19 patients presented higher amounts of pro-inflammatory and pro-thrombotic lipid mediators as compared to healthy subjects (65.7 pg/ml vs. 10.2 pg/ml), including thromboxane (2142.6 pg/ml vs. 10.4 pg/ml), and the ratio between total plasma pro-inflammatory mediators versus total SPM's was 13.2 to 0,4, respectively. CONCLUSIONS: A clear disbalance favoring the pro-inflammatory axis is described, showing the need to perform future clinical interventions in these patients using SPM's or monohydroxylated lipid mediators derivates from fatty acids.


Assuntos
COVID-19/diagnóstico , Eicosanoides/sangue , Mediadores da Inflamação/sangue , Doença Aguda , Adulto , COVID-19/patologia , COVID-19/virologia , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Ácidos Graxos Insaturados/sangue , Humanos , Masculino , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem , Tromboxanos/sangue
2.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34639055

RESUMO

Organ fibrosis often ends in eventual organ failure and leads to high mortality. Although researchers have identified many effector cells and molecular pathways, there are few effective therapies for fibrosis to date and the underlying mechanism needs to be examined and defined further. Epoxyeicosatrienoic acids (EETs) are endogenous lipid metabolites of arachidonic acid (ARA) synthesized by cytochrome P450 (CYP) epoxygenases. EETs are rapidly metabolized primarily via the soluble epoxide hydrolase (sEH) pathway. The sEH pathway produces dihydroxyeicosatrienoic acids (DHETs), which have lower activity. Stabilized or increased EETs levels exert several protective effects, including pro-angiogenesis, anti-inflammation, anti-apoptosis, and anti-senescence. Currently, intensive investigations are being carried out on their anti-fibrotic effects in the kidney, heart, lung, and liver. The present review provides an update on how the stabilized or increased production of EETs is a reasonable theoretical basis for fibrosis treatment.


Assuntos
Suscetibilidade a Doenças , Eicosanoides/efeitos adversos , Fibrose/etiologia , Animais , Ácido Araquidônico/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Gerenciamento Clínico , Eicosanoides/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Fibrose/terapia , Humanos , Redes e Vias Metabólicas , Especificidade de Órgãos
3.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34707002

RESUMO

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tract tumors with a poor prognosis and high recurrence rate. Recently, ferroptosis resistance has been found in PDAC. However, the underlying mechanism of ferroptosis resistance has not been fully elucidated. Cytochrome P450 2J2 (CYP2J2) is the main enzyme which mediates arachidonic acid to produce epoxyeicosatrienoic acids (EETs) in human tissues. It has been reported that EETs involve in the development of cancer, while the roles of EETs in PDAC and ferroptosis remain unclear.This study aims to explore the effect of CYP2J2/EETs on ferroptosis of human pancreatic ductal adenocarcinoma cells PANC-1 cells and the underlying mechanisms. METHODS: The tumor tissues and para-carcinoma tissues of 9 patients with PDAC were collected and the expression of CYP2J2 was detected with real-time PCR and Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of 8,9-dihydroxyeicosatrienoic acid (8,9-DHET), and the degradation product of 8,9-epoxyeicosa-trienoic acid (8,9-EET). PANC-1 cells were used in this study. The ferroptosis inducer erastin was used to induce ferroptosis. The intracellular long-chain acyl-CoA synthetase 4 (ACSL4) protein level, lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) content, Fe2+ concentration, and cell survival were detected. The 8,9-EET was pretreated to observe its effect on erastin-induced ferroptosis in PANC-1 cells. Lentivirus was used to construct a CYP2J2 knockdown cell line to observe its effect on the ferroptosis of PANC-1 cells induced by erastin. A peroxisome proliferation-activated receptor γ (PPARγ) blocker was used to observe the effect of 8,9-EET on erastin-induced glutathione peroxidase 4 (GPX4) and MDA content in PANC-1 cells. RESULTS: High expression of CYP2J2 was found in PDAC, accompanied by an increased level of 8,9-DHET. The 8,9-EET pretreatment significantly attenuated the PANC-1 cell death induced by erastin. The 8,9-EET reduced the Fe2+ concentration, LDH activity and MDA content, and ACSL4 protein expression in erastin-treated PANC-1 cells. The 8,9-EET also restored the ferroportin (FPN) and ferroptosis suppressor protein 1 (FSP1) mRNA expressions in erastin-treated PANC-1 cells. But CYP2J2 knockdown exacerbated the erastin-induced ferroptosis in PANC-1 cells. Besides, CYP2J2 knockdown furtherly down-regulated the gene expression of FPN and FSP1. The 8,9-EET increased the expression of GPX4 in the erastin-treated PANC-1 cells, which was eliminated by a PPARγ blocker GW9662. And GW9662 abolished the anti-ferroptosis effects of 8,9-EET. CONCLUSIONS: CYP2J2/EETs are highly expressed in PDAC tissues. EETs inhibit the ferroptosis via up-regulation of GPX4 in a PPARγ-dependent manner, which contributes to the ferroptosis resistance of PDAC.


