RESUMEN
BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substance (PFAS) has endocrine-disrupting properties and may affect blood pressure. Endogenous hormones also play a crucial role in the progression of hypertension. However, their interaction with hypertension remains to be explored. METHODS: This study included 10â 794 adults aged ≥18 years from the China National Human Biomonitoring program. Weighted multiple logistic regression and linear regression were used to examine the associations of serum PFAS with hypertension, diastolic blood pressure, and systolic blood pressure. Joint effects of PFAS mixtures on hypertension, diastolic blood pressure, and systolic blood pressure were evaluated using quantile-based g-computation. Additive and multiplicative interactions were used to assess the role of PFAS with testosterone and estradiol on hypertension. RESULTS: The prevalence of hypertension in Chinese adults was 35.50%. Comparing the fourth quartile with the first quartile, odds ratio (95% CI) of hypertension were 1.53 (1.13-2.09) for perfluorononanoic acid, 1.40 (1.03-1.91) for perfluorodecanoic acid, 1.34 (1.02-1.78) for perfluoroheptane sulfonic acid, and 1.46 (1.07-1.99) for perfluorooctane sulfonic acid. Moreover, PFAS mixtures, with perfluorononanoic acid contributing the most, were positively associated with hypertension, diastolic blood pressure, and systolic blood pressure. PFAS and endogenous hormones had an antagonistic interaction in hypertension. For example, the relative excess risk ratio, attributable proportion, and synergy index for perfluorononanoic acid and estradiol were -3.61 (-4.68 to -2.53), -1.65 (-2.59 to -0.71), and 0.25 (0.13-0.47), respectively. CONCLUSIONS: Perfluorononanoic acid, perfluorodecanoic acid, perfluoroheptane sulfonic acid, perfluorooctane sulfonic acid, and PFAS mixtures showed positive associations with hypertension, systolic blood pressure, and diastolic blood pressure. Positive associations of PFAS with hypertension might be attenuated by increased levels of endogenous sex hormones.
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Ácidos Alcanesulfónicos , Fluorocarburos , Hipertensión , Humanos , Fluorocarburos/sangre , Femenino , Hipertensión/epidemiología , Hipertensión/sangre , Masculino , Estudios Transversales , China/epidemiología , Persona de Mediana Edad , Adulto , Ácidos Alcanesulfónicos/sangre , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Exposición a Riesgos Ambientales/efectos adversos , Ácidos Decanoicos/sangre , Disruptores Endocrinos/sangre , Disruptores Endocrinos/efectos adversos , Ácidos Grasos/sangre , Prevalencia , Hormonas Esteroides Gonadales/sangre , Ácidos Sulfónicos/sangre , Contaminantes Ambientales/sangre , Contaminantes Ambientales/efectos adversos , Ácidos Láuricos/sangre , Ácidos Láuricos/farmacologíaRESUMEN
Lauric acid (LA) is a crucial medium-chain fatty acid (MCFA) that has many beneficial effects on humans and animals. This study aimed to investigate the effects of LA on the intestinal barrier, immune functions, serum metabolism, and gut microbiota of broilers under lipopolysaccharide (LPS) challenge. A total of 384 one-day-old broilers were randomly divided into four groups, and fed with a basal diet, or a basal diet supplemented with 75 mg/kg antibiotic (ANT), or a basal diet supplemented with 1000 mg/kg LA. After 42 days of feeding, three groups were intraperitoneally injected with 0.5 mg/kg Escherichia coli- derived LPS (LPS, ANT+LPS and LA+LPS groups) for three consecutive days, and the control (CON) group was injected with the same volume of saline. Then, the birds were sacrificed. Results showed that LA pretreatment significantly alleviated the weight loss and intestinal mucosal injuries caused by LPS challenge. LA enhanced immune functions and inhibited inflammatory responses by upregulating the concentrations of immunoglobulins (IgA, IgM, and IgY), decreasing IL-6 and increasing IL-4 and IL-10. Metabolomics analysis revealed a significant difference of serum metabolites by LA pretreatment. Twenty-seven serum metabolic biomarkers were identified and mostly belong to lipids. LA also markedly modulated the pathway for sphingolipid metabolism, suggesting its ability to regulate lipid metabolism. Moreover,16S rRNA analysis showed that LA inhibited LPS-induced gut dysbiosis by altering cecal microbial composition (reducing Escherichia-Shigella, Barnesiella and Alistipes, and increasing Lactobacillus and Bacteroides), and modulating the production of volatile fatty acids (VFAs). Pearson's correlation assays showed that alterations in serum metabolism and gut microbiota were strongly correlated to the immune factors; there were also strong correlations between serum metabolites and microbiota composition. The results highlight the potential of LA as a dietary supplement to combat bacterial LPS challenge in animal production and to promote food safety.
