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1.
Artigo em Inglês | MEDLINE | ID: mdl-36608621

RESUMO

We investigated whether gestational diabetes mellitus (GDM) associated with maternal obesity modifies the placental profile of F4-Neuroprostanes and F2-Isoprostanes, metabolites of non-enzymatic oxidation of docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively. Twenty-five placental samples were divided into lean (n=11), obesity (n=7) and overweight/obesity+GDM (n=7) groups. F4-Neuroprostanes and F2-Isoprostanes were higher in obesity compared to lean controls, but reduced to levels similar to lean women when obesity is further complicated with GDM. Lower content of F2-Isoprostanes suggests adaptive placental responses in GDM attenuating oxidative stress. However, low levels of placental F4-Neuroprostanes may indicate impaired DHA metabolism in GDM, affecting fetal development and offspring health. These results were not related to differences in placental content of DHA, AA and polyunsaturated fatty acids status nor to maternal diet or gestational weight gain. Placental DHA and AA metabolism differs in obesity and GDM, highlighting the importance of investigating the signalling roles of F4-Neuroprostanes and F2-Isoprostanes in the human term placenta.


Assuntos
Diabetes Gestacional , Neuroprostanos , Obesidade Materna , Humanos , Feminino , Gravidez , Neuroprostanos/metabolismo , Isoprostanos , Diabetes Gestacional/metabolismo , Placenta/metabolismo , F2-Isoprostanos/metabolismo , Obesidade Materna/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Araquidônico/metabolismo , Obesidade/metabolismo
2.
Nutrients ; 13(8)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34444927

RESUMO

The rise in prevalence of obesity in women of reproductive age in developed and developing countries might propagate intergenerational cycles of detrimental effects on metabolic health. Placental lipid metabolism is disrupted by maternal obesity, which possibly affects the life-long health of the offspring. Here, we investigated placental lipid metabolism in women with pre-gestational obesity as a sole pregnancy complication and compared it to placental responses of lean women. Open profile and targeted lipidomics were used to assess placental lipids and oxidised products of docosahexaenoic (DHA) and arachidonic acid (AA), respectively, neuroprostanes and isoprostanes. Despite no overall signs of lipid accumulation, DHA and AA levels in placentas from obese women were, respectively, 2.2 and 2.5 times higher than those from lean women. Additionally, a 2-fold increase in DHA-derived neuroprostanes and a 1.7-fold increase in AA-derived isoprostanes were seen in the obese group. These changes correlated with a 70% decrease in placental FABP1 protein. Multivariate analyses suggested that neuroprostanes and isoprostanes are associated with maternal and placental inflammation and with birth weight. These results might shed light on the molecular mechanisms associated with altered placental fatty acid metabolism in maternal pre-gestational obesity, placing these oxidised fatty acids as novel mediators of placental function.


Assuntos
Proteínas de Ligação a Ácido Graxo/metabolismo , Isoprostanos/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/genética , Neuroprostanos/metabolismo , Obesidade Materna/metabolismo , Adulto , Peso ao Nascer , Feminino , Humanos , Inflamação , Metabolismo dos Lipídeos , Placenta/metabolismo , Gravidez
3.
Essays Biochem ; 64(3): 463-484, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32602531

RESUMO

Polyunsaturated fatty acids (PUFAs) are essential components in eukaryotic cell membrane. They take part in the regulation of cell signalling pathways and act as precursors in inflammatory metabolism. Beside these, PUFAs auto-oxidize through free radical initiated mechanism and release key products that have various physiological functions. These products surfaced in the early nineties and were classified as prostaglandin isomers or isoprostanes, neuroprostanes and phytoprostanes. Although these molecules are considered robust biomarkers of oxidative damage in diseases, they also contain biological activities in humans. Conceptual progress in the last 3 years has added more understanding about the importance of these molecules in different fields. In this chapter, a brief overview of the past 30 years and the recent scope of these molecules, including their biological activities, biosynthetic pathways and analytical approaches are discussed.