Assuntos
Adenocarcinoma , Sistema Enzimático do Citocromo P-450 , Eicosanoides , Ferroptose , PPAR gama , Humanos , Recidiva Local de Neoplasia
5.
Sheng Li Xue Bao ; 73(4): 539-550, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34405210

RESUMO

The article aims to study the effect and mechanism of shear stress on eicosanoids produced by the metabolism of polyunsaturated fatty acids in endothelial cells. First, human umbilical vein endothelial cells were treated by control (Static), laminar shear stress (LSS) and oscillatory shear stress (OSS) for 6 h. Then the endothelial cells were incubated with fresh M199 medium for 3 h, and the cell culture medium was collected. Ultra-performance liquid chromatography-mass spectrometer was used to detect the level of eicosanoid metabolites secreted by endothelial cells. The results showed that under different shear stress, the level of eicosanoid metabolites were changed significantly. We found 10 metabolites were significantly up-regulated by OSS compared with those in LSS group, including PGD2, PGE2, PGF2α and PGJ2 produced by cyclooxygenase; 11-HETE, 15-HETE, 13-HDoHE produced by lipoxygenase or spontaneous oxidation; 12,13-EpOME, 9,10-EpOME, 9,10-DiHOME produced by cytochrome P450 oxidase and soluble epoxide hydrolase. The transcription levels of these up-regulated eicosanoids metabolic enzyme-related genes were also increased in vitro and in vivo. These results indicate that OSS may promote the increase of metabolites by up-regulating the transcription level of metabolic enzyme-related genes, which playing a key role in the development of atherosclerosis. This study reveals the effect of shear stress on eicosanoid metabolism in endothelial cells, which provides a novel supplement to the systems biology approach to study systemic hemodynamics.


Assuntos
Eicosanoides , Metabolômica , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Estresse Mecânico
6.
Sheng Li Xue Bao ; 73(4): 606-616, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34405217

RESUMO

Eicosanoids are oxidized derivatives of 20-carbon polyunsaturated fatty acids (PUFAs). In recent years, the role and mechanism of eicosanoids in cardiovascular diseases have attracted extensive attention. Substrate PUFAs including arachidonic acid are metabolized by cyclooxygenase, lipoxygenase, cytochrome P450 oxidase enzymes, or non-enzymatic auto-oxidation. Eicosanoid metabolomics is an effective approach to study the complex metabolic network of eicosanoids. In this review, we discussed the biosynthesis and functional activities of eicosanoids, the strategies of eicosanoid metabolomics, and applications and research progress of eicosanoid metabolomics in cardiovascular diseases, which might offer new insights and strategies for the treatment of cardiovascular diseases.