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Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Ácidos Láuricos/farmacología , Animales , Pollos , Inflamación/inducido químicamente , Inflamación/metabolismo , Intestinos/efectos de los fármacos , Intestinos/metabolismo , Ácidos Láuricos/sangre , Ácidos Láuricos/metabolismo , Lipopolisacáridos , Masculino , Metabolómica , Pérdida de Peso/efectos de los fármacosRESUMEN
CONTEXT: Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. OBJECTIVE: We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. DESIGN AND METHODS: We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. RESULTS: Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 µM). CONCLUSIONS: This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.
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Densidad Ósea/fisiología , Ácidos Láuricos/sangre , Osteoporosis Posmenopáusica/diagnóstico por imagen , Posmenopausia/sangre , Absorciometría de Fotón , Adulto , Animales , Biomarcadores/sangre , Línea Celular , China , Estudios Transversales , Femenino , Humanos , Metaboloma , Ratones , Persona de Mediana Edad , Osteogénesis/fisiología , Osteoporosis Posmenopáusica/sangreRESUMEN
The therapeutic effect of reactive oxygen species (ROS)-involved cancer therapies is significantly limited by shortage of oxy-substrates, such as hypoxia in photodynamic therapy (PDT) and insufficient hydrogen peroxide (H2O2) in chemodynamic therapy (CDT). Here, we report a H2O2/O2 self-supplying nanoagent, (MSNs@CaO2-ICG)@LA, which consists of manganese silicate (MSN)-supported calcium peroxide (CaO2) and indocyanine green (ICG) with further surface modification of phase-change material lauric acid (LA). Under laser irradiation, ICG simultaneously generates singlet oxygen and emits heat to melt the LA. The exposed CaO2 reacts with water to produce O2 and H2O2 for hypoxia-relieved ICG-mediated PDT and H2O2-supplying MSN-based CDT, acting as an open source strategy for ROS production. Additionally, the MSNs-induced glutathione depletion protects ROS from scavenging, termed reduce expenditure. This open source and reduce expenditure strategy is effective in inhibiting tumor growth both in vitro and in vivo, and significantly improves ROS generation efficiency from multi-level for ROS-involved cancer therapies.
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Quimioterapia , Fotoquimioterapia , Especies Reactivas de Oxígeno/metabolismo , Animales , Circulación Sanguínea , Compuestos de Calcio/química , Línea Celular Tumoral , Supervivencia Celular , Sinergismo Farmacológico , Femenino , Humanos , Peróxido de Hidrógeno/metabolismo , Verde de Indocianina/química , Ácidos Láuricos/sangre , Ácidos Láuricos/química , Imagen por Resonancia Magnética , Manganeso/química , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/ultraestructura , Óxidos/química , Silicatos/química , Superóxidos/metabolismo , Distribución TisularRESUMEN
BACKGROUND: Preterm birth and feeding are the most important pathogenic factors of neonatal necrotizing enterocolitis (NEC). Metabonomic has been widely used in the diagnosis and treatment of other diseases, but there is no research on the related diseases of premature infants. Compared with full-term infants, the metabolism of preterm infants has its own specificity, so it can easily lead to NEC and other digestive tract inflammatory diseases. Metabonomic may be applied to the diagnosis of preterm related diseases, such as NEC. METHODS: The model was established with premature infant serum samples from 19 premature infants in our hospital, which was compared with the full-term infant control group. Serum was analyzed by gas chromatography-mass spectrometry (GC-MS), coupled with the analysis of serum metabolic characteristics. The variable important in projection, P value and Pearson correlation coefficient of samples were analyzed by using SIMCA, SPSS and other multivariate statistical analysis software. RESULTS: Compared to the term infants, premature infants had significantly higher levels of luteolin, and lower levels of xylose, O-succinyl-L-homoserine and lauric acid in the serum. There were some correlations among several different metabolites and clinically related indices (albumin, total bilirubin) for premature birth related diseases. CONCLUSIONS: There are metabolic alterations in the serum of premature infants, which make contribution to the diagnosis of NEC.
