RESUMEN
We hypothesized that polymorphisms of genes involved in the prostaglandin pathway could be associated with COPD. In this study we explored the involvement of genetic polymorphisms in PTGS2, PTGER2 and PTGER4 genes in the development and severity of COPD and their effects on plasma concentrations of inflammatory/oxidative stress markers. We identified genotypes of PTGS2, PTGER2 and PTGER4 SNPs in a Tunisian cohort including COPD patients (n = 138) and control subjects (n = 216) using PCR-RFLP and PCR TaqMan. Pulmonary function (FEV1 and FVC) were assessed by plethsmography. PGE2, PGD2 and cytokine plasma (IL-6, IL-18, TNF-α, TGF-ß) concentrations were measured using ELISA and colorimetric standard methods were used to determine oxidative stress concentrations. Genotype frequencies of rs2745557 in PTGS2 and rs2075797 in PTGER2 were different between COPD cases and controls. There was no correlation between these polymorphisms and lung function parameters. For rs2745557, the A allele frequency was higher in COPD cases than in controls. For rs2075797, carriers of the GG genotype were more frequent in the COPD group than in controls. Only rs2745557 in PTGS2 had an effect on PGD2 and cytokine plasma concentrations. PGD2 was significantly decreased in COPD patients with the GA or AA genotypes. In contrast, IL-18 and NO plasma concentrations were increased in COPD rs2745557 A allele carriers as compared to homozygous GG subjects. Our findings suggest that rs2745557 in PTGS2 and rs2075797 in PTGER2 are associated with COPD development but not with its severity.
Asunto(s)
Ciclooxigenasa 2/genética , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Subtipo EP2 de Receptores de Prostaglandina E/genética , Anciano , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Citocinas/sangre , Dinoprostona/sangre , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Prostaglandina D2/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Subtipo EP4 de Receptores de Prostaglandina E/genética , Factores de Riesgo , Túnez/epidemiologíaRESUMEN
BACKGROUND & AIMS: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) have been reported to have beneficial cardiovascular effects, but its mechanism of protection against acute myocardial infarction (AMI) who are under guideline-based therapy is not fully understood. Here, we used a metabolomic approach to systematically analyze the eicosanoid metabolites induced by ω-3 PUFA supplementation and investigated the underlying mechanisms. METHODS: Participants with AMI after successful percutaneous coronary intervention were randomized to 3 months of 2 g daily ω-3 PUFA and guideline-adjusted therapy (n = 30, ω-3 therapy) or guideline-adjusted therapy alone (n = 30, Usual therapy). Functional PUFA-derived eicosanoids in plasma were profiled by metabolomics. Clinical and laboratory tests were obtained before and 3 months after baseline and after the study therapy. RESULTS: By intent-to-treat analysis, the content of 11-HDoHE, 20-HDoHE and 16,17-EDP and that of epoxyeicosatetraenoic acids (EEQs), derived from docosahexaenoic acid and eicosapentaenoic acid, respectively, were significantly higher with ω-3 group than Usual therapy, whereas that of prostaglandin J2 (PGJ2) and leukotriene B4, derived from arachidonic acid, was significantly decreased. As compared with Usual therapy, ω-3 PUFA therapy significantly reduced levels of triglycerides (-6.3%, P < 0.05), apolipoprotein B (-4.9%, P < 0.05) and lipoprotein(a) (-37.0%, P < 0.05) and increased nitric oxide level (62.2%, P < 0.05). In addition, the levels of these variables were positively correlated with change in 16,17-EDP and EEQs content but negatively with change in PGJ2 content. CONCLUSIONS: ω-3 PUFA supplementation may improve lipid metabolism and endothelial function possibly by affecting eicosanoid metabolic status at a systemic level during convalescent healing after AMI. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1900025859.