Assuntos
Doenças Cardiovasculares , Ácido Araquidônico , Sistema Enzimático do Citocromo P-450 , Eicosanoides , Humanos , Metabolômica
7.
Sheng Li Xue Bao ; 73(4): 617-630, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34405218

RESUMO

The morbidity and mortality of cardiovascular diseases are increasing annually, which is one of the primary causes of human death. Recent studies have shown that epoxyeicosatrienoic acids (EETs), endogenous metabolites of arachidonic acid (AA) via CYP450 epoxygenase, possess a spectrum of protective properties in cardiovascular system. EETs not only alleviate cardiac remodeling and injury in different pathological models, but also improve subsequent hemodynamic disturbances and cardiac dysfunction. Meanwhile, various studies have demonstrated that EETs, as endothelial-derived hyperpolarizing factors, regulate vascular tone by activating various ion channels on endothelium and smooth muscle, which in turn can lower blood pressure, improve coronary blood flow and regulate pulmonary artery pressure. In addition, EETs are protective in endothelium, including inhibiting inflammation and adhesion of endothelial cells, attenuating platelet aggregation, promoting fibrinolysis and revascularization. EETs can also prevent aortic remodeling, including attenuating atherosclerosis, adventitial remodeling, and aortic calcification. Therefore, it is clinically important to study the physiological and pathophysiological effects of EETs in the cardiovascular system to further elucidate the mechanisms, as well as provide new strategy for the prevention and treatment of cardiovascular diseases. This review summarizes the endogenous cardioprotective effects and mechanisms of EETs in order to provide a new insight for research in this field.


Assuntos
Sistema Cardiovascular , Células Endoteliais , Ácido 8,11,14-Eicosatrienoico/farmacologia , Sistema Enzimático do Citocromo P-450 , Eicosanoides , Humanos
8.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445404

RESUMO

Chronic UV radiation causes oxidative stress and inflammation of skin and blood cells. Therefore, in this study, we assessed the effects of cannabidiol (CBD), a natural phytocannabinoid with antioxidant and anti-inflammatory properties, on the phospholipid (PL) and ceramide (CER) profiles in the plasma of nude rats irradiated with UVA/UVB and treated topically with CBD. The results obtained showed that UVA/UVB radiation increased the levels of phosphatidylcholines, lysophospholipids, and eicosanoids (PGE2, TxB2), while downregulation of sphingomyelins led to an increase in CER[NS] and CER[NDS]. Topical application of CBD to the skin of control rats significantly upregulated plasma ether-linked phosphatidylethanolamines (PEo) and ceramides. However, CBD administered to rats irradiated with UVA/UVB promoted further upregulation of CER and PEo and led to significant downregulation of lysophospholipids. This was accompanied by the anti-inflammatory effect of CBD, manifested by a reduction in the levels of proinflammatory PGE2 and TxB2 and a dramatic increase in the level of anti-inflammatory LPXA4. It can therefore be suggested that topical application of CBD to the skin of rats exposed to UVA/UVB radiation prevents changes in plasma phospholipid profile resulting in a reduction of inflammation by reducing the level of LPE and LPC species and increasing antioxidant capacity due to upregulation of PEo species.


Assuntos
Canabidiol/administração & dosagem , Ceramidas/sangue , Eicosanoides/sangue , Fosfolipídeos/sangue , Raios Ultravioleta/efeitos adversos , Administração Tópica , Animais , Canabidiol/farmacologia , Ceramidas/efeitos da radiação , Cromatografia de Fase Reversa , Eicosanoides/efeitos da radiação , Masculino , Fosfolipídeos/efeitos da radiação , Ratos , Ratos Nus , Espectrometria de Massas em Tandem
9.
Biochem Pharmacol ; 192: 114732, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34411565