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Enterocolitis Necrotizante/sangre , Homoserina/análogos & derivados , Enfermedades del Prematuro/sangre , Ácidos Láuricos/sangre , Luteolina/sangre , Xilosa/sangre , Estudios de Casos y Controles , Estudios Transversales , Femenino , Cromatografía de Gases y Espectrometría de Masas , Homoserina/sangre , Humanos , Recién Nacido , Recien Nacido Prematuro , MasculinoRESUMEN
BACKGROUND: One of the topics discussed in sports science is the use of medium-chain saturated fat as an energy-saving nutrient additive when approaching high-intensity exercise. The purpose of this study was to compare the blood concentrations of medium-chain and long-chain fatty acids (FAs) across different intensity loads. METHODS: Fifteen male highly trained athletes from the Russian cross-country skiing team participated in the study. Blood samples were drawn at rest, at the peak of veloergometric test with a growing exercise load till exhaustion (97-100% VO2max), and after competitions. The plasma FA profile was determined using gas-liquid chromatography. RESULTS: We observed a substantial increase in the concentrations of capric acid (С10:0) (+ 164.1%), lauric acid (С12:0) (+ 223.9%), and myristic acid (С14:0) (+ 130.2%) in skiers after a sprint distance (1.3 km). A less intense increase in the concentrations of these acids (p < 0.05) was observed after a middle length distance or cycle exercise «until exhaustion¼. No significant differences in long-chain saturated FA content relative to baselines during exercise tests or competitions were revealed. CONCLUSIONS: In conclusion, the obtained results demonstrate activation of the lipolysis and the oxidation of medium-chain FA involved in the energy supply for highly trained athletes at maximum exercise loads.
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Ácidos Grasos/sangre , Esquí/fisiología , Adolescente , Adulto , Ácidos Decanoicos/sangre , Frecuencia Cardíaca , Humanos , Ácidos Láuricos/sangre , Masculino , Ácido Mirístico/sangre , Consumo de Oxígeno , Descanso , Federación de Rusia , Adulto JovenRESUMEN
Perfluoroalkyl substances (PFAS) are persistent bio-accumulative chemicals that impact the health of pregnant women and their children. PFAS derive from environmental and consumer products, which depend on human lifestyle, socioeconomic characteristics, and time variation. Here, we aimed to explore the temporal trends of PFAS in pregnant women and the characteristics related to maternal PFAS concentration. Our study is part of the Hokkaido Study on Environment and Children's Health, the Hokkaido large-scale cohort that recruited pregnant women between 2003 and 2011. Blood samples were acquired from pregnant women during the third trimester to measure PFAS and cotinine concentrations. Maternal basic information was collected with a baseline structured questionnaire. Eleven PFAS were measured from 2123 samples with ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Eight PFAS were above 80% detection rate and were included in the final analysis. We used multivariable linear regression to analyze the association of pregnant women characteristics with the levels of eight PFAS. The temporal trend of PFAS was observed in two periods (August 2003 to January 2006 and February 2006 to July 2012). The concentration of perfluorooctane sulfonate (PFOS) significantly decreased from August 2003 to January 2006 and from February 2006 to July 2012. The concentrations of perfluorododecanoic acid (PFDoDA), perfluoroundecanoic acid (PFUnDA), and perfluorotridecanoic acid (PFTrDA) increased significantly between August 2003 and January 2006, whereas they decreased significantly between February 2006 and July 2012. Women with pre-pregnancy body mass index (BMI) >25 kg/m² had lower PFUnDA, PFDoDA, and PFTrDA levels than did those with normal BMI (18.5â»24.9 kg/m²). Pregnant women, who were active smokers (cotinine > 11.49 ng/mL), had higher PFOS than the non-smokers (cotinine < 0.22 ng/mL). Lower levels of PFHxS, PFOS, PFOA, PFNA, and PFDA were observed in women, who had given birth to more than one child. There were also significant positive associations between PFAS levels and annual income or maternal education. PFAS levels varied in women with higher pre-pregnancy BMI, active smoking status, higher education level and annual income. The causes of the individual PFAS differences should be explored in an independent study.