Assuntos
Neuroprostanos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido alfa-Linolênico/metabolismo , Biomarcadores/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Humanos , Oxirredução , Estresse Oxidativo , Plantas/química , Plantas/metabolismo , Transdução de Sinais
4.
Lipids ; 55(6): 693-706, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32602621

RESUMO

Oxidized polyunsaturated fatty acids (PUFA) are associated to pathogenesis of diseases including cardiovascular and neurodegeneration. The novel products are not only biomarkers but also lipid mediators in gene regulation and signaling pathways. Herein, simultaneous quantitation of 28 products derived from nonenzymatic and enzymatic oxidation of PUFA i.e. 5-, 15-F2t -isoprostanes, 7-, 17-F2t -dihomo-isoprostanes, 7-, 17-F2t -dihomo-isofurans, 5-, 8-, 18-F3t -isoprostanes, 4-, 10-, 13-, 14-, 20-F4t -neuroprostanes, 5-, 8-, 9-, 11-,12-, 15-, 20-HETE, 4-, 7-, 11-, 14-, 17-HDHA, RvE1, and NPD1 using LC-(ESI)-QTOF-MS/MS was developed. These products were measurable in a single sample and the analytical time was relative short (~15 min). Furthermore, we showed that the use of internal standards is a requisite to normalize matrix effects and preparation loss for the quantitation. Validation assays indicated the method to be robust for plasma and mid-stream urine sample analysis in particular from those of age-related macular degeneration subjects, where the accuracy of quantitation displayed good repeatability.


Assuntos
Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/urina , Degeneração Macular/metabolismo , Espectrometria de Massas em Tandem/métodos , Análise Química do Sangue/métodos , Cromatografia Líquida , Ácidos Graxos Insaturados/metabolismo , Humanos , Isoprostanos/sangue , Isoprostanos/metabolismo , Isoprostanos/urina , Limite de Detecção , Degeneração Macular/sangue , Degeneração Macular/urina , Neuroprostanos/sangue , Neuroprostanos/metabolismo , Neuroprostanos/urina , Oxirredução , Espectrometria de Massas por Ionização por Electrospray , Urinálise/métodos
5.
FEBS Lett ; 594(11): 1797-1808, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32215916

RESUMO

Docosahexaenoic acid (DHA), an abundant fatty acid in the brain, is susceptible to auto-oxidation in situ and releases metabolites such as F4 -neuroprostane (4-F4t -NeuroP). The presence of 4-F4t -NeuroP in the brain is not well explored. In this study, 4-F4t -NeuroP was introduced into neuroblastoma cells (SH-SY5Y) and, by in vivo infusion, into rodents. Targeted lipidomic analysis of liver and brain tissues shows significant elevation of anti-inflammatory hydroxylated DHA metabolites and an isomer of neuroprotectin D1, suggesting potential beneficial bioactivities of 4-F4t -NeuroP. Additionally, 4-F4t -NeuroP treatment in SH-SY5Y cells and primary neuronal culture consistently upregulates the transcriptional level of the antioxidant enzyme heme oxygenase-1, but the effect is reduced when 4-F4t -NeuroP is further oxidized. Our data suggest that 4-F4t -NeuroP could be neuroprotective in the native state but may have disadvantageous bioactivity when oxidized extensively.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Neurônios/metabolismo , Neuroprostanos/química , Neuroprostanos/metabolismo , Oxigênio/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Catalase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Lipidômica , Fígado/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção , Oxirredução , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
6.
Free Radic Biol Med ; 139: 46-54, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100476

