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This study aimed to identify and quantify free fatty acids (FFAs), secretory phospholipase A2 group IIa (sPLA2-IIa) and cytosolic phospholipase A2 (cPLA2) in serum of superior limbic keratoconjunctivitis (SLK) patients and explored the association between FFAs, sPLA2-IIa and cPLA2 variations and SLK. Targeted metabolomic analysis of FFAs in serum was performed by gas chromatography tandem mass spectrometry (GC-MS/MS) analysis on 16 SLK patients (43.88 ± 7.88 years; female: 62.50%) and 25 healthy controls (43.12 ± 7.88 years; female: 64.00%). Qualitative and absolute quantitative results of FFAs were obtained and classified according to gender and thyroid tests. Differential lipid metabolites, metabolomic pathways and biomarkers were further evaluated. The serum sPLA2-IIa and cPLA2 were determined by enzyme linked immunosorbent assay (ELISA). Among 40 FFAs identified, 6 FFAs showed significant changes (P < 0.05) in SLK patients, including 4 decreased and 2 increased. They were mainly related to unsaturated fatty acid biosynthesis, α-linolenic acid and linoleic acid metabolism, and fatty acid biosynthesis. When dividing the data by gender or abnormal thyroid tests, some comparable FFAs alterations displayed in SLK patients. The ROC analysis revealed that the AUC values of linoleic acid, γ-linolenic acid, cis-8,11,14-eicosatrienoic acid, stearic acid, and palmitic acid, were all greater than 0.8. The serum concentrations of sPLA2-IIa and cPLA2 in patients with SLK were significantly higher than that in healthy controls. Lipidomics disturbance might be the potential mechanism of SLK. Serum FFA biomarkers associated with SLK have potential for the diagnosis and treatment of the disease.
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Biomarcadores , Ácidos Grasos no Esterificados , Lipidómica , Metabolómica , Humanos , Femenino , Masculino , Adulto , Ácidos Grasos no Esterificados/sangre , Lipidómica/métodos , Persona de Mediana Edad , Metabolómica/métodos , Biomarcadores/sangre , Cromatografía de Gases y Espectrometría de Masas , Queratoconjuntivitis/sangre , Queratoconjuntivitis/diagnóstico , Ensayo de Inmunoadsorción Enzimática , Espectrometría de Masas en Tándem , Fosfolipasas A2 Grupo II/sangreRESUMEN
Previous research suggests that group IIA-secreted phospholipase A2 (sPLA2-IIA) plays a role in and predicts lethal COVID-19 disease. The current study reanalyzed a longitudinal proteomic data set to determine the temporal relationship between levels of several members of a family of sPLA2 isoforms and the severity of COVID-19 in 214 ICU patients. The levels of six secreted PLA2 isoforms, sPLA2-IIA, sPLA2-V, sPLA2-X, sPLA2-IB, sPLA2-IIC, and sPLA2-XVI, increased over the first 7 ICU days in those who succumbed to the disease but attenuated over the same time period in survivors. In contrast, a reversed pattern in sPLA2-IID and sPLA2-XIIB levels over 7 days suggests a protective role of these two isoforms. Furthermore, decision tree models demonstrated that sPLA2-IIA outperformed top-ranked cytokines and chemokines as a predictor of patient outcome. Taken together, proteomic analysis revealed temporal sPLA2 patterns that reflect the critical roles of sPLA2 isoforms in severe COVID-19 disease.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/mortalidad , COVID-19/sangre , Femenino , Masculino , Persona de Mediana Edad , Anciano , Fosfolipasas A2 Secretoras/sangre , Proteómica/métodos , Índice de Severidad de la Enfermedad , Fosfolipasas A2 Grupo II/sangre , Adulto , Isoformas de Proteínas/sangre , Citocinas/sangreRESUMEN
There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
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COVID-19/sangre , COVID-19/mortalidad , Fosfolipasas A2 Grupo II/sangre , SARS-CoV-2/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Tasa de SupervivenciaRESUMEN
The aim of this study was to determine the association between secretory phospholipase A2 group IIA (sPLA2-IIA) and eicosanoid pathway metabolites in patients with bacterial sepsis syndrome (BSS). Levels of sPLA2-IIA, eicosanoids prostaglandin (PG)E2, PGD synthase were quantified in the sera from patients confirmed to have bacterial sepsis (BS; N = 45), bacterial severe sepsis/septic shock (BSS/SS; N = 35) and healthy subjects (N = 45). Cyclooxygenase (COX)-1 and COX-2 activities were analyzed from cell lysate. Serum levels of sPLA2-IIA, PGE2, and PGDS increased significantly in patients with BS and BSS/SS compared to healthy subjects (p<0.05). COX-2 activity was significantly increased in patients with BS compared to healthy subjects (p<0.05), but not COX-1 activity. Binary logistic regression analysis showed that sPLA2-IIA and PGE2 were independent factors predicting BSS severity. In conclusion, high level of sPLA2-IIA is associated with eicosanoid metabolism in patients with BSS.