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Ácidos Alcanesulfónicos/sangre , Monitoreo del Ambiente , Contaminantes Ambientales/sangre , Ácidos Grasos/sangre , Fluorocarburos/sangre , Ácidos Láuricos/sangre , Exposición Materna/estadística & datos numéricos , Embarazo/sangre , Adulto , Cromatografía , Cotinina/sangre , Femenino , Humanos , Japón , Modelos Lineales , Estudios Prospectivos , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
SCOPE: The aim of the paper is to investigate whether changes in the metabolome could explain observed changes in body composition in overweight adults after consumption of butter with high level of medium-chain fatty acids (MCFAs) in combination with casein or whey. METHODS AND RESULTS: With GC-TOF and LC-Q/MS, metabolites in plasma and urine from a 12-week randomized double-blinded human intervention including 52-abdominally overweight adults were analyzed. The participants consumed 63 g per day of milk fat (high or low in MCFAs) and 60 g per day of protein (whey or casein). Urinary loss of the tricarboxylic acid cycle metabolites and a concomitantly increase of glycerol in blood were observed in the whey + high-MCFAs group, indicating potential lower anabolic processes, such as lipogenesis, by draining substrates. High intake of MCFAs resulted in elevated level of urinary adipic (independently of protein type) and plasma sebacic acid (with whey), indicating a potential increase in oxidation of MCFAs, which might lead to energy loss. CONCLUSION: The type of protein showed highest effect on the overall metabolic profiles, but ω-oxidation of MCFAs in the liver seemed to be the main reason for the observed reduction in body fat mass after consumption of high MCFAs, independent of type of protein.
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Ácidos Grasos/farmacología , Leche/química , Obesidad/metabolismo , Suero Lácteo , Adulto , Animales , Sangre/metabolismo , Caseínas/farmacocinética , Caseínas/farmacología , Ciclo del Ácido Cítrico/fisiología , Ácidos Grasos/química , Ácidos Grasos/farmacocinética , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Ácidos Láuricos/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Obesidad/dietoterapia , Orina/fisiologíaRESUMEN
Coconut oil has recently attracted considerable attention as a potential Alzheimer's disease therapy because it contains large amounts of medium-chain fatty acids (MCFAs) and its consumption is thought to stimulate hepatic ketogenesis, supplying an alternative energy source for brains with impaired glucose metabolism. In this study, we first reevaluated the responses of plasma ketone bodies to oral administration of coconut oil to rats. We found that the coconut oil-induced increase in plasma ketone body concentration was negligible and did not significantly differ from that observed after high-oleic sunflower oil administration. In contrast, the administration of coconut oil substantially increased the plasma free fatty acid concentration and lauric acid content, which is the major MCFA in coconut oil. Next, to elucidate whether lauric acid can activate ketogenesis in astrocytes with the capacity to generate ketone bodies from fatty acids, we treated the KT-5 astrocyte cell line with 50 and 100 µM lauric acid for 4 h. The lauric acid treatments increased the total ketone body concentration in the cell culture supernatant to a greater extent than oleic acid, suggesting that lauric acid can directly and potently activate ketogenesis in KT-5 astrocytes. These results suggest that coconut oil intake may improve brain health by directly activating ketogenesis in astrocytes and thereby by providing fuel to neighboring neurons.