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Suplementos Dietéticos , Endotelio Vascular/efectos de los fármacos , Ácidos Grasos Omega-3/administración & dosificación , Metabolismo de los Lípidos/efectos de los fármacos , Infarto del Miocardio/terapia , Enfermedad Aguda , Anciano , Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Muerte Súbita Cardíaca/prevención & control , Eicosanoides/sangre , Endotelio Vascular/fisiopatología , Femenino , Humanos , Análisis de Intención de Tratar , Leucotrieno B4/sangre , Masculino , Metaboloma , Metabolómica , Persona de Mediana Edad , Infarto del Miocardio/sangre , Óxido Nítrico/biosíntesis , Política Nutricional , Intervención Coronaria Percutánea , Prostaglandina D2/análogos & derivados , Prostaglandina D2/sangreRESUMEN
Background: The popularity of apneic diving is continually growing. As apnea diving substantially burdens the cardiovascular system, special focus is warranted. Regarding inflammation processes and associated inflammatory-related diseases (e.g., cardiovascular diseases), eicosanoids play an important role. This study aims to investigate polyunsaturated fatty acids (PUFAs) and eicosanoids in voluntary apnea divers, and so to further improve understanding of pathophysiological processes focusing on proinflammatory effects of temporarily hypercapnic hypoxia.. Methods: The concentration of PUFAs and eicosanoids were investigated in EDTA plasma in apnea divers (n=10) before and immediately after apnea, 0.5 hour and four hours later, applying liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Mean age was 41±10 years, and divers performed a mean breath-hold time of 317±111 seconds. PUFAs, eicosanoids and related lipids could be classified in four different kinetical reaction groups following apnea. The first group (e.g., Ω-6 and Ω-3-PUFAs) showed an immediate concentration increase followed by a decrease below baseline four hours after apnea. The second group (e.g., thromboxane B2) showed a slower increase, with its maximum concentration 0.5 hour post-apnea followed by a decrease four hours post-apnea. Group 3 (9- and 13-hydroxyoctadecadienoic acid) is characterized by two concentration increase peaks directly after apnea and four hours afterward compared to baseline. Group 4 (e.g., prostaglandin D2) shows no clear response. Conclusion: Changes in the PUFA metabolism after even a single apnea revealed different kinetics of pro- and anti-inflammatory regulations and changes for oxidative stress levels. Due to the importance of these mediators, apnea diving should be evaluated carefully and be performed only with great caution against the background of cardiovascular diseases and inflammation processes.
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Apnea/sangre , Contencion de la Respiración , Buceo/fisiología , Eicosanoides/sangre , Ácidos Grasos Insaturados/sangre , Adulto , Cromatografía Liquida/métodos , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Femenino , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Prostaglandina D2/sangre , Espectrometría de Masas en Tándem/métodos , Tromboxano B2/sangre , Factores de TiempoRESUMEN
BACKGROUND: Prostaglandin D2 (PGD2) induces sleep and may play a role in sleep and neurological disorders. We investigated PGD synthase (PGDS) levels in various sleep and neurological disorders. METHODS: Sixty-three patients with neurological or sleep disorders (Parkinson's disease with excessive daytime sleepiness (PDS), n = 19; PD without sleepiness (PDWS), n = 14; Alzheimer's disease (AD), n = 10; narcolepsy (NA), n = 10; sleep apnea syndrome (SAS), n = 10) and 21 healthy controls were included in this study. Plasma lipocalin-type PGDS (L-PGDS) and glutathione-dependent hematopoietic PGDS (H-PGDS) levels were assessed using an enzyme-linked immunosorbent assay. RESULTS: H-PGDS levels were not significantly different among the groups. Compared with healthy controls, the PDWS, PDS and AD groups had higher levels of L-PGDS. Neither H-PGDS nor L-PGDS levels correlated with scores on the Epworth Sleepiness Scale or Pittsburgh Sleep Quality Index in any group. CONCLUSION: We found higher levels of L-PGDS in patients with neurodegenerative diseases such as PD and AD. Whether increased L-PGDS levels reflect underlying sleepiness or the pathophysiology of neurodegenerative diseases needs further study.
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Oxidorreductasas Intramoleculares , Lipocalinas , Enfermedades del Sistema Nervioso/sangre , Prostaglandina D2/sangre , Trastornos del Sueño-Vigilia/sangre , Humanos , SueñoRESUMEN
Renal fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Recently, asiatic acid (AA), a triterpenoid compound from Chinese medicine Centella asiatica, has been found to attenuate renal fibrosis. In the current study, we explored the mechanisms underlying antifibrotic effect of AA on UUO model. SD rats and ICR mice were subjected to unilateral ureteral occlusion (UUO) surgery. Prior the surgery, rats were administered AA (10 mg·kg-1 per day, ig) for 7 days, whereas the mice received AA (15 mg·kg-1 per day, ig) for 3 days. UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-ß/Smad and Wnt/ß-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. In addition, we found that co-treatment with GW9662, a selective PPAR-γ antagonist (1 mg·kg-1 per day, ip) for 7 days, abolished the protective effects of AA. We further revealed that AA pretreatment did not significantly change the expression levels of PPAR-γ in the kidney, but markedly increase the plasma levels of 15d-PGJ2, an endogenous ligand of PPAR-γ. In UUO mice, pretreatment with 15d-PGJ2 (24 µg·kg-1 per day, ip, for 7 days) produced similar protective effect as AA. Moreover, AA pretreatment upregulated the expression levels of active, nuclear-localized SREBP-1 (nSREBP-1), whereas fatostatin, a specific inhibitor of SREBP-1, decreased the expression of nSREBP-1, as well as the level of 15d-PGJ2. These results provide new insight into the antifibrotic mechanism of AA and endogenous metabolites might become a new clue for investigation of drug mechanism.