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Bacteriemia/sangre , Dinoprostona/sangre , Fosfolipasas A2 Grupo II/sangre , Adulto , Anciano , Bacteriemia/patología , Biomarcadores/sangre , Ciclooxigenasa 1/sangre , Ciclooxigenasa 2/sangre , Femenino , Humanos , Oxidorreductasas Intramoleculares/sangre , Lipocalinas/sangre , Masculino , Persona de Mediana EdadRESUMEN
Phospholipase A2 (PLA2) enzymes are small lipolytic hydrolases that can regulate immune responses through generation of Arachidonic Acid (AA), a precursor molecule of lipid mediators like prostaglandins, leukotrienes and thromboxanes. One of the family members of PLA2, secretory Phospholipase A2 Group IIA (PLA2G2A), was associated with different types of malignancies including prostate cancer. Elevated serum levels of PLA2G2A was found in prostate cancer (PCa) patients and associated with increased tumor grade in literature. 5'UTR regions have regulatory role in protein expression by controlling the accessibility of factors necessary for the translation initiation. Single nucleotide polymorphisms at 5'UTR regions have the potential to affect mRNA translation efficiency resulting in altered protein levels depending on structure and nucleotide content. Given that the 5'UTR polymorphism in PLA2G2A gene (rs11573156) is associated with increased serum levels of PLA2G2A, the association of this 5'UTR polymorphism with PCa susceptibility and metastasis was investigated in this study. Total of 261 PCa patients and 128 control individuals were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Individuals with heterozygous CG genotype was found to have significantly reduced risk of PCa metastasis with an Odds Ratio (OR) of 0.405 (p = 0.028, 95%CI = 0.181-0.906), compared to the carriers of homozygous CC genotype (p > 0.05) suggesting an anti-metastatic effect for the G allele. No association was found between PCa susceptibility and Gleason score (p > 0.05) in Turkish population.
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Predisposición Genética a la Enfermedad , Fosfolipasas A2 Grupo II/genética , Neoplasias de la Próstata/genética , Regiones no Traducidas 5'/genética , Anciano , Alelos , Estudios de Casos y Controles , Fosfolipasas A2 Grupo II/sangre , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Próstata/patología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patología , Biosíntesis de Proteínas/genética , ARN Mensajero/genética , Turquía/epidemiologíaRESUMEN
Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA2-IIA (group IIA secretory phospholipase A2) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA2-IIA in secondary prevention, we prospectively evaluated sPLA2-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA2-IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA2-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA2-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA2-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA2-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.