RESUMO

Krabbe disease (KD) is a rare and devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. The disease leads to impaired myelin formation and extensive myelin damage in the brain. Oxidative stress is implicated in the pathogenesis of KD but insofar few information is available. The gray and white matter of the brain are rich in docosahexaenoic acid and adrenic acid respectively and under non-enzymatic oxidative stress, release isoprostanoids, i.e. F4-neuroprostanes (F4-NeuroPs) and F2-dihomo-isoprostanes (F2-dihomo-IsoPs). In this study, the formation of isoprostanoids in brain tissue was investigated in a well-established KD mouse model (twitcher) that recapitulates the human pathology. According to the genotype determinations, three groups of mice were selected: wild-type control mice (n = 13), heterozygotes mice (carriers of GALC mutations, n = 14) and homozygous twitcher mice (n = 13). Measurement of F2-dihomo-IsoP and F4-NeuroP levels were performed on whole brain tissue obtained at day 15 and day 35 of the life cycle. Brain isoprostanoid levels were significantly higher in the twitcher mice compared to the heterozygous and wild-type control mice. However, F2-dihomo-IsoP and F4-NeuroP levels did not differ in brain of day 15 compared to day 35 of the heterozygote mice. Interestingly, isoprostanoid levels were proportionally enhanced with disease severity (F2-dihomo-IsoPs, rho = 0.54; F4-NeuroPs, rho = 0.581; P values ≤ 0.05; n = 13). Our findings are the first to show the key role of polyunsaturated fatty acid oxidative damage to brain grey and white matter in the pathogenesis and progression of KD. This shed new insights on the biochemical indexes of KD progression, and potentially provide information for novel therapeutic targets.


Assuntos
Galactosilceramidase/genética , Substância Cinzenta/metabolismo , Isoprostanos/metabolismo , Leucodistrofia de Células Globoides/metabolismo , Neuroprostanos/metabolismo , Substância Branca/metabolismo , Animais , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Galactosilceramidase/deficiência , Expressão Gênica , Substância Cinzenta/patologia , Heterozigoto , Homozigoto , Humanos , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/patologia , Camundongos , Mutação , Estresse Oxidativo , Índice de Gravidade de Doença , Substância Branca/patologia
7.
Exp Gerontol ; 121: 91-98, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980923

RESUMO

BACKGROUND: Neuroinflammation is recognized as part of the pathological progression of Alzheimer's disease (AD), but the molecular mechanisms are still not entirely clear. Systemically, physical exercise has shown to have a positive modulating effect on markers of inflammation. It is not known if this general effect also takes place in the central nervous system in AD. The aim of this study was to investigate the effect of 16 weeks of moderate to high-intensity physical exercise on selected biomarkers of inflammation both systemically and in the CNS, in patients with AD. METHODS: Plasma and cerebrospinal fluid (CSF) from 198 patients with Alzheimer's disease participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study were analyzed for concentrations of 8­isoprostane, soluble trigger receptor expressed on myeloid cells 2 (sTREM2), and the MSD v-plex proinflammation panel 1 human containing interferon gamma (IFNγ), Interleukin-10 (IL10), IL12p70, IL13, IL1ß, IL2, IL4, IL6, IL8, and tumor necrosis factor alpha (TNFα), before and after a 16-week intervention with physical exercise, and we studied whether changes were modulated by the patients' APOE genotype. RESULTS: Most inflammatory markers remained unchanged after exercise. We found an increasing effect of 16 weeks of physical exercise on sTREM2 measured in CSF. Further, IL6 in plasma increased in the exercise group after physical exercise (mean relative change 41.03, SD 76.7), compared to controls (-0.97, SD 49.4). In a sub-analysis according to APOE genotype, we found that in ε4 carriers, exercise had a stabilizing effect on IFNγ concentration with a mean relative change of 7.84 (SD 42.6), as compared to controls (114.7 (SD 188.3), p = 0.038. CONCLUSION: Our findings indicate an effect of physical exercise on markers of neuroinflammation in CSF measured by an increase in sTREM2 in patients with AD. Further, there may be a small inflammatory systemic effect related to physical exercise in patients with AD.


Assuntos
Doença de Alzheimer/reabilitação , Terapia por Exercício/métodos , Neurite (Inflamação)/prevenção & controle , Atividades Cotidianas , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Índice de Massa Corporal , Cognição , Transtornos Cognitivos/sangue , Transtornos Cognitivos/líquido cefalorraquidiano , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Células Musculares/metabolismo , Neurite (Inflamação)/sangue , Neurite (Inflamação)/líquido cefalorraquidiano , Neuroprostanos/metabolismo , Qualidade de Vida , Receptores Imunológicos/metabolismo
8.
Mol Aspects Med ; 64: 161-168, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29572110