RESUMO

Eicosanoids are lipid signaling molecules derived from the oxidation of ω-6 fatty acids, usually arachidonic acid. There are three major pathways, including the cyclooxygenase (COX), lipoxygenase (LOX), and P450 cytochrome epoxygenase (CYP) pathway. Prostanoids, which include prostaglandins (PG) and thromboxanes (Tx), are formed via the COX pathway, leukotrienes (LT) and lipoxins (LX) by the action of 5-LOX, and hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) by CYP. Although eicosanoids are usually associated with pro-inflammatory responses, non-classic eicosanoids, as LX, have anti-inflammatory and pro-resolving properties. Eicosanoids like PGE2, LTB4 and EETs have been involved in promoting liver regeneration after partial hepatectomy. PGE2 and LTB4 have also been reported to participate in the regenerative phase after ischemia and reperfusion (I/R), while cysteinyl leukotrienes (Cys-LT) contribute to the inflammatory process associated with I/R and are also involved in liver fibrosis and cirrhosis. However, LX, another product of 5-LOX, have the opposite effect, acting as pro-resolving mediators in these pathologies. In liver cancer, most studies show that eicosanoids, with the exception of LX, promote the proliferation of hepatocellular carcinoma cells and favor metastasis. This review summarizes the synthesis of different eicosanoids in the liver and discusses key findings from basic research linking eicosanoids to liver repair, regeneration and cancer and the impact of targeting eicosanoid cascade. In addition, studies in patients are presented that explore the potential use of eicosanoids as biomarkers and show correlations between eicosanoid production and the course and prognosis of liver disease.


Assuntos
Eicosanoides/metabolismo , Neoplasias Hepáticas/metabolismo , Regeneração Hepática/fisiologia , Fígado/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Transdução de Sinais/fisiologia
10.
Biomolecules ; 11(8)2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34439896

RESUMO

Endometriosis is a benign disease affecting one in ten women of reproductive age worldwide. Although the pain level is not correlated to the extent of the disease, it is still one of the cardinal symptoms strongly affecting the patients' quality of life. Yet, a molecular mechanism of this pathology, including the formation of pain, remains to be defined. Recent studies have indicated a close interaction between newly generated nerve cells and macrophages, leading to neurogenic inflammation in the pelvic area. In this context, the responsiveness of an endometriotic cell culture model was characterized upon inflammatory stimulation by employing a multi-omics approach, including proteomics, metabolomics and eicosanoid analysis. Differential proteomic profiling of the 12-Z endometriotic cell line treated with TNFα and IL1ß unexpectedly showed that the inflammatory stimulation was able to induce a protein signature associated with neuroangiogenesis, specifically including neuropilins (NRP1/2). Untargeted metabolomic profiling in the same setup further revealed that the endometriotic cells were capable of the autonomous production of 7,8-dihydrobiopterin (BH2), 7,8-dihydroneopterin, normetanephrine and epinephrine. These metabolites are related to the development of neuropathic pain and the former three were found up-regulated upon inflammatory stimulation. Additionally, 12-Z cells were found to secrete the mono-oxygenated oxylipin 16-HETE, a known inhibitor of neutrophil aggregation and adhesion. Thus, inflammatory stimulation of endometriotic 12-Z cells led to specific protein and metabolite expression changes suggesting a direct involvement of these epithelial-like cells in endometriosis pain development.


Assuntos
Linhagem Celular , Endometriose/metabolismo , Células Epiteliais/metabolismo , Macrófagos/metabolismo , Neurônios/metabolismo , Dor/metabolismo , Técnicas de Cultura de Células , Ciclo Celular , Eicosanoides/química , Feminino , Humanos , Inflamação , Metaboloma , Metabolômica , Fenótipo , Proteoma , Proteômica/métodos , Fator de Necrose Tumoral alfa/metabolismo
11.
Front Cell Infect Microbiol ; 11: 669623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307194

RESUMO

Introduction: Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes. Methods: Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56. Plasma eicosanoids were analyzed by ELISA and liquid chromatography-mass spectrometry (LC-MS), plasma cytokines by multiplex, and monocyte signaling by phospho-flow with a defined set of phospho-specific antibodies. Results: Lipoxygenase (LOX)-derived products (LXA4 and 12-HETE) and pro-inflammatory cytokines were associated with TB disease severity and were reduced during TB therapy, possibly accelerated by adjunctive COX-2i. Phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes as well as plasma levels of MIG/CXCL9 and procalcitonin were reduced in the COX-2i group compared to controls. Conclusion: COX-2i may reduce excess inflammation in TB via the LOX-pathway in addition to modulation of phosphorylation patterns in monocytes. Immunomodulatory effects of adjunctive COX-2i in TB should be further investigated before recommended for use as a HDT strategy.