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Fibrosis/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , PPAR gamma/metabolismo , Triterpenos Pentacíclicos/farmacología , Prostaglandina D2/análogos & derivados , Obstrucción Ureteral/tratamiento farmacológico , Administración Oral , Anilidas/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fibrosis/metabolismo , Fibrosis/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ligandos , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , PPAR gamma/antagonistas & inhibidores , Triterpenos Pentacíclicos/administración & dosificación , Triterpenos Pentacíclicos/antagonistas & inhibidores , Prostaglandina D2/administración & dosificación , Prostaglandina D2/biosíntesis , Prostaglandina D2/sangre , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
Objective: The inflammatory mechanisms underpinning asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) have not been fully elucidated. Here, we examined the levels of cysteinyl leukotrienes (cys-LTs), prostaglandin D2 (PG-D2), prostaglandin E2 (PG-E2), interleukin 5 (IL-5), and a disintegrin and metalloprotease domain (ADAM 33) in ACOS patients to determine the relationship between levels of these inflammatory markers and pulmonary functions.Methods: Blood samples were obtained from asthma, COPD, and ACOS patients who received combined therapy and were stable for the last month to measure cys-LTs, PG-D2, PG-E2, IL-5, and ADAM33 levels. Differences between groups and their correlations with pulmonary function tests were evaluated.Results: In total, 24 ACOS, 27 asthma, and 35 COPD patients were included. . PG-D2 levels were higher in ACOS (120.9 ± 117.2 ng/L) and asthma (119.6 ± 111.7 ng/L) patients than in COPD (82.6 ± 46.7 ng/L) patients (p = 0.036 and p = 0.038, respectively). In ACOS patients, PG-D2, cys-LTs, and ADAM33 levels were negatively correlated with FEV1/FVC% values (p = 0.021, p = 0.008, and p = 0.028, respectively). In COPD patients, a negative correlation was detected between PG-E2 and FEV1/FVC% (p = 0.007), whereas positive correlations were detected between IL-5 and pulmonary function tests, including FVC, FVC%, FEV1, FEV1%, FEF25-75, and FEF25-75% (p = 0.047, p = 0.005, p = 0.002, p = 0.002, p = 0.010, and p = 0.005, respectively). In asthma patients, cys-LTs levels were negatively correlated with FEV1 and FEF25-75 values (p = 0.045 and p = 0.037, respectively).Conclusions: PG-D2 levels may be a valuable biomarker to differentiate COPD in asthma and ACOS patients.
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Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/diagnóstico , Asma/diagnóstico , Mediadores de Inflamación/sangre , Prostaglandina D2/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Proteínas ADAM/sangre , Proteínas ADAM/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Asma/sangre , Asma/inmunología , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/sangre , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/inmunología , Biomarcadores/sangre , Estudios Transversales , Diagnóstico Diferencial , Dinoprostona/sangre , Dinoprostona/inmunología , Femenino , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/inmunología , Mediadores de Inflamación/inmunología , Interleucina-5/sangre , Interleucina-5/inmunología , Masculino , Persona de Mediana Edad , Prostaglandina D2/inmunología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Espirometría , Adulto JovenRESUMEN
Many hypotheses have been proposed for the development of schizophrenia, including the one proposing that exogenous and endogenous factors are linked to inflammatory processes. There is strong evidence about the immunological and inflammatory dysfunction in schizophrenia. In this study, we aimed to measure serum 15-deoxy-delta(12,14)-prostaglandin J (15d-PGJ), peroxisome proliferator-activated receptor gamma(PPARγ), prostaglandin E2 (PGE2) and C-reactive protein (CRP) levels. Forty-four patients and 39 healthy volunteers were included in the study. Serum PGE2, 15d-PGJ, PPARγ and CRP levels were measured in both the groups. Demographic data forms were filled out for the patient group, and the Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale and Calgary Depression scale were used to assess patients' clinical status. Serum PGE2, 15d-PGJ and PPARγ levels were found to be significantly lower in patients with schizophrenia than in healthy controls. There was no significant relationship between the serum PGE2, 15d-PGJ and PPARγ levels and CRP levels.In this study, the evidence of systemic inflammatory conditions in patients with schizophrenia was found. The duration of the disease has been found to be the only variable that independently affects all three biomarker levels in the patients with schizophrenia.