RESUMO

ω3 Polyunsaturated fatty acids (ω3 PUFAs) have several biological properties including anti-arrhythmic effects. However, there are some evidences that it is not solely ω3 PUFAs per se that are biologically active but the non-enzymatic oxygenated metabolites of polyunsaturated fatty acids (NEO-PUFAs) like isoprostanes and neuroprostanes. Recent question arises how these molecules take part in physiological homeostasis, show biological bioactivities and anti-inflammatory properties. Furthermore, they are involved in the circulations of childbirth, by inducing the closure of the ductus arteriosus. In addition, oxidative stress which can be beneficial for the heart in given environmental conditions such as the presence of ω3 PUFAs on the site of the stress and the signaling pathways involved are also explained in this review.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Ácidos Graxos Ômega-3/metabolismo , Isoprostanos/metabolismo , Neuroprostanos/metabolismo , Antiasmáticos/uso terapêutico , Arritmias Cardíacas/patologia , Canal Arterial/efeitos dos fármacos , Canal Arterial/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Isoprostanos/uso terapêutico , Neuroprostanos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Prog Lipid Res ; 68: 83-108, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28923590

RESUMO

Since the beginning of the 1990's diverse types of metabolites originating from polyunsaturated fatty acids, formed under autooxidative conditions were discovered. Known as prostaglandin isomers (or isoprostanoids) originating from arachidonic acid, neuroprostanes from docosahexaenoic acid, and phytoprostanes from α-linolenic acid proved to be prevalent in biology. The syntheses of these compounds by organic chemists and the development of sophisticated mass spectrometry methods has boosted our understanding of the isoprostanoid biology. In recent years, it has become accepted that these molecules not only serve as markers of oxidative damage but also exhibit a wide range of bioactivities. In addition, isoprostanoids have emerged as indicators of oxidative stress in humans and their environment. This review explores in detail the isoprostanoid chemistry and biology that has been achieved in the past three decades.


Assuntos
Ciclopentanos/química , Ciclopentanos/metabolismo , Neuroprostanos/química , Neuroprostanos/metabolismo , Animais , Humanos , Estresse Oxidativo
10.
Neuroscience ; 354: 1-10, 2017 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-28433650

RESUMO

Brain microvascular endothelial cell (BMEC) injury induced by ischemia-reperfusion (I/R) is the initial stage of blood-brain barrier (BBB) disruption, which results in a poor prognosis in ischemic stroke patients. Autophagy has been shown to have protective effects on BMECs against cerebral ischemic insults. However, molecular mechanism of BMEC autophagy during I/R is unclear. Long noncoding RNAs (lncRNAs) are emerging as new factors involved in cell autophagy. LncRNA Malat1 is one of the most highly upregulated I/R or OGD/R-responsive endothelial lncRNA and plays a protective role in BMECs against cerebral ischemic insults. Oxygen-glucose deprivation/reoxygenation (OGD/R) is used to mimic I/R injury in vitro. Based on these findings, we hypothesized that Malat1 might play a protective role by enhancing BMEC autophagy. We performed GFP-LC3 puncta formation, LC3 conversion, p62 expression, and cell death assays, and the results were consistent with our hypothesis that Malat1 promoted BMEC autophagy and survival under OGD/R condition. We further explored the molecular mechanisms by which Malat1 exerted regulatory effects, and found that Malat1 served as an endogenous sponge to downregulate miR-26b expression by binding directly to miR-26b. Furthermore, Malat1 overturned the inhibitory effect of miR-26b on BMEC autophagy and survival, which involved in promoting the expression of miR-26b target ULK2. Collectively, our study illuminated a new Malat1-miR-26b-ULK2 regulatory axis in which Malat1 served as a competing endogenous RNA by sponging miR-26b and upregulating ULK2 expression, thereby promoting BMEC autophagy and survival under OGD/R condition.