Assuntos
Inibidores de Ciclo-Oxigenase 2 , Tuberculose , Eicosanoides , Humanos , Leucócitos Mononucleares , Lipoxigenase , Monócitos , Tuberculose/tratamento farmacológico
12.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298977

RESUMO

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.


Assuntos
Sistema Nervoso Central/fisiopatologia , Inflamação/fisiopatologia , Lipídeos de Membrana/fisiologia , Modelos Biológicos , Degeneração Neural/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Esfingolipídeos/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Ceramidas/fisiologia , Eicosanoides/fisiologia , Previsões , Homeostase , Humanos , Inflamação/patologia , Lipoxigenase/fisiologia , Lisofosfolipídeos/fisiologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia
13.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298981

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), ß or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARß/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARß/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARß/δ to alleviate skin inflammation is discussed.


Assuntos
Dermatite Atópica/metabolismo , Queratinócitos/metabolismo , PPAR delta/fisiologia , Psoríase/metabolismo , Pele/metabolismo , Anaerobiose , Animais , Dimerização , Eicosanoides/metabolismo , Ácidos Graxos/metabolismo , Glicólise , Humanos , Camundongos , Camundongos Mutantes , Especificidade de Órgãos , Fosforilação , Isoformas de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional , Proteólise , Receptores X de Retinoides/metabolismo , Pele/patologia
14.
Cells ; 10(7)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206530

RESUMO

Vitamins K exert a range of activities that extend far beyond coagulation and include anti-inflammatory effects, but the mechanisms involved in anti-inflammatory action remain unclear. In the present study, we showed that various forms of exogenous vitamins-K1, K3, K2 (MK-4, MK-5, MK-6 and MK-7)-regulated a wide scope of inflammatory pathways in murine macrophages in vitro, including NOS-2, COX-2, cytokines and MMPs. Moreover, we demonstrated for the first time that macrophages are able to synthesise endogenous MK-4 on their own. Vitamins with shorter isoprenoid chains-K1, K3 and MK-5-exhibited stronger anti-inflammatory potential than vitamins with longer isoprenoid chains (MK-6 and MK-7) and simultaneously were preferably used as a substrate for MK-4 endogenous production. Most interesting, atorvastatin pretreatment inhibited endogenous MK-4 production but had no impact on the anti-inflammatory activity of vitamins K. In summary, our results demonstrate that macrophages are able to synthesise endogenous MK-4 using exogenous vitamins K, and statin inhibits this process. However, the anti-inflammatory effect of exogenous vitamins K was independent of endogenous MK-4 synthesis.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/metabolismo , Vitamina K/farmacologia , Animais , Atorvastatina/farmacologia , Respiração Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/biossíntese , Citocinas/biossíntese , Eicosanoides/biossíntese , Indução Enzimática/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Especificidade por Substrato/efeitos dos fármacos
15.
Clin Chem Lab Med ; 59(12): 1891-1905, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34332518

RESUMO

Human Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection activates a complex interaction host/virus, leading to the reprogramming of the host metabolism aimed at the energy supply for viral replication. Alterations of the host metabolic homeostasis strongly influence the immune response to SARS-CoV-2, forming the basis of a wide range of outcomes, from the asymptomatic infection to the onset of COVID-19 and up to life-threatening acute respiratory distress syndrome, vascular dysfunction, multiple organ failure, and death. Deciphering the molecular mechanisms associated with the individual susceptibility to SARS-CoV-2 infection calls for a system biology approach; this strategy can address multiple goals, including which patients will respond effectively to the therapeutic treatment. The power of metabolomics lies in the ability to recognize endogenous and exogenous metabolites within a biological sample, measuring their concentration, and identifying perturbations of biochemical pathways associated with qualitative and quantitative metabolic changes. Over the last year, a limited number of metabolomics- and lipidomics-based clinical studies in COVID-19 patients have been published and are discussed in this review. Remarkable alterations in the lipid and amino acid metabolism depict the molecular phenotype of subjects infected by SARS-CoV-2; notably, structural and functional data on the lipids-virus interaction may open new perspectives on targeted therapeutic interventions. Several limitations affect most metabolomics-based studies, slowing the routine application of metabolomics. However, moving metabolomics from bench to bedside cannot imply the mere determination of a given metabolite panel; rather, slotting metabolomics into clinical practice requires the conversion of metabolic patient-specific data into actionable clinical applications.