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Enfermedades Cardiovasculares/enzimología , Dislipidemias/enzimología , Fosfolipasas A2 Grupo II/sangre , Inflamación/enzimología , Anciano , Antiinflamatorios/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/prevención & control , Método Doble Ciego , Dislipidemias/tratamiento farmacológico , Dislipidemias/epidemiología , Dislipidemias/genética , Femenino , Predisposición Genética a la Enfermedad , Fosfolipasas A2 Grupo II/genética , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Incidencia , Inflamación/tratamiento farmacológico , Inflamación/epidemiología , Inflamación/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Prevención Primaria , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Rosuvastatina Cálcica/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Inflammation may occur in Type2 diabetes mellitus. sPLA2 is among the factors that contribute to the activation of pathways involved in inflammation. Several agents affect serum sPLA2 level, one of which is genetic diversity. OBJECTIVE: The current study was performed to determine whether there is a relationship between sPLA2 gene (-763C > G) polymorphism and circulating sPLA2 level in patients with Type 2 diabetes. METHODS: DNA was extracted from blood samples and used for the amplification of sPLA2 gene using ARMS-PCR. RESULTS: A statistical analysis using SPSS (version 16) revealed a significant correlation between -763C > G sPLA2 gene polymorphisms and the disease incidence in patients with T2DM. Among the three possible genotypes (GG, CC, and CG), CG genotype was found to have a higher frequency(53%) in T2DM patients. GG and CC genotypes frequencies were 20 and 27%, respectively. In healthy individuals, the frequencies of CC, GG, and GC genotypes were 77, 9.8% and 13.2%, respectively). Patients with genotype GG had the highest level of sPLA2. We showed that C>G polymorphism at position- 763 is associated with a high level of sPLA2 in both T2DM patients and healthy individuals. The average of sPLA2 circulating level was (170.48± 84.90), (106.62 ± 74.31), in patients and normal individuals, respectively. CONCLUSION: Our findings show that sPLA2 serum level is significantly higher in patients with T2DM disease than that in healthy individuals.
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Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Fosfolipasas A2 Grupo II/sangre , Fosfolipasas A2 Grupo II/genética , Mediadores de Inflamación/sangre , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Incidencia , Irán/epidemiología , Fenotipo , Regulación hacia ArribaRESUMEN
This study aims to test the hypothesis that vitamin D deficiency can influence long-chain polyunsaturated fatty acid metabolism through alterations in the one-carbon cycle. Wistar rats (n = 8 per group) were given either a control (1,000 IU D3/kg diet) or a vitamin D deficient (VDD) (0 IU D3/kg diet) diet from pre-pregnancy to delivery. On day 20 of gestation, pregnant female rats were delivered by C-section to collect placenta and blood. VDD group demonstrated high serum parathyroid hormone, low serum phosphate, low plasma folate, higher plasma homocysteine, and higher plasma malondialdehyde levels (P < 0.05 for all) as compared to control. Lower protein levels of placental cystathionine-ß-synthase enzyme (P < 0.05) were observed in the VDD group as compared to control. VDD group demonstrated higher placental mRNA levels of the enzymes phospholipase A2 and cyclooxygenase-2 (P < 0.05 for both) as compared to control. Protein levels of the enzymes phospholipase A2 and cyclooxygenase-2 were lower (P < 0.05 for both) in the VDD group as compared to the control group. The ratio of thromboxane B2 and 6-keto prostaglandin F1α in serum was higher (P < 0.05) in the VDD group as compared to control; although the serum levels of 6-keto prostaglandin F1α and thromboxane B2 were similar in both the groups. Our findings suggest that increased oxidative stress due to maternal vitamin D deficiency results in the imbalance between the vasoconstrictor (thromboxane B2 ) and vasodilator (6-keto prostaglandin F1α ) eicosanoids, which may lead to endothelial dysfunction and poor pregnancy outcome. © 2019 BioFactors, 45 (4):548-555, 2019.