Assuntos
Autofagia/efeitos dos fármacos , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Neuroprostanos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima/fisiologia , Animais , Autofagia/fisiologia , Encéfalo/anatomia & histologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Células Endoteliais/efeitos dos fármacos , Endotélio/citologia , Inibidores Enzimáticos/farmacologia , Glucose/deficiência , Carbonato de Lítio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neuroprostanos/farmacologia , Neuroprostanos/uso terapêutico , Oxigênio/farmacologia , Ligação Proteica/fisiologia , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/farmacologia , Regulação para Cima/efeitos dos fármacos
11.
Neonatology ; 112(1): 1-8, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28142140

RESUMO

BACKGROUND: Perinatal hypoxic-ischemic brain damage is a major cause of acute mortality and chronic neurological morbidity in infants and children. Oxidative stress due to free radical formation and the initiation of abnormal oxidative reactions appears to play a key role. Docosahexanoic acid (DHA), a main component of brain membrane phospholipids, may act as a neuroprotectant after hypoxia-ischemia by regulating multiple molecular pathways and gene expression. OBJECTIVES: The aims of this study were to test the hypothesis that DHA provides significant protection against lipoperoxidation damage in the cerebral cortex and hippocampus in a neonatal piglet model of severe hypoxia-reoxygenation. METHODS: Newborn piglets, Noroc (LYLD), were subjected to severe global hypoxia. One group was resuscitated with ambient air (21% group, n = 11) and another also received 5 mg/kg of DHA 4 h after the end of hypoxia (21% DHA group, n = 10). After 9.5 h, tissues from the prefrontal cortex and hippocampus were sampled and the levels of isoprostanes, neuroprostanes, neurofurans, and F2-dihomo-isoprostanes were determined by the liquid chromatography triple quadrupole mass spectrometry technique. RESULTS: Lipid peroxidation biomarkers were significantly lower in both the cortex and hippocampus in the DHA-treated group compared with the untreated group. CONCLUSIONS: The present study demonstrates that DHA administration after severe hypoxia in newborn piglets has an antioxidative effect in the brain, suggesting a protective potential of DHA if given after injuries to the brain.


Assuntos
Antioxidantes/farmacologia , Asfixia Neonatal/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Asfixia Neonatal/metabolismo , Asfixia Neonatal/patologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , Furanos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Isoprostanos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Neuroprostanos/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Sus scrofa
12.
Redox Biol ; 11: 586-591, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110214

RESUMO

We analyzed biomarkers of lipid peroxidation of the nervous system -F2-dihomo-isoprostanes, F3-neuroprostanes, and F4-neuroprostanes- in urine samples from 158 healthy volunteers ranging from 4 to 88 years old with the aim of analyzing possible associations between their excretion values and age (years). Ten biomarkers were screened in the urine samples by UHPLC-QqQ-MS/MS. Four F2-dihomo-isoprostanes (ent-7-(R)-7-F2t-dihomo-isoprostane, ent-7-epi-7-F2t-dihomo-isoprostane, 17-F2t-dihomo-isoprostane, 17-epi-17-F2t-dihomo-isoprostane), and one DPA-neuroprostane (4-F3t-neuroprostane) were detected in the samples. On the one hand, we found a significant, positive correlation (Rho: 0.197, P=0.015) between the age increase and the amount of total F2-dihomo-IsoPs. On the other hand, the values were significantly higher in the childhood group (4-12 years old), when compared to the adolescence group (13-17 years old) and the young adult group (18-35 years old). Surprisingly, no significant differences were found between the middle-aged adults (36-64 years old) and the elderly adults (65-88 years old). We display a snapshot situation of excretory values of oxidative stress biomarkers of the nervous system, using healthy volunteers representative of the different stages of human growth and development. The values reported in this study could be used as a basal or starting point in clinical interventions related to aging processes and/or pathologies associated with the nervous system.