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Proteína C-Reactiva/metabolismo , Dinoprostona/sangre , Inflamación/sangre , PPAR gamma/sangre , Prostaglandina D2/análogos & derivados , Esquizofrenia/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prostaglandina D2/sangreRESUMEN
RATIONALE: Fluid shear stress (FSS) maintains NOS-3 (endothelial NO synthase) expression. Homozygosity for the C variant of the T-786C single-nucleotide polymorphism of the NOS3 gene, which solely exists in humans, renders the gene less sensitive to FSS, resulting in a reduced endothelial cell (EC) capacity to generate NO. Decreased bioavailability of NO in the arterial vessel wall facilitates atherosclerosis. Consequently, individuals homozygous for the C variant have an increased risk for coronary heart disease (CHD). OBJECTIVE: At least 2 compensatory mechanisms seem to minimize the deleterious effects of this single-nucleotide polymorphism in affected individuals, one of which is characterized herein. METHODS AND RESULTS: Human genotyped umbilical vein ECs and THP-1 monocytes were used to investigate the role of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in vitro. Its concentration in plasma samples from genotyped patients with CHD and age-matched CHD-free controls was determined using quantitative ultraperformance LC-MS/MS. Exposure of human ECs to FSS effectively reduced monocyte transmigration particularly through monolayers of CC-genotype ECs. Primarily in CC-genotype ECs, FSS elicited a marked rise in COX (cyclooxygenase)-2 and L-PGDS (lipocalin-type prostaglandin D synthase) expression, which appeared to be NO sensitive, and provoked a significant release of 15d-PGJ2 over baseline. Exogenous 15d-PGJ2 significantly reduced monocyte transmigration and exerted a pronounced anti-inflammatory effect on the transmigrated monocytes by downregulating, for example, transcription of the IL (interleukin)-1ß gene (IL1B). Reporter gene analyses verified that this effect is due to binding of Nrf2 (nuclear factor [erythroid-derived 2]-like 2) to 2 AREs (antioxidant response elements) in the proximal IL1B promoter. In patients with CHD, 15d-PGJ2 plasma levels were significantly upregulated compared with age-matched CHD-free controls, suggesting that this powerful anti-inflammatory prostanoid is part of an endogenous defence mechanism to counteract CHD. CONCLUSIONS: Despite a reduced capacity to form NO, CC-genotype ECs maintain a robust anti-inflammatory phenotype through an enhanced FSS-dependent release of 15d-PGJ2.
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Células Endoteliales/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico/sangre , Polimorfismo de Nucleótido Simple , Prostaglandina D2/análogos & derivados , Adaptación Fisiológica , Anciano , Anciano de 80 o más Años , Enfermedad Coronaria/sangre , Enfermedad Coronaria/genética , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/genética , Inducción Enzimática , Femenino , Genes Reporteros , Predisposición Genética a la Enfermedad , Hemorreología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación , Oxidorreductasas Intramoleculares/biosíntesis , Oxidorreductasas Intramoleculares/genética , Lipocalinas/biosíntesis , Lipocalinas/genética , Masculino , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/fisiología , Óxido Nítrico Sintasa de Tipo III/genética , Prostaglandina D2/biosíntesis , Prostaglandina D2/sangre , Prostaglandina D2/fisiología , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Células THP-1RESUMEN
Tree nuts are among "Big Eight" and have been reported globally for causing allergy. Buchanania lanzan (Bl) is one of the major tree nuts consumed by Indian population. However, very little is known about B. lanzan's induced allergic manifestation. Therefore, evaluation of it's allergenic potential was undertaken. Bl-crude protein extract sensitized BALB/c mice sera were used to identify the allergic proteins by it's IgE binding capability. The major IgE binding proteins found with molecular weight of 11, 20, 23, 25, 48, 54, and 65â¯kDa. Specific IgE, specific IgG1, MCPT-1, PGD2 and histamine were assessed in mice sera. Enormous amount of mast cell infiltration was noted in different organs. The levels of Th1/Th2 transcription factors GATA-3, SOCS3 and STAT-6 were found upregulated, whereas T-bet was downregulated. Furthermore, elevated Th1/Th2 cytokine responses were observed in mice sera. All together, these reactions developed systemic anaphylaxis upon Bl-CPE challenge in sensitized BALB/c mice. In order to confirm the evidences obtained from the studies carried out in BALB/c, the investigation was extended to human subjects as well. Control subjects and allergic patients were subjected to skin prick test (SPT). Later sera collected from those positive to SPT along with controls were used for IgE immunoblotting. The study evaluated the allergic manifestation associated with Bl, and identified it's proteins attributing Bl-mediated allergy. This work may help in managing tree nuts mediated allergies especially due to Buchanania lanzan sensitization.