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6-Cetoprostaglandina F1 alfa/sangre , Ciclooxigenasa 2/genética , Cistationina betasintasa/genética , Fosfolipasas A2 Grupo II/genética , Tromboxano B2/sangre , Deficiencia de Vitamina D/sangre , Animales , Calcio/sangre , Ciclooxigenasa 2/sangre , Cistationina betasintasa/sangre , Modelos Animales de Enfermedad , Femenino , Ácido Fólico/sangre , Regulación de la Expresión Génica , Fosfolipasas A2 Grupo II/sangre , Homocisteína/sangre , Humanos , Malondialdehído/sangre , Hormona Paratiroidea/sangre , Hormona Paratiroidea/genética , Fosfatos/sangre , Placenta/metabolismo , Placenta/patología , Embarazo , Ratas , Ratas Wistar , Transducción de Señal , Vitamina B 12/sangre , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/patologíaRESUMEN
Human Group IIA secreted phospholipase A2 (hGIIA) is an acute phase protein with bactericidal activity against Gram-positive bacteria. Infection models in hGIIA transgenic mice have suggested the importance of hGIIA as an innate defense mechanism against the human pathogens Group A Streptococcus (GAS) and Group B Streptococcus (GBS). Compared to other Gram-positive bacteria, GAS is remarkably resistant to hGIIA activity. To identify GAS resistance mechanisms, we exposed a highly saturated GAS M1 transposon library to recombinant hGIIA and compared relative mutant abundance with library input through transposon-sequencing (Tn-seq). Based on transposon prevalence in the output library, we identified nine genes, including dltA and lytR, conferring increased hGIIA susceptibility. In addition, seven genes conferred increased hGIIA resistance, which included two genes, gacH and gacI that are located within the Group A Carbohydrate (GAC) gene cluster. Using GAS 5448 wild-type and the isogenic gacI mutant and gacI-complemented strains, we demonstrate that loss of the GAC N-acetylglucosamine (GlcNAc) side chain in the ΔgacI mutant increases hGIIA resistance approximately 10-fold, a phenotype that is conserved across different GAS serotypes. Increased resistance is associated with delayed penetration of hGIIA through the cell wall. Correspondingly, loss of the Lancefield Group B Carbohydrate (GBC) rendered GBS significantly more resistant to hGIIA-mediated killing. This suggests that the streptococcal Lancefield antigens, which are critical determinants for streptococcal physiology and virulence, are required for the bactericidal enzyme hGIIA to exert its bactericidal function.
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Antibacterianos/farmacología , Pared Celular/metabolismo , Fosfolipasas A2 Grupo II/inmunología , Inmunidad Innata/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Infecciones Estreptocócicas/microbiología , Streptococcus/inmunología , Actividad Bactericida de la Sangre , Fosfolipasas A2 Grupo II/sangre , Fosfolipasas A2 Grupo II/genética , Interacciones Huésped-Patógeno , Humanos , Infecciones Estreptocócicas/sangre , Infecciones Estreptocócicas/enzimología , Streptococcus/patogenicidadRESUMEN
INTRODUCTION: This paper investigates the role of Group II Secretory Phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults. Sepsis and bacterial infection are common problems encountered by patients in the hospital and often carry adverse outcomes if not managed early. METHODS: Two independent reviewers conducted a comprehensive search using Ovid MEDLINE published from years 1993 to 2016 and SCOPUS published from year 1985 to 2017 to screen for relevant studies. The main inclusion criteria included adult subjects, patients with suspected or confirmed signs of infection and relevant outcomes which looked into the role of sPLA2-IIA in detecting the presence of sepsis and bacterial infection in the subjects. RESULTS AND DISCUSSION: Four studies met the inclusion criteria. SPLA2-IIA was found to be effective in detecting the presence of sepsis and bacterial infection in adults. The levels of serum sPLA2-IIA also correlated well with the presence of sepsis and bacterial infection. CONCLUSION: This systematic review highlights the role of sPLA2-IIA as a reliable tool to diagnose sepsis and bacterial infection in adult patients. Nonetheless, further studies should be done in the future to provide more compelling evidence on its application in the clinical setting.