Assuntos
Biomarcadores/metabolismo , Peroxidação de Lipídeos , Sistema Nervoso/metabolismo , Estresse Oxidativo , Adolescente , Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , F2-Isoprostanos/metabolismo , Feminino , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Neuroprostanos/metabolismo , Oxirredução , Espectrometria de Massas em Tandem , Adulto Jovem
13.
Free Radic Res ; 49(12): 1419-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26271312

RESUMO

Several events occurring during the secondary damage of traumatic brain injury (TBI) can cause oxidative stress. F(2)-isoprostanes (F(2)-IsoPs) and F(4)-neuroprostanes (F(4)-NPs) are specific lipid peroxidation markers generated from arachidonic acid and docosahexaenoic acid, respectively. In this study, we evaluated oxidative stress in patients with moderate and severe TBI. Since sedatives are routinely used to treat TBI patients and propofol has been considered an antioxidant, TBI patients were randomly treated with propofol or midazolam for 72 h postoperation. We postoperatively collected cerebrospinal fluid (CSF) and plasma from 15 TBI patients for 6-10 d and a single specimen of CSF or plasma from 11 controls. Compared with the controls, the TBI patients exhibited elevated levels of F(2)-IsoPs and F(4)-NPs in CSF throughout the postsurgery period regardless of the sedative used. Compared with the group of patients who received midazolam, those who received propofol exhibited markedly augmented levels of plasma F(2)-IsoPs, which were associated with higher F(4)-NPs levels and lower total nitrate/nitrite levels in CSF early in the postsurgery period. Furthermore, the higher CSF F(2)-IsoPs levels correlated with 6-month and 12-month worse outcomes, which were graded according to the Glasgow Outcome Scale. The results demonstrate enhanced oxidative damage in the brain of TBI patients and the association of higher CSF levels of F(2)-IsoPs with a poor outcome. Moreover, propofol treatment might promote lipid peroxidation in the circulation, despite possibly suppressing nitric oxide or peroxynitrite levels in CSF, because of the increased loading of the lipid components from the propofol infusion.


Assuntos
Lesões Encefálicas/metabolismo , F2-Isoprostanos/metabolismo , Neuroprostanos/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Adolescente , Adulto , Idoso , Anestésicos Intravenosos/uso terapêutico , Biomarcadores/análise , Cromatografia Gasosa , Ensaio de Imunoadsorção Enzimática , F2-Isoprostanos/análise , Feminino , Escala de Coma de Glasgow , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Espectrometria de Massas , Midazolam/uso terapêutico , Pessoa de Meia-Idade , Neuroprostanos/análise , Nitratos/análise , Nitritos/análise , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Propofol/uso terapêutico , Adulto Jovem
14.
Nat Rev Neurosci ; 16(1): 17-29, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25423896

RESUMO

Hormones regulate homeostasis by communicating through the bloodstream to the body's organs, including the brain. As homeostatic regulators of brain function, some hormones exert neuroprotective actions. This is the case for the ovarian hormone 17ß-oestradiol, which signals through oestrogen receptors (ERs) that are widely distributed in the male and female brain. Recent discoveries have shown that oestradiol is not only a reproductive hormone but also a brain-derived neuroprotective factor in males and females and that ERs coordinate multiple signalling mechanisms that protect the brain from neurodegenerative diseases, affective disorders and cognitive decline.


Assuntos
Encéfalo/metabolismo , Estradiol , Neuroprostanos , Receptores de Estrogênio/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encefalopatias/tratamento farmacológico , Encefalopatias/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Estradiol/uso terapêutico , Feminino , Humanos , Masculino , Neuroprostanos/metabolismo , Neuroprostanos/farmacologia , Neuroprostanos/uso terapêutico
15.
Oxid Med Cell Longev ; 2014: 572491, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24868314

RESUMO

Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders. The literature data indicate that in vivo or postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs) especially F4-neuroprotanes (F4-NPs) are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease. Central nervous system is the most metabolically active organ of the body characterized by high requirement for oxygen and relatively low antioxidative activity, what makes neurons and glia highly susceptible to destruction by reactive oxygen/nitrogen species and neurodegeneration. The discovery of F2-IsoPs and F4-NPs as markers of lipid peroxidation caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesis of human neurodegenerative diseases. This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.