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Alérgenos/administración & dosificación , Anacardiaceae/inmunología , Hipersensibilidad a los Alimentos/inmunología , Nueces/inmunología , Extractos Vegetales/administración & dosificación , Proteínas de Plantas/administración & dosificación , Alérgenos/inmunología , Animales , Quimasas/sangre , Citocinas/sangre , Femenino , Hipersensibilidad a los Alimentos/patología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Intestinos/efectos de los fármacos , Intestinos/inmunología , Intestinos/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones Endogámicos BALB C , Extractos Vegetales/inmunología , Proteínas de Plantas/inmunología , Prostaglandina D2/sangre , Pruebas Cutáneas , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patologíaRESUMEN
Endothelial dysfunction contributes to sepsis outcome. Metabolic phenotypes associated with endothelial dysfunction are not well characterised in part due to difficulties in assessing endothelial metabolism in situ. Here, we describe the construction of iEC2812, a genome scale metabolic reconstruction of endothelial cells and its application to describe metabolic changes that occur following endothelial dysfunction. Metabolic gene expression analysis of three endothelial subtypes using iEC2812 suggested their similar metabolism in culture. To mimic endothelial dysfunction, an in vitro sepsis endothelial cell culture model was established and the metabotypes associated with increased endothelial permeability and glycocalyx loss after inflammatory stimuli were quantitatively defined through metabolomics. These data and transcriptomic data were then used to parametrize iEC2812 and investigate the metabotypes of endothelial dysfunction. Glycan production and increased fatty acid metabolism accompany increased glycocalyx shedding and endothelial permeability after inflammatory stimulation. iEC2812 was then used to analyse sepsis patient plasma metabolome profiles and predict changes to endothelial derived biomarkers. These analyses revealed increased changes in glycan metabolism in sepsis non-survivors corresponding to metabolism of endothelial dysfunction in culture. The results show concordance between endothelial health and sepsis survival in particular between endothelial cell metabolism and the plasma metabolome in patients with sepsis.
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Células Endoteliales/efectos de los fármacos , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Metaboloma , Sepsis/metabolismo , Biomarcadores/sangre , Línea Celular , Cromatografía Líquida de Alta Presión , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ácidos Grasos/metabolismo , Glicocálix/química , Glicocálix/efectos de los fármacos , Glicocálix/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Quinurenina/sangre , Lisofosfolípidos/sangre , Modelos Biológicos , Óxido Nítrico/sangre , Permeabilidad , Polisacáridos/química , Polisacáridos/metabolismo , Prostaglandina D2/sangre , Sepsis/clasificación , Sepsis/diagnóstico , Sepsis/mortalidad , Esfingosina/análogos & derivados , Esfingosina/sangre , Análisis de Supervivencia , Triptófano/análogos & derivados , Triptófano/sangre , Ácido gamma-Aminobutírico/sangreRESUMEN
Conventional allergic rhinitis (AR) treatments have limitations due to the lack of safety and complete cure strategy. We evaluated the effects of silent information regulator 1 (SIRT1), a multifunctional molecule involved in a variety of inflammatory pathways, on murine AR model. Ovalbumin (OVA)-induced murine model was constructed, and recombinant SIRT1 was administered into the nostril continuously. The expression of SIRT1 was measured at mRNA and protein levels, and the allergic symptoms were evaluated. Protein levels of OVA-specific IgE, leukotriene C4 (LTC4), eosinophil cation protein (ECP), prostaglandin D2 (PGD2), as well as different inflammatory cytokine mediators in the serum and nasal lavage fluid (NLF), were assessed by ELISA. The effects of SIRT1 on human primary nasal epithelial cells challenged with tumour necrosis factor (TNF)-α were also evaluated by investigating the HMGB1/TLR4 signalling pathway. Administration of SIRT1 significantly alleviated OVA-induced AR symptoms with lower numbers of sneezing and nasal rubbing events, decreased levels of OVA-specific IgE, LTC4, ECP, PGD2, less inflammatory cells and downregulated levels of Th2 type cytokines. SIRT1 also reduced the genes of HMGB1/TLR4 signalling pathway in the murine model and cultured human nasal epithelial cells. Expression of SIRT1 is impaired in OVA-induced AR model. The administration of SIRT1 alleviates the allergic symptoms of mice, regulates the production of pro-inflammatory mediators predominantly produced by Th2 cells in AR and attenuates expressions of proteins relevant to HMGB1/TLR4 signalling pathway. All the results showed that SIRT1 is promising as a therapeutic agent of AR.