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Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Cuerpos Cetónicos/biosíntesis , Ácidos Láuricos/farmacología , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Cuerpos Cetónicos/sangre , Ácidos Láuricos/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The goal of this paper is to determine concentrations of seven selected perfluoroalkylated substances (PFASs): perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA) in the blood serum of men and women of reproductive age from the central region of Poland. The relation between sex of tested subjects and the levels of compounds in blood serum of humans will also be considered and analysed as an element of the risk assessment. The study was made on the blood serum samples collected from 253 women and 176 men of reproductive age between 20 and 44 years from Warsaw and surrounding areas. Higher concentrations of five (PFOS, PFOA, PFNA, PFDA, PFUnDA) from among seven selected PFASs were observed in men in comparison to women from the same populations. Only the concentrations of PFHxS and PFDoDA were slightly higher in women than in men. These differences were statistically significant in all cases, except for PFUnDA. The hypothesis that the concentrations of said compounds increase with age of the test subjects, regardless of gender has not been confirmed.
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Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/sangre , Fluorocarburos/sangre , Adulto , Ácidos Alcanesulfónicos/sangre , Caprilatos/sangre , Ácidos Decanoicos/sangre , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Humanos , Ácidos Láuricos/sangre , Masculino , Persona de Mediana Edad , Polonia , Suero , Adulto JovenRESUMEN
Contributions of direct and indirect (via precursors) pathways of human exposure to perfluorooctane sulfonic acid (PFOS) isomers and perfluoroalkyl carboxylic acids (PFCAs) are estimated using a Scenario-Based Risk Assessment (SceBRA) modelling approach. Monitoring data published since 2008 (including samples from 2007) are used. The estimated daily exposures (resulting from both direct and precursor intake) for the general adult population are highest for PFOS and perfluorooctanoic acid (PFOA), followed by perfluorohexanoic acid (PFHxA) and perfluorodecanoic acid (PFDA), while lower daily exposures are estimated for perfluorobutanoic acid (PFBA) and perfluorododecanoic acid (PFDoDA). The precursor contributions to the individual perfluoroalkyl acid (PFAA) daily exposures are estimated to be 11-33% for PFOS, 0.1-2.5% for PFBA, 3.7-34% for PFHxA, 13-64% for PFOA, 5.2-66% for PFDA, and 0.7-25% for PFDoDA (ranges represent estimated precursor contributions in a low- and high-exposure scenario). For PFOS, direct intake via diet is the major exposure pathway regardless of exposure scenario. For PFCAs, the dominant exposure pathway is dependent on perfluoroalkyl chain length and exposure scenario. Modelled PFOS and PFOA concentrations in human serum using the estimated intakes from an intermediate-exposure scenario are in agreement with measured concentrations in different populations. The isomer pattern of PFOS resulting from total intakes (direct and via precursors) is estimated to be enriched with linear PFOS (84%) relative to technical PFOS (70% linear). This finding appears to be contradictory to the observed enrichment of branched PFOS isomers in recent human serum monitoring studies and suggests that either external exposure is not fully understood (e.g. there are unknown precursors, missing or poorly quantified exposure pathways) and/or that there is an incomplete understanding of the isomer-specific human pharmacokinetic processes of PFOS, its precursors and intermediates.