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Infecciones Bacterianas/diagnóstico , Biomarcadores/sangre , Fosfolipasas A2 Grupo II/sangre , Sepsis/diagnóstico , Infecciones Bacterianas/enzimología , Humanos , Sepsis/enzimologíaRESUMEN
BACKGROUND: Hepatitis B virus (HBV) infection causes acute and chronic liver disease, ultimately leading to the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Phospholipase A2 group IIA (PLA2G2A) plays important roles in the development and progression of many tumors. Thus far, there have been no reports on the association between HBV and PLA2G2A. The present study investigated the effect of HBV infection on PLA2G2A expression and its application in the diagnosis of HBV-related diseases. METHODS: Serum levels of PLA2G2A in 308 HBV-infected patients and 185 healthy controls were measured using an enzyme-linked immunosorbent assay (ELISA). The difference in serum levels of PLA2G2A was analyzed among chronic hepatitis B (CHB), LC, and HCC patients. PLA2G2A mRNA and protein expression in HepG2 and HepG2.2.15 cells carrying the integrated HBV genome were measured using reverse transcription polymerase chain reaction (RT-PCR) and western blot assays. The HBV infectious clone pHBV1.3, the control plasmid pBlue-ks and PLA2G2A gene promoter were transfected into HepG2 and HepG2.2.15 cells. After transfection, the luciferase activity was measured in the cells. PLA2G2A mRNA and protein expression levels were examined using RT-PCR and western blot assays. RESULTS: The serum levels of PLA2G2A were 258.3 ± 20.3ng/dl in the healthy controls and 329.0 ± 22.5ng/dl, 385.4 ± 29.3ng/dl and 459.2 ± 38.6ng/dl in the CHB, LC, and HCC patients, respectively. Statistical analyses revealed significantly higher serum levels of PLA2G2A in CHB, LC, and HCC patients than in the healthy controls (P < 0.05), and PLA2G2A levels were elevated in the order of HCC > LC > CHB group. High serum PLA2G2A levels in HCC patients were associated with a lower prevalence of lymph node metastasis and a lower TNM stage. HepG2.2.15 cells carrying the HBV genome expressed higher levels of PLA2G2A mRNA and protein than the HepG2 cells. In addition, HBV triggered PLA2G2A promoter activity and enhanced PLA2G2A mRNA and protein expression compared to the empty vector pBlue-ks. CONCLUSION: HBV can upregulate the expression of PLA2G2A, and serum levels of PLA2G2A are associated with the progression of HBV-related diseases.
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Carcinoma Hepatocelular/genética , Fosfolipasas A2 Grupo II/genética , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/genética , Interacciones Huésped-Patógeno , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Adulto , Anciano , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Femenino , Expresión Génica , Genes Reporteros , Fosfolipasas A2 Grupo II/sangre , Células Hep G2 , Virus de la Hepatitis B/crecimiento & desarrollo , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Luciferasas/genética , Luciferasas/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Plásmidos/química , Plásmidos/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/sangre , ARN Mensajero/genética , TransfecciónRESUMEN
This study was undertaken to analyze the association of type II secretory phospholipase A2 (sPLA2 -II) and surfactant protein D (SP-D) with the pulmonary oxygenation potential in patients with septic shock during polymyxin-B immobilized fiber-direct hemoperfusion (PMX-DHP). The study was conducted in 25 patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). PMX-DHP lowered the blood endotoxin level in all patients. Following PMX-DHP, there were decreases from day 0 â day 1 â day 2 in both the mean plasma sPLA2 -II level (340 â 260 â 189 ng/mL) and plasma SP-D level (483 â 363 â 252 ng/mL). The PaO2/FiO2 ratio (P/F ratio) rose (210 â 237 â 262) in all patients. Upon the onset of ALI or ARDS, there was a significant negative correlation between the sPLA2 -II level and the P/F ratio. Furthermore, there was a significant positive correlation between the sPLA2 -II and TNF-α levels. The results suggest that as the blood endotoxin levels were lowered by the PMX-DHP, the inflammatory reactions were suppressed, with suppressed formation of sPLA2 -II and improved pulmonary oxygenation potential. The results also suggested possible involvement of TNF-α in the production of sPLA2 -II.
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Fosfolipasas A2 Grupo II/sangre , Hemoperfusión/métodos , Proteína D Asociada a Surfactante Pulmonar/sangre , Choque Séptico/terapia , Lesión Pulmonar Aguda/sangre , Lesión Pulmonar Aguda/fisiopatología , Lesión Pulmonar Aguda/terapia , Anciano , Anciano de 80 o más Años , Endotoxinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/fisiología , Polimixina B , Ventilación Pulmonar , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Choque Séptico/sangre , Choque Séptico/fisiopatología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
A critical association between type II secretory phospholipase A2 (sPLA2-IIa) and established atherosclerotic cardiovascular disease has been demonstrated. However, the contribution of sPLA2-IIa to early atherosclerosis remains unknown. This study investigated the association between early-stage atherosclerosis and sPLA2-IIa in metabolic syndrome (MetS) patients. One hundred and thirty-six MetS patients and 120 age- and gender-matched subjects without MetS were included. Serum sPLA2-IIa protein levels and activity were measured using commercial kits. Circulating endothelial activation molecules (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin), and carotid intima-media thickness (cIMT), were measured as parameters of vascular endothelial dysfunction and early atherosclerosis. MetS patients exhibited significantly higher sPLA2-IIa protein and activity levels than the controls. Both correlated positively with fasting blood glucose and waist circumference in MetS patients. Additionally, MetS patients exhibited strikingly higher levels of endothelial activation molecules and increased cIMT than controls. These levels correlated positively with serum sPLA2-IIa protein levels and activity. Moreover, multivariate analysis showed that high sPLA2-IIa protein and activity levels were independent risk factors of early atherosclerosis in MetS patients. This study demonstrates an independent association between early-stage atherosclerosis and increased levels of sPLA2-IIa, implying that increased sPLA2-IIa may predict early-stage atherosclerosis in MetS patients.