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Proteína HMGB1/biosíntesis , Rinitis Alérgica/terapia , Sirtuina 1/uso terapéutico , Receptor Toll-Like 4/biosíntesis , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Regulación hacia Abajo , Proteína Catiónica del Eosinófilo/sangre , Femenino , Humanos , Inmunoglobulina E/sangre , Leucotrieno C4/sangre , Ratones , Ratones Endogámicos BALB C , Líquido del Lavado Nasal/química , Mucosa Nasal/citología , Ovalbúmina/efectos adversos , Prostaglandina D2/sangre , Proteínas Recombinantes/uso terapéutico , Rinitis Alérgica/inducido químicamente , Rinitis Alérgica/patología , Transducción de Señal/efectos de los fármacos , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/efectos adversosAsunto(s)
Dolor Abdominal/tratamiento farmacológico , Anafilaxia/tratamiento farmacológico , Angioedema/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Mastocitosis/tratamiento farmacológico , Urticaria/tratamiento farmacológico , Dolor Abdominal/diagnóstico , Dolor Abdominal/inmunología , Dolor Abdominal/patología , Adulto , Anafilaxia/diagnóstico , Anafilaxia/inmunología , Anafilaxia/patología , Angioedema/diagnóstico , Angioedema/inmunología , Angioedema/patología , Antiasmáticos/uso terapéutico , Biomarcadores/sangre , Cromolin Sódico/uso terapéutico , Diarrea/diagnóstico , Diarrea/inmunología , Diarrea/patología , Dinoprost/sangre , Femenino , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Leucotrieno E4/sangre , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/patología , Mastocitosis/diagnóstico , Mastocitosis/inmunología , Mastocitosis/patología , Persona de Mediana Edad , Omalizumab/uso terapéutico , Prostaglandina D2/sangre , Resultado del Tratamiento , Triptasas/sangre , Urticaria/diagnóstico , Urticaria/inmunología , Urticaria/patologíaAsunto(s)
Eosinófilos/inmunología , Mastocitos/inmunología , Mastocitosis/diagnóstico , Prurito/diagnóstico , Piel/patología , Anciano , Alérgenos/inmunología , Antiinflamatorios no Esteroideos/inmunología , Antiinflamatorios no Esteroideos/uso terapéutico , Biomarcadores/sangre , Femenino , Histamina/sangre , Humanos , Ibuprofeno/inmunología , Ibuprofeno/uso terapéutico , Prostaglandina D2/sangre , Triptasas/sangreRESUMEN
In systemic lupus erythematosus (SLE), autoantibody production can lead to kidney damage and failure, known as lupus nephritis. Basophils amplify the synthesis of autoantibodies by accumulating in secondary lymphoid organs. Here, we show a role for prostaglandin D2 (PGD2) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD2 receptors (PTGDR) on blood basophils and increased concentration of PGD2 metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD2 induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD2 can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD2/PTGDR axis as a ready-to-use therapeutic modality in SLE.