Assuntos
COVID-19/patologia , Metabolômica/métodos , Aminoácidos/análise , Aminoácidos/metabolismo , COVID-19/epidemiologia , COVID-19/virologia , Citocinas/análise , Eicosanoides/sangue , Humanos , Lipídeos/sangue , Pandemias , Fenilalanina/análise , Fenilalanina/metabolismo , SARS-CoV-2/isolamento & purificação
16.
Int J Chron Obstruct Pulmon Dis ; 16: 1415-1424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079245

RESUMO

Purpose: Lipid mediators, particularly eicosanoids, are associated with airway inflammation, especially with the eosinophilic influx. This study aimed to measure lipid mediators and cells in induced sputum, that could possibly reflect the inflammatory process in the bronchial tree of COPD subjects. Patients and Methods: Eighty patients diagnosed with COPD and 37 healthy controls participated in the study. Induced sputum samples were ascertained for differential cell count and induced sputum supernatant concentrations of selected eicosanoids by the means of gas chromatography/mass spectrometry and high-performance liquid chromatography/tandem mass spectrometry. Results: Increased sputum eosinophilia was associated with higher concentrations of selected proinflammatory eicosanoids. In COPD subjects prostaglandin D2 and 11-dehydro-thromboxane B2 correlated negatively with airway obstruction measured by FEV1 and FEV1/FVC values. COPD subjects with disease exacerbations during past 12 months had significantly higher concentrations of prostaglandin D2, 12-oxo-eicosatetraenoic acid and 5-oxo-eicosatetraenoic acid. Conclusion: Stable COPD is often associated with eosinophil influx in the lower airways and elevated concentrations of eicosanoids that is reflected by some disease characteristics.


Assuntos
Eosinofilia , Doença Pulmonar Obstrutiva Crônica , Ácidos Araquidônicos , Eicosanoides , Eosinofilia/diagnóstico , Eosinófilos , Humanos , Inflamação , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Escarro
17.
J Allergy Clin Immunol ; 148(2): 368-380.e3, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34111453

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to a variety of clinical outcomes, ranging from the absence of symptoms to severe acute respiratory disease and ultimately death. A feature of patients with severe coronavirus disease 2019 (COVID-19) is the abundance of inflammatory cytokines in the blood. Elevated levels of cytokines are predictive of infection severity and clinical outcome. In contrast, studies aimed at defining the driving forces behind the inflammation in lungs of subjects with severe COVID-19 remain scarce. OBJECTIVE: Our aim was to analyze and compare the plasma and bronchoalveolar lavage (BAL) fluids of patients with severe COVID-19 (n = 45) for the presence of cytokines and lipid mediators of inflammation (LMIs). METHODS: Cytokines were measured by using Luminex multiplex assay, and LMIs were measured by using liquid chromatography-tandem mass spectrometry. RESULTS: We revealed high concentrations of numerous cytokines, chemokines, and LMIs in the BAL fluid of patients with severe COVID-19. Of the 13 most abundant mediators in BAL fluid, 11 were chemokines, with CXCL1 and CXCL8 being 200 times more abundant than IL-6 and TNF-α. Eicosanoid levels were also elevated in the lungs of subjects with severe COVID-19. Consistent with the presence chemotactic molecules, BAL fluid samples were enriched for neutrophils, lymphocytes, and eosinophils. Inflammatory cytokines and LMIs in plasma showed limited correlations with those present in BAL fluid, arguing that circulating inflammatory molecules may not be a reliable proxy of the inflammation occurring in the lungs of patients with severe COVID-19. CONCLUSIONS: Our findings indicate that hyperinflammation of the lungs of patients with severe COVID-19 is fueled by excessive production of chemokines and eicosanoids. Therapeutic strategies to dampen inflammation in patients with COVID-19 should be tailored accordingly.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Eicosanoides/imunologia , Inflamação/imunologia , Pulmão/imunologia , SARS-CoV-2 , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/sangue , Citocinas/sangue , Feminino , Humanos , Inflamação/sangue , Pulmão/citologia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Índice de Gravidade de Doença
18.
J Dermatol ; 48(9): 1442-1446, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34114674