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Aterosclerosis/complicaciones , Fosfolipasas A2 Grupo II/sangre , Síndrome Metabólico/complicaciones , Anciano , Aterosclerosis/sangre , Aterosclerosis/metabolismo , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , China , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Riesgo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
INTRODUCTION: Early diagnosis of sepsis and bacterial infection is imperative as treatment relies on early antibiotic administration. There is a need to develop new biomarkers to detect patients with sepsis and bacterial infection as early as possible, thereby enabling prompt antibiotic treatment and improving the survival rate. METHODS: Fifty-one adult patients with suspected bacterial sepsis on admission to the Emergency Department (ED) of a teaching hospital were included into the study. All relevant cultures and serology tests were performed. Serum levels for Group II Secretory Phospholipase A2 (sPLA2-IIA) and CD64 were subsequently analyzed. RESULTS AND DISCUSSION: Sepsis was confirmed in 42 patients from a total of 51 recruited subjects. Twenty-one patients had culture-confirmed bacterial infections. Both biomarkers were shown to be good in distinguishing sepsis from non-sepsis groups. CD64 and sPLA2-IIA also demonstrated a strong correlation with early sepsis diagnosis in adults. The area under the curve (AUC) of both Receiver Operating Characteristic curves showed that sPLA2-IIA was better than CD64 (AUC = 0.93, 95% confidence interval (CI) = 0.83-0.97 and AUC = 0.88, 95% CI = 0.82-0.99, respectively). The optimum cutoff value was 2.13µg/l for sPLA2-IIA (sensitivity = 91%, specificity = 78%) and 45 antigen bound cell (abc) for CD64 (sensitivity = 81%, specificity = 89%). In diagnosing bacterial infections, sPLA2-IIA showed superiority over CD64 (AUC = 0.97, 95% CI = 0.85-0.96, and AUC = 0.95, 95% CI = 0.93-1.00, respectively). The optimum cutoff value for bacterial infection was 5.63µg/l for sPLA2-IIA (sensitivity = 94%, specificity = 94%) and 46abc for CD64 (sensitivity = 94%, specificity = 83%). CONCLUSIONS: sPLA2-IIA showed superior performance in sepsis and bacterial infection diagnosis compared to CD64. sPLA2-IIA appears to be an excellent biomarker for sepsis screening and for diagnosing bacterial infections, whereas CD64 could be used for screening bacterial infections. Both biomarkers either alone or in combination with other markers may assist in decision making for early antimicrobial administration. We recommend incorporating sPLA2-IIA and CD64 into the diagnostic algorithm of sepsis in ED.
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Infecciones Bacterianas/sangre , Infecciones Bacterianas/diagnóstico , Biomarcadores/sangre , Fosfolipasas A2 Grupo II/sangre , Receptores de IgG/sangre , Sepsis/sangre , Sepsis/diagnóstico , Área Bajo la Curva , Diagnóstico Precoz , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Sensibilidad y Especificidad , Tasa de SupervivenciaRESUMEN
Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.