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Basófilos/inmunología , Lupus Eritematoso Sistémico/inmunología , Sistema Linfático/inmunología , Prostaglandina D2/inmunología , Adulto , Animales , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Prostaglandina D2/sangre , Receptores CXCR4/sangre , Receptores CXCR4/inmunología , Receptores Inmunológicos/sangre , Receptores Inmunológicos/inmunología , Receptores de Prostaglandina/sangre , Receptores de Prostaglandina/inmunología , Transducción de Señal/inmunología , Adulto JovenRESUMEN
Fetal pain and fetal anesthesia are still matter of debate: some authors hypothesize that several intrauterine endocrine neuroinhibitors (ENIn) anesthetize the fetus, keeping it in a constant state of sleep, and making pharmacological fetal anesthesia useless for fetal surgery, while others argue fetal pain is possible and shoud be prevented with fetal anesthesy. AIM: To retrieve evidences about fetal pain, fetal arousability and about the level of sedation induced by the ENIn, in order to assess the necessity of direct fetal anesthesia during prenatal fetal surgery. METHODS: We performed a careful literature review (1990-2016) on fetal arousability, and on the possibility that ENIn at the average fetal blood levels induce actual anesthesia. We retrieved the papers that fulfilled the research criteria, with particular attention to the second half of pregnancy, the period when most fetal surgery is performed. RESULTS: Fetuses are awake about 10% of the total time in the last gestational weeks, and they can be aroused by external stimuli. ENIn have not an anesthetic effect at normal fetal values, but only when they areartificialy injected at high doses; their blood levels in the last trimester of average pregnancies are not dissimilar either in the fetus or in the mother. CONCLUSIONS: During the second half of the pregnancy, external stimuli can awake the fetuses, although they spend most of the time in sleeping state; the presence of ENIn is absolutely not enough to guarantee an effective anesthesia during surgery. Thus, direct fetal analgesia/anesthesia is mandatory, though further studies on its possible drawbacks are necessary.
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Analgesia , Feto/cirugía , Dolor/embriología , Dolor/prevención & control , Adenosina/sangre , Adenosina/fisiología , Analgesia/métodos , Anestesia/métodos , Nivel de Alerta , Femenino , Sangre Fetal/química , Feto/inervación , Edad Gestacional , Humanos , MEDLINE , Sistema Nervioso/embriología , Manejo del Dolor , Embarazo , Pregnanolona/sangre , Pregnanolona/fisiología , Prostaglandina D2/sangre , Prostaglandina D2/fisiologíaRESUMEN
Mast cell activation syndrome (MCAS) involves the skin, gastrointestinal, cardiovascular, respiratory, and neurologic systems, classified as primary, secondary, and idiopathic. Earlier criteria for MCAS diagnosis included episodic symptoms with mast cell mediators affecting two or more organ systems with urticaria, angioedema, flushing, nausea, vomiting, diarrhea, abdominal cramping, hypotensive syncope, tachycardia, wheezing, conjunctival injection, pruritus, nasal stuffiness, decrease in frequency, severity, or resolution of symptoms with anti-mediator therapy including H1/H2 receptor antagonists, anti-leukotrienes, or mast cell stabilizers. Laboratory data includes an increased validated urinary or serum markers of MCAS, documentation of an increase of the marker above the patient's baseline value during symptomatic periods on more than two occasions, or baseline serum tryptase levels that are persistently above 15 ng/mL. Laboratory data also includes an increase of the tryptase level above baseline value on one occasion. Other assays are 24-h urine histamine metabolites, PGD2 or its metabolite, and 11-ß-prostaglandin F2 alpha. A recent global classification is a response of clinical symptoms, a substantial transient increase in serum total tryptase or increase in other mast cell-derived mediators, histamine or PGD2 or urinary metabolites, and agents that attenuate production or mast cell mediator activities. "Spectrum of MCAS disorders" has been proposed, highlighting symptoms' diagnostic tests and treatments.