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Ácidos Alcanesulfónicos/análisis , Exposición a Riesgos Ambientales , Fluorocarburos/análisis , Adulto , Ácidos Alcanesulfónicos/sangre , Ácidos Alcanesulfónicos/química , Caproatos/análisis , Caproatos/sangre , Caprilatos/análisis , Caprilatos/sangre , Ácidos Decanoicos/análisis , Ácidos Decanoicos/sangre , Monitoreo del Ambiente , Fluorocarburos/sangre , Fluorocarburos/química , Humanos , Isomerismo , Ácidos Láuricos/análisis , Ácidos Láuricos/sangreRESUMEN
BACKGROUND/OBJECTIVES: Evidence on the association between fatty acids and adiponectin and leptin concentrations is scarce and inconsistent, which may in part be due to limitations of dietary reporting methods. We aimed to estimate the association of fatty acids, derived from a food frequency questionnaire (FFQ) and measured in the erythrocyte membrane, with adiponectin and leptin concentrations. SUBJECTS/METHODS: We studied 330 non-institutionalized inhabitants of Porto (52.4% women; age range: 26-64 years) evaluated in 2010-2011, as part of the EPIPorto cohort study. Fatty acids were derived from a validated semiquantitative FFQ and measured in the erythrocyte membrane by gas chromatography. Serum concentrations of adiponectin and leptin were determined through radioimmunoassay. Regression coefficients (ß) and 95% confidence intervals (95% CI) were obtained from linear regression models, after controlling for gender, age, education, leisure time physical activity and total body fat percentage (obtained from dual energy X-ray absorptiometry). RESULTS: Fatty acids measured by FFQ showed no significant associations with both adipokines. Lauric and linoleic acids, measured in the erythrocyte membrane, were significantly and positively associated with adiponectin (ß=0.292, 95% CI: 0.168-0.416; ß=0.150, 95% CI: 0.020-0.280) and leptin (ß=0.071, 95% CI: 0.003-0.138; ß=0.071, 95% CI: 0.002-0.140), whereas total n-3, eicosapentaenoic and docosahexaenoic acids were significantly but negatively associated with adiponectin (ß=-0.289, 95% CI: -0.420 to -0.159; ß=-0.174, 95% CI -0.307 to -0.040; ß=-0.253, 95% CI -0.383 to -0.124) and leptin (ß=-0.151, 95% CI: -0.220 to -0.083; ß=-0.080, 95% CI: -0.151 to -0.009; ß=-0.146, 95% CI: -0.214 to -0.078). Positive significant associations of palmitic and trans-fatty acids with adiponectin were also observed. CONCLUSIONS: A positive association of lauric and linoleic acids and a negative association of total n-3 fatty acids with both adipokines were observed only with fatty acids measured in the erythrocyte membrane.
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Adiponectina/sangre , Membrana Eritrocítica/química , Ácidos Grasos/sangre , Leptina/sangre , Encuestas y Cuestionarios , Absorciometría de Fotón , Adulto , Estudios Transversales , Dieta , Grasas de la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/sangre , Ácidos Grasos/administración & dosificación , Femenino , Humanos , Ácidos Láuricos/administración & dosificación , Ácidos Láuricos/sangre , Modelos Lineales , Ácido Linoleico/administración & dosificación , Ácido Linoleico/sangre , Masculino , Persona de Mediana Edad , Actividad Motora , Estudios Prospectivos , Factores Socioeconómicos , Ácidos Grasos trans/administración & dosificación , Ácidos Grasos trans/sangre , Triglicéridos/sangreRESUMEN
BACKGROUND: The triggering receptor expressed on myeloid cells-1 is an immunoreceptor that amplifies the inflammatory response mediated by toll-like receptors engagement. Triggering receptor expressed on myeloid cells-1 inhibitory peptides such LR12 have been shown to prevent hyperresponsiveness and death in several experimental models of septic shock. METHODS: Twelve adult male Cynomolgus (Macaca fascicularis) monkeys exposed to an intravenous bolus of endotoxin (10 µg/kg) were randomized to receive LR12 or placebo (n = 6 per group) as an initial intravenous bolus followed by an 8-h continuous intravenous infusion. An additional group of four only received vehicle infusion. Vital signs were monitored for 8 h. Blood was sampled at H0, 1, 2, 4, and 8 for analysis of clinical chemistries, leukocyte count, coagulation parameters, and cytokine plasma concentration. RESULTS: LR12 showed no effect on heart rate and body temperature. By contrast to the placebo group, which experienced a 25 to 40% blood pressure decrease after endotoxin administration, LR12-treated monkeys remained normotensive. Endotoxin induced leukopenia at 2 h (mean leukocyte count, 7.62 g/l vs. 21.1 at H0), which was attenuated by LR12. LR12 also attenuated cytokine production. CONCLUSIONS: The triggering receptor expressed on myeloid cells-1 inhibitor LR12 is able to mitigate endotoxin-associated clinical and biological alterations, with no obvious side effects. This study paves the way for future phases Ia and Ib trials in humans.