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Artritis Reumatoide/diagnóstico , Fosfolipasas A2 Grupo II/sangre , Adulto , Anciano , Artritis Psoriásica/diagnóstico , Biomarcadores/sangre , Proteína C-Reactiva , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas en el Punto de AtenciónRESUMEN
BACKGROUND: Single nucleotide polymorphisms (SNPs) of the secretory phospholipase A2 type IIa (sPLA-IIa) gene (PLA2G2A) affect sPLA2-IIa level and activity in patients with diabetes mellitus, acute coronary syndrome or recent cardiovascular surgical interventions. Our study examined the effects of PLA2G2A SNPs on sPLA2-IIa levels and activity in patients with stable CHD. METHODS AND RESULTS: The study included a total of 396 patients (30% women). Six SNPs of PLA2G2A: rs1774131, rs11573156, rs3753827, rs2236771, rs876018, and rs3767221, sPLA2-IIa level and activity were determined for all patients. Four SNPs (rs1774131, rs11573156, rs3753827, rs3767221) correlated with sPLA2-IIa level but not activity with the strongest correlation observed for rs11573156 (r=0.49, p=3.7·10(-13)). All partial correlations controlling for rs11573156 became insignificant, whereas, the partial correlation of rs11573156 with sPLA2-IIa level controlling for other SNPs remained significant. Only rs11573156 showed association with sPLA2-IIa level in multiple regression analysis. Haplotype CGGGTT was associated with a significantly higher sPLA2-IIa level but not activity compared with all other haplotypes after adjustment for gender, age, diabetes mellitus and statin use (p=0.0023). CONCLUSIONS: According to our results the examined SNPs affect the sPLA2-IIa level to a greater extent than its activity in patients with stable CHD. It seems that, the impact of these SNPs on sPLA2-IIa level is caused by their linkage to rs11573156 whose minor alleles were associated with higher sPLA2-IIa level. At the same time haplotype CGGGTT, which includes the minor allele of rs11573156, was the dominant haplotype and was associated with the highest sPLA2-IIa level.
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Enfermedad Coronaria/genética , Fosfolipasas A2 Grupo II/sangre , Fosfolipasas A2 Grupo II/genética , Polimorfismo de Nucleótido Simple , Anciano , Enfermedad Coronaria/sangre , Enfermedad Coronaria/enzimología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Homocigoto , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana EdadRESUMEN
Our previous gene expression analysis identified phospholipase A2 group IIA (PLA2G2A) as a potential biomarker of ovarian endometriosis. The aim of this study was to evaluate PLA2G2A mRNA and protein levels in tissue samples (endometriomas and normal endometrium) and in serum and peritoneal fluid of ovarian endometriosis patients and control women. One-hundred and sixteen women were included in this study: the case group included 70 ovarian endometriosis patients, and the control group included 38 healthy women and 8 patients with benign ovarian cysts. We observed 41.6-fold greater PLA2G2A mRNA levels in endometrioma tissue, compared to normal endometrium tissue. Using Western blotting, PLA2G2A was detected in all samples of endometriomas, but not in normal endometrium, and immunohistochemistry showed PLA2G2A-specific staining in epithelial cells of endometrioma paraffin sections. However, there were no significant differences in PLA2G2A levels between cases and controls according to ELISA of peritoneal fluid (6.0 ± 4.4 ng/ml, 6.6 ± 4.3 ng/ml; p = 0.5240) and serum (2.9 ± 2.1 ng/ml, 3.1 ± 2.2 ng/ml; p = 0.7989). Our data indicate that PLA2G2A is implicated in the pathophysiology of ovarian endometriosis, but that it cannot be used as a diagnostic biomarker.
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Líquido Ascítico/metabolismo , Endometriosis/metabolismo , Endometrio/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Enfermedades del Ovario/metabolismo , Adulto , Estudios de Casos y Controles , Endometriosis/sangre , Endometriosis/genética , Femenino , Fosfolipasas A2 Grupo II/sangre , Fosfolipasas A2 Grupo II/genética , Humanos , Persona de Mediana Edad , Quistes Ováricos/sangre , Quistes Ováricos/genética , Quistes Ováricos/metabolismo , Enfermedades del Ovario/sangre , Enfermedades del Ovario/genética , Adulto JovenRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Different therapeutic effects for Zataria multiflora have been described in Iranian traditional medicine. In addition anti-inflammatory and anti-oxidant effects of this plant were previously described. The effect of the extract of Zataria multiflora on tracheal responsiveness (TR) and inflammatory mediators of sensitized guinea pigs was examined. MATERIALS AND METHODS: Five groups of sensitized guinea pigs to ovalbumin (OA) were given drinking water alone, drinking water containing three concentrations of the extract and dexamethasone. TR to methacholine and OA, serum levels of NO, nitrite, PLA2, TP and histamine were measured (n=6, for each groups). RESULTS: TR to methacholine and OA, serum levels of NO, nitrite, PLA2, TP and histamine were increased in sensitized animals compared to control group (p<0.05 to p<0.001). Treatment of sensitized animals with dexamethasone and most concentration of the extract lead to significantly decrease in all measured parameters compared to sensitized group (p<0.05 to p<0.001) except TP and histamine levels in treated group with dexamethasone. CONCLUSION: These results showed a preventive effect of the extract of Zataria multiflora on tracheal responsiveness, serum level of NO, nitrite, total protein, PLA2 and histamine in sensitized guinea pigs which was equal or even more potent than dexamethasone at used concentrations.