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Histamina/metabolismo , Mastocitos/inmunología , Mastocitosis/inmunología , Biomarcadores/sangre , Humanos , Mastocitosis/diagnóstico , Mastocitosis/tratamiento farmacológico , Omalizumab/uso terapéutico , Prostaglandina D2/sangre , Triptasas/sangreRESUMEN
The determination of individual prostaglandins (PG) in humans is mainly performed in urine samples. The quantification of PGs in human plasma could improve the understanding of particular PG species under various physiological and pathological conditions. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a dehydrated downstream product of PGD2 and is of high interest due to its recently discovered anti-inflammatory effects. Increasing availability of highly sensitive mass spectrometry allows the quantification of low abundant biomarkers like 15d-PGJ2 in human plasma samples. Herein, a sensitive LC-MS/MS method for the determination of 15d-PGJ2 was established. The method was validated according to the guidance of the American Food and Drug Administration and tested in plasma samples from patients with poorly controlled diabetes, considered to be a pro-inflammatory condition. Extraction of 15d-PGJ2 was achieved with an easy-to-use liquid-liquid extraction by ethyl acetate following a methanol precipitation. The lower limit of quantification was 2.5 pg mL-1 and linearity (R 2 = 0.998) was guaranteed between 2.5 and 500 pg mL-1 for 15d-PGJ2. Selectivity was assured by the use of two individual mass transitions (qualifier and quantifier). Precision and accuracy were validated in an inter- and intraday assay with a coefficient of variation below 11.8% (intraday) and 14.7% (interday). In diabetic patients with an HbA1C > 9%, increased plasma concentrations of 15d-PGJ2 compared to control plasma were measured. 15d-PGJ2 correlated negatively with the inflammation marker C-reactive protein. The developed LC-MS/MS method represents a new possibility to quantify 15d-PGJ2 with high specificity in human plasma samples. This may contribute to a better understanding of the potential anti-inflammatory effects of 15d-PGJ2 in severe long-term pro-inflammatory disorders like diabetes, cancer, or cardiovascular disease.
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Diabetes Mellitus Tipo 2/sangre , Prostaglandina D2/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Adulto , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Inflamación/sangre , Límite de Detección , Masculino , Persona de Mediana Edad , Prostaglandina D2/sangreRESUMEN
Schizophrenia is a serious mental illness of unclear aetiology. The reduced ability of methylnicotinate to induce a topical vasodilatory response in patients with the disorder is well established. Methylnicotinate causes vasodilation via stimulating the release of prostaglandins (including prostaglandin D2) in the skin which in turn leads to relaxation of vascular smooth muscle. To determine whether the abnormality is likely to be due to decreased prostaglandin production, or a decreased effect of prostaglandins upon the vessels, topical methylnicotinate was applied to the forearms of patients with schizophrenia or healthy controls, followed by rating of the resulting erythema. The concentration of prostaglandin D2 and its metabolite 11ß-prostaglandin F2α in the blood draining the arm was also measured. Although erythema was reduced in the patient group, this was not correlated with plasma prostaglandin concentrations. This data suggests the abnormality underlying the reduced potency of methylnicotinate to produce vasodilation in the disorder occurs downstream of prostaglandin synthesis possibly within the vasculature itself.
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Ácidos Nicotínicos/farmacología , Prostaglandina D2/sangre , Esquizofrenia/metabolismo , Vasodilatadores/farmacología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/sangre , Piel/efectos de los fármacosRESUMEN
Background: Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Results: Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Conclusion: Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors.
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Depresión/sangre , Trastorno Depresivo Mayor/sangre , Prostaglandina D2/sangre , Adolescente , Adulto , Animales , Antidepresivos Tricíclicos/uso terapéutico , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Liquida , Depresión/tratamiento farmacológico , Depresión/etiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Femenino , Preferencias Alimentarias/efectos de los fármacos , Humanos , Imipramina/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Selenio/farmacología , Estrés Psicológico/complicaciones , Natación/psicología , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND: Mast cell activation syndrome (MCAS), a recently recognized nonneoplastic mast cell disease driving chronic multisystem inflammation and allergy, appears prevalent and thus important. We report the first systematic characterization of a large MCAS population. METHOD: Demographics, comorbidities, symptoms, family histories, physical examination and laboratory findings were reviewed in 298 retrospective and 115 prospective patients with MCAS. Blood samples from prospective subjects were examined by flow cytometry for clonal mast cell disease and tested for cytokines potentially driving the monocytosis frequent in MCAS. RESULTS: Demographically, white females dominated. Median ages at symptom onset and diagnosis were 9 and 49 years, respectively (range: 0-88 and 16-92, respectively) and median time from symptom onset to diagnosis was 30 years (range: 1-85). Median numbers of comorbidities, symptoms, and family medical issues were 11, 20, and 4, respectively (range: 1-66, 2-84, and 0-33, respectively). Gastroesophageal reflux, fatigue and dermatographism were the most common comorbidity, symptom and examination finding. Abnormalities in routine laboratories were common and diverse but typically modest. The most useful diagnostic markers were heparin, prostaglandin D2, histamine and chromogranin A. Flow cytometric and cytokine assessments were unhelpful. CONCLUSIONS: Our study highlights MCAS׳s morbidity burden and challenging heterogeneity. Recognition is important given good survival and treatment prospects.