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Ácidos Láuricos/administración & dosificación , Leucopenia/tratamiento farmacológico , Células Mieloides/metabolismo , Rodaminas/administración & dosificación , Choque Séptico/inducido químicamente , Choque Séptico/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Endotoxinas/sangre , Inyecciones Intravenosas , Ácidos Láuricos/sangre , Ácidos Láuricos/farmacocinética , Leucopenia/sangre , Leucopenia/inducido químicamente , Macaca fascicularis , Masculino , Oligopéptidos , Distribución Aleatoria , Rodaminas/sangre , Rodaminas/farmacocinética , Choque Séptico/sangreRESUMEN
BACKGROUND: Obesity is considered a low-grade inflammatory state and has been associated with increased acute phase proteins as well as changes in serum fatty acids. Few studies have assessed associations between acute phase proteins and serum fatty acids in morbidly obese patients. OBJECTIVE: To investigate the relationship between acute phase proteins (C-Reactive Protein, Orosomucoid, and Albumin) and serum fatty acids in morbidly obese patients. METHODS: Twenty-two morbidly obese patients were enrolled in this study. Biochemical and clinical data were obtained before bariatric surgery, and fatty acids measured in preoperative serum. RESULTS: Orosomucoid was negatively correlated with lauric acid (P = 0.027) and eicosapentaenoic acid (EPA) (P = 0.037) and positively with arachidonic acid (AA) (P = 0.035), AA/EPA ratio (P = 0.005), and n-6/n-3 polyunsaturated fatty acids ratio (P = 0.035). C-Reactive Protein (CRP) was negatively correlated with lauric acid (P = 0.048), and both CRP and CRP/Albumin ratio were negatively correlated with margaric acid (P = 0.010, P = 0.008, resp.). Albumin was positively correlated with EPA (P = 0.027) and margaric acid (P = 0.008). Other correlations were not statistically significant. CONCLUSION: Our findings suggest that serum fatty acids are linked to acute phase proteins in morbidly obese patients.
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Proteínas de Fase Aguda/metabolismo , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Obesidad Mórbida/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Ácidos Láuricos/sangre , Masculino , Persona de Mediana EdadRESUMEN
Perfluoroalkyl acids (PFAAs) are persistent organic pollutants that are used in a wide range of consumer products. Recent epidemiological studies have shown that prenatal exposure to toxic levels of PFAAs in the environment may adversely affect fetal growth and humoral immune response in infants and children. Here we have characterized levels of prenatal exposure to PFAA between 2003 and 2011 in Hokkaido, Japan, by measuring PFAA concentrations in plasma samples from pregnant women. The study population comprised 150 women who enrolled in a prospective birth cohort study conducted in Hokkaido. Eleven PFAAs were measured in maternal plasma samples using simultaneous analysis by ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. At the end of the study, in 2011, age- and parity-adjusted mean concentrations of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA), perfluorotridecanoic acid (PFTrDA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were 1.35ng/mL, 1.26ng/mL, 0.66ng/mL, 1.29ng/mL, 0.25ng/mL, 0.33ng/mL, 0.28ng/mL, and 3.86ng/mL, respectively. Whereas PFOS and PFOA concentrations declined 8.4%/y and 3.1%/y, respectively, PFNA and PFDA levels increased 4.7%/y and 2.4%/y, respectively, between 2003 and 2011. PFUnDA, PFDoDA, and PFTrDA were detected in the vast majority of maternal samples, but no significant temporal trend was apparent. Future studies must involve a larger population of pregnant women and their children to determine the effects of prenatal exposure to PFAA on health outcomes in infants and children.