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Fosfolipasas A2 Grupo II/sangre , Histamina/sangre , Lamiaceae/química , Óxido Nítrico/sangre , Nitritos/sangre , Extractos Vegetales/farmacología , Tráquea/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Dexametasona/farmacología , Cobayas , Cloruro de Metacolina/metabolismo , Ovalbúmina/farmacología , Extractos Vegetales/químicaRESUMEN
OBJECTIVE: High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet. APPROACH AND RESULTS: sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice (P<0.01). Varespladib acid effectively inhibited plasma sPLA2-IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a proatherogenic plasma lipoprotein profile that appears in response to sPLA2-IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA-modified very low-density lipoproteins specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP. CONCLUSIONS: These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.
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Aorta/enzimología , Enfermedades de la Aorta/enzimología , Aterosclerosis/enzimología , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Acetatos/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/tratamiento farmacológico , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Aterosclerosis/sangre , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/patología , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Fosfolipasas A2 Grupo II/antagonistas & inhibidores , Fosfolipasas A2 Grupo II/sangre , Fosfolipasas A2 Grupo II/genética , Humanos , Hipercolesterolemia/complicaciones , Hipercolesterolemia/enzimología , Hipercolesterolemia/genética , Indoles/farmacología , Cetoácidos , Lipoproteínas VLDL/sangre , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Placa AteroscleróticaRESUMEN
INTRODUCTION: Serum amyloid A (SAA), secreted group IIA phospholipase A2 (sPLA2-IIA), and C-reactive protein (CRP) are acute-phase proteins whose serum concentrations increase not only during inflammatory disorders, but also in the course of malignant diseases. MATERIALS AND METHODS: In this study we analyzed serum levels of these inflammatory markers along with prostate-specific antigens (PSA) in patients with benign prostatic hyperplasia (BPH, n = 55), localized prostate cancers (PCa, n = 55), and metastatic prostate cancers (mPCa, n = 27) using immunological assays. RESULTS: We found that in comparison to healthy individuals (n = 55), patients with BPH, PCa and mPCa have elevated serum levels of SAA, sPLA2-IIA, and CRP, in addition to elevated levels of PSA. Significant differences with respect to inflammatory biomarkers were found between localized and metastatic PCa (p < 0.001), suggesting a prognostic value of these parameters. In addition, serum concentrations of SAA and sPLA2-IIA positively correlate with CRP in BPH patients (p < 0.05) and in patients with PCa and mPCa (p < 0.001), but not with PSA levels, Gleason score, or tumor stage, emphasizing a role of SAA and sPLA2-IIA as circulating biomarkers of inflammation rather than of neoplastic transformation. In contrast to PSA, which differed significantly between BPH and localized PCa patients (p < 0.01), such a difference was not found for SAA, sPLA2-IIA, and CRP. In order to elucidate whether the elevated levels of SAA and sPLA2-IIA can be caused by cancer cell-associated synthesis, in vitro studies were performed. These analyses demonstrated the expression of SAA and sPLA2-IIA in LNCaP and PC-3 prostate cell lines, which can be further upregulated by pro-inflammatory cytokines in a cell type-dependent manner. This might suggest that, in addition to the hepatic origin, SAA and sPLA2-IIA can also be synthesized and secreted by prostatic cancer tissue itself. CONCLUSION: The results of the present study emphasize the utility of SAA, sPLA2-IIA, and CRP as circulating biomarkers of inflammation during BPH development and PCa progression.