RESUMO

Pachydermoperiostosis (PDP) is a genetic disease characterized by digital clubbing, periostosis, and pachydermia caused by mutated HPGD or SLCO2A1. Plasma prostaglandin (PG)E2 levels are increased in these patients. However, other eicosanoids have not been quantitated. We aimed to quantitate plasma eicosanoid levels in four patients carrying SLCO2A1 mutations by high-performance liquid chromatography-tandem mass spectrometry. PGE2 level was elevated in all patients; PGD2 and 11ß-PGF2 α levels were also increased in some patients, whereas eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were decreased in all patients. Our data indicate a dysfunctional eicosanoid homeostasis and varied levels of PG in patients with a complete form of PDP carrying SLCO2A1 mutations. PGE2 levels seem to mostly affect the symptoms, with other eicosanoids possibly having a minor effect.


Assuntos
Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Dinoprostona , Eicosanoides , Humanos , Mutação , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/diagnóstico , Osteoartropatia Hipertrófica Primária/genética
19.
Toxicol Sci ; 183(1): 170-183, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34175951

RESUMO

Ozone (O3) is a criteria air pollutant known to increase the morbidity and mortality of cardiopulmonary diseases. This occurs through a pulmonary inflammatory response characterized by increased recruitment of immune cells into the airspace, pro-inflammatory cytokines, and pro-inflammatory lipid mediators. Recent evidence has demonstrated sex-dependent differences in the O3-induced pulmonary inflammatory response. However, it is unknown if this dimorphic response is evident in pulmonary lipid mediator metabolism. We hypothesized that there are sex-dependent differences in lipid mediator production following acute O3 exposure. Male and female C57BL/6J mice were exposed to 1 part per million O3 for 3 h and were necropsied at 6 or 24 h following exposure. Lung lavage was collected for cell differential and total protein analysis, and lung tissue was collected for mRNA analysis, metabololipidomics, and immunohistochemistry. Compared with males, O3-exposed female mice had increases in airspace neutrophilia, neutrophil chemokine mRNA, pro-inflammatory eicosanoids such as prostaglandin E2, and specialized pro-resolving mediators (SPMs), such as resolvin D5 in lung tissue. Likewise, precursor fatty acids (arachidonic and docosahexaenoic acid; DHA) were increased in female lung tissue following O3 exposure compared with males. Experiments with ovariectomized females revealed that loss of ovarian hormones exacerbates pulmonary inflammation and injury. However, eicosanoid and SPM production were not altered by ovariectomy despite depleted pulmonary DHA concentrations. Taken together, these data indicate that O3 drives an increased pulmonary inflammatory and bioactive lipid mediator response in females. Furthermore, ovariectomy increases susceptibility to O3-induced pulmonary inflammation and injury, as well as decreases pulmonary DHA concentrations.


Assuntos
Ozônio , Caracteres Sexuais , Animais , Eicosanoides , Feminino , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ozônio/toxicidade
20.
Sci Rep ; 11(1): 12771, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140546

RESUMO

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.


Assuntos
Bovinos/imunologia , Perda do Embrião/imunologia , Perda do Embrião/veterinária , Inflamação/imunologia , Inflamação/veterinária , Leucócitos/metabolismo , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Bovinos/sangue , Eicosanoides/metabolismo , Perda do Embrião/sangue , Feminino , Regulação da Expressão Gênica , Glutationa Peroxidase/metabolismo , Inflamação/sangue , Interferons/metabolismo , Oxirredução , Gravidez , Prostaglandinas/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Superóxido Dismutase/metabolismo , Ultrassonografia
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