Assuntos
Isoprostanos/metabolismo , Doenças Neurodegenerativas/metabolismo , Neuroprostanos/metabolismo , Estresse Oxidativo , Biomarcadores/metabolismo , Humanos , Doenças Neurodegenerativas/patologia
16.
Zebrafish ; 11(3): 248-54, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24798242

RESUMO

The zebrafish is a versatile model organism with the potential to contribute to our understanding of the molecular pathological mechanisms underlying Alzheimer's disease (AD). An early characteristic of AD brain pathology is lipid peroxidation resulting from oxidative stress. However, changes in lipid peroxidation have not yet been assessed in zebrafish brains, and an earlier attempt to observe changes in F2-isoprostane levels in the brains of zebrafish exposed to hypoxia was unsuccessful. In this article, we examine the utility of various assays of lipid peroxidation and more general assays of intracellular oxidative stress to detect the changes in oxidative stress in the brains of adult zebrafish exposed to hypoxia or explanted into a sodium azide solution for chemical mimicry of hypoxia. Levels of F2-isoprostanes and F4-neuroprostanes were low and variable in zebrafish brains such that statistically significant changes due to hypoxia or chemical mimicry of hypoxia could not be observed. However, measurement of lipid hydroperoxides did reveal significant changes in lipid peroxidation under these conditions, while analyses of catalase gene expression and an assay based on 2',7'-dicholorofluorescein oxidation also revealed changes in oxidative stress levels.


Assuntos
Encéfalo/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Peroxidação de Lipídeos , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Peixe-Zebra/metabolismo , Animais , Catalase/genética , Catalase/metabolismo , F2-Isoprostanos/metabolismo , Feminino , Fluoresceínas/metabolismo , Expressão Gênica , Peróxidos Lipídicos/metabolismo , Masculino , Neuroprostanos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
Neurobiol Dis ; 68: 66-77, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24769161

RESUMO

Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.


Assuntos
Lesões Encefálicas/etiologia , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Estresse Oxidativo/fisiologia , Síndrome de Rett/complicações , Síndrome de Rett/genética , Aldeídos/metabolismo , Análise de Variância , Animais , Ácido Araquidônico/metabolismo , Lesões Encefálicas/sangue , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Isoprostanos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nestina/genética , Neuroprostanos/metabolismo , Síndrome de Rett/sangue
18.
PLoS One ; 9(2): e89393, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24558496

RESUMO

The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention. A special emphasis was given to the non-enzymatic metabolites knowing the high susceptibility of DHA to free radical-mediated peroxidation and the increased oxidative stress associated with plaque formation. Atherosclerosis prone mice (LDLR(-/-)) received increasing doses of DHA (0, 0.1, 1 or 2% of energy) during 20 weeks leading to a dose-dependent reduction of atherosclerosis (R(2) = 0.97, p = 0.02), triglyceridemia (R(2) = 0.97, p = 0.01) and cholesterolemia (R(2) = 0.96, p<0.01). Targeted lipidomic analyses revealed that both the profiles of EPA and DHA and their corresponding oxygenated metabolites were substantially modulated in plasma and liver. Notably, the hepatic level of F4-neuroprostanes, a specific class of DHA peroxidized metabolites, was strongly correlated with the hepatic DHA level. Moreover, unbiased statistical analysis including correlation analyses, hierarchical cluster and projection to latent structure discriminate analysis revealed that the hepatic level of F4-neuroprostanes was the variable most negatively correlated with the plaque extent (p<0.001) and along with plasma EPA-derived diols was an important mathematical positive predictor of atherosclerosis prevention. Thus, oxygenated n-3 PUFAs, and F4-neuroprostanes in particular, are potential biomarkers of DHA-associated atherosclerosis prevention. While these may contribute to the anti-atherogenic effects of DHA, further in vitro investigations are needed to confirm such a contention and to decipher the molecular mechanisms of action.