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Monitoreo del Ambiente/estadística & datos numéricos , Contaminantes Ambientales/sangre , Fluorocarburos/sangre , Embarazo/sangre , Adulto , Ácidos Alcanesulfónicos/sangre , Caprilatos/sangre , Ácidos Decanoicos/sangre , Ácidos Grasos/sangre , Femenino , Humanos , Japón , Ácidos Láuricos/sangre , Estudios Prospectivos , Ácidos Sulfónicos/sangre , Espectrometría de Masas en TándemRESUMEN
Oxidative stress has been implicated as a causative factor of atherosclerosis. Defense systems against oxidative stress are maintained by radical scavenging antioxidants and/or by regulating the expression of antioxidant genes by activating oxidative stress-sensitive transcription factor: nuclear factor (erythroid-derived 2)-like 2 (Nrf2). We investigated the anti-atherogenic effects of three synthesized compounds (shogaol A: radical scavenging antioxidant activity; shogaol N: Nrf2-activating activity; shogaol N + A: both activities) and curcumin (both activities) in apolipoprotein E (apoE)-deficient mice. We expected compounds with both activities to have additive or synergistic anti-atherogenic effects; however, atherosclerosis was exacerbated significantly by curcumin and slightly by shogaol N + A. Shogaol A, shogaol N, and shogaol N + A showed no significant effect on atherosclerosis development. Immunohistochemical analysis of the aorta revealed that expression of CD36, an Nrf2-regulated gene, was strongly induced by treatment with curcumin. The total antioxidant capacity of plasma collected from mice administered the three compounds was evaluated using a hydrophilic probe, pyranine. Shogaol N or shogaol N + A significantly enhanced the antioxidant capacity of plasma, whereas shogaol A and curcumin did not show this activity. The concentrations of the three shogaol derivatives in plasma were similar (approximately 100 nM), while that of curcumin was much lower. These results suggest that plasma antioxidant capacity is maintained at high levels via Nrf2 activation and that CD36 expression enhances atherosclerosis development.
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Antioxidantes/metabolismo , Apolipoproteínas E/deficiencia , Aterosclerosis/etiología , Antígenos CD36/biosíntesis , Catecoles/farmacología , Depuradores de Radicales Libres/farmacología , Factor 2 Relacionado con NF-E2/fisiología , Animales , Aorta/metabolismo , Aterosclerosis/prevención & control , Caprilatos/sangre , Caprilatos/farmacología , Catecoles/sangre , Curcumina/farmacología , Ácidos Láuricos/sangre , Ácidos Láuricos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Estrés Oxidativo , Regulación hacia ArribaRESUMEN
UNLABELLED: Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution ("good" and "poor" responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT00451828.
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Aminoácidos Esenciales/sangre , Biomarcadores Farmacológicos/sangre , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Metabolómica , Simvastatina/farmacología , Adulto , Citrulina/sangre , Cistina/sangre , Femenino , Fructosa/sangre , Cromatografía de Gases y Espectrometría de Masas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ácidos Láuricos/sangre , Masculino , Óxido Nítrico Sintasa/sangre , Ornitina/sangre , Simvastatina/uso terapéutico , Ácidos Esteáricos/sangre , Ácido Succínico/sangre , Xantina/sangre , alfa-Tocoferol/sangreRESUMEN
Methylmalonic acid (MMA) is a metabolic intermediate transformed to succinic acid (SA) by a vitamin B(12)-dependent catalytic step, and is broadly used as a clinical biomarker of functional vitamin B12 status. However, reported methods use between 100 and 1000 µL of serum or plasma making them sub-optimal for sample-limited studies, including those with neonates and infants. LC-MS/MS based protocols to measure MMA as n-butyl esters in the presence of tri-deuterated MMA (MMA-d(3)) were modified for use with 25 µL of human serum by scaling down sample processing volumes and analysis by UPLC-MS/MS. Plasma-based calibration solutions were found to be unnecessary, and chromatographic resolution and peak shape of SA and MMA was optimized in <4 min with isocratic 53:47 methanol/1.67 mM (pH 6.5) ammonium formate. Additionally, 1-cyclohexyl-urido-3-dodecanoic acid (CUDA) was included as internal standard allowing direct assessment of MMA recovery. Sample concentrations in the low normal range produced a signal:noise of >100:1. MMA intra- and inter-assay variability was under 10%. MMA-d(3) surrogate recovery averaged 93±14%. MMA stability exceeded three years in frozen samples and was unaffected by up to five freeze/thaw cycles. In conclusion, we report that methylmalonic acid can be measured with 25 µL of serum using water based standards. The assay signal:noise per concentration indicates that the method could perform as implemented with as little as 5 µL of serum. The reported method is applicable for studies of functional B12 status in sample limited experiments including investigations of nutritional status in neonates and in studies where low normal MMA levels are expected.