Assuntos
Aterosclerose/prevenção & controle , Biomarcadores/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Metabolismo dos Lipídeos/fisiologia , Neuroprostanos/metabolismo , Análise de Variância , Animais , Pressão Sanguínea , Cromatografia Líquida , Análise por Conglomerados , Ácidos Docosa-Hexaenoicos/administração & dosagem , Relação Dose-Resposta a Droga , Ácidos Graxos Insaturados/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Frequência Cardíaca , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Espectrometria de Massas em Tandem
19.
Food Chem Toxicol ; 53: 205-13, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23220612

RESUMO

Free radical products including reactive oxygen species are potent to oxidize lipids and reliable measurements have been established mostly in human and rodent. To date, robust biomarkers were not used to assess the peroxidation in marine fish. The changes of oxidized lipid products from polyunsaturated fatty acids and cholesterol were assessed after exposure of H(2)O(2) to fish (medaka). Oxidized lipid products released by free radical reaction (F(2)-isoprostanes and metabolites, F(3)-isoprostanes, neuroprostanes, 7-ketocholesterol, 7ß-hydroxycholesterol), by lipoxygenase enzymes (5(S)-, 8(S)-, 12(S)- and 15(S)-HETE, and resolvin D1) and by cytochrome P450 (9(S)-, 11(S)- and 20-HETE, and 27-hydroxycholestrol) were measured in fish muscle using LC/MS/MS. Arachidonate, docosahexaenoate, eicosapentaenoate and cholesterol levels, and antioxidant enzymes activity (catalase, SOD and gluthathione reductase) measurement were also determined. Activity of antioxidant enzymes especially catalase were elevated in presence of H(2)O(2) however longer exposure time suppressed the antioxidant activities. Arachidonate, docosahexaenoate, eicosapentaenoate and cholesterol levels were reduced in presence of H(2)O(2) and oxidized lipid products (isoprostanes, neuroprostanes 5(S)-HETE, 20-HETE, 7-ketocholesterol, 27-hydroxycholesterol and resolvin D1) were rapidly released in the fish muscle. This study validates oxidized lipid products, noticeably isoprostanes are measurable in marine fish muscle and should be considered when assessing oxidative stress especially due to exogenous factors.


Assuntos
Manipulação de Alimentos/métodos , Peroxidação de Lipídeos , Oryzias/metabolismo , Estresse Oxidativo , Animais , Antioxidantes/farmacologia , Ácido Araquidônico/análise , Ácido Araquidônico/metabolismo , Biomarcadores/análise , Colesterol/análise , Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Docosa-Hexaenoicos/análise , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/análise , Ácido Eicosapentaenoico/metabolismo , F2-Isoprostanos/análise , F2-Isoprostanos/metabolismo , Feminino , Peróxido de Hidrogênio , Hidroxicolesteróis/análise , Hidroxicolesteróis/metabolismo , Ácidos Hidroxieicosatetraenoicos/análise , Ácidos Hidroxieicosatetraenoicos/metabolismo , Isoprostanos/análise , Isoprostanos/metabolismo , Cetocolesteróis/análise , Cetocolesteróis/metabolismo , Lipoxigenase/metabolismo , Masculino , Neuroprostanos/análise , Neuroprostanos/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
20.
Free Radic Biol Med ; 51(7): 1302-19, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21782935

RESUMO

Lipid peroxidation is a complex process involving the interaction of oxygen-derived free radicals with polyunsaturated fatty acids, resulting in a variety of highly reactive electrophilic aldehydes. Since 1975, lipid peroxidation has been extensively studied in a variety of organisms. As neurodegenerative diseases became better understood, research establishing a link between this form of oxidative damage, neurodegeneration, and disease has provided a wealth of knowledge to the scientific community. With the advent of proteomics in 1995, the identification of biomarkers for neurodegenerative disorders became of paramount importance to better understand disease pathogenesis and develop potential therapeutic strategies. This review focuses on the relationship between lipid peroxidation and neurodegenerative diseases. It also demonstrates how findings in current research support the common themes of altered energy metabolism and mitochondrial dysfunction in neurodegenerative disorders.


Assuntos
Aldeídos/metabolismo , Metabolismo Energético/fisiologia , Ácidos Graxos Insaturados/metabolismo , Peroxidação de Lipídeos , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Biomarcadores/análise , Radicais Livres/metabolismo , Humanos , Isoprostanos/metabolismo , Camundongos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/fisiopatologia , Neuroprostanos/metabolismo , Oxirredução , Estresse Oxidativo , Proteômica , Ratos , Índice de Gravidade de Doença
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