ArticleLiterature Review

Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids

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... The biomarkers are indicators of normal biological and pathologic processes, or a pharmacologic response to a therapeutic intervention [84]. Although to date there is no specific biological marker or additional exam to help the diagnosis of ASD, some studies have shown changes in levels of damage markers for neuronal cells such as the NSE [16], of neurotrophic factors such as BDNF [85], as well as changes in growth factors such as TGF-b [28]. ...
... A review study conducted by Das [85] in 2013 found that a neuroinflammation process during the intrauterine period may lead to changes in PUFA metabolism and its metabolites. u-3 PUFAs are known to raise levels of BDNF in the brain, and both u-3 PUFA and BDNF have important roles in the development of CNS and cognitive function [85,97,98]. The results of this study showed that supplementation with u-3 PUFA increased, although not significantly, the expression of BDNF levels in the hippocampus and cerebellum of animals prenatally exposed to LPS. ...
... The results of this study showed that supplementation with u-3 PUFA increased, although not significantly, the expression of BDNF levels in the hippocampus and cerebellum of animals prenatally exposed to LPS. These data can be related to the metabolite capacity of PUFAs to increase the levels of BDNF receptors [85]. In this regard, it is suggested that neurobehavioral disorders in the offspring may be related to u-3 PUFA deficiency. ...
Article
Objective: Supplementation with ω-3 polyunsaturated fatty acids (PUFAs) can positively contribute to neurologic development, modulating inflammatory responses, promoting homeostasis, and having a positive effect on animal behaviors associated with mental disorders. The aim of this study was to evaluate behavioral and biochemical effects of ω-3 fatty acid supplementation in an animal model for mental disorders by prenatal maternal exposure to lipopolysaccardies (LPS) from the maternal immune activation. Methods: Twelve pregnant Wistar rats were used. Each rat received 100 μg/kg of LPS or saline solution on gestational day (GD) 9.5. The offspring remained with mothers until weaning and from postnatal day (PND) 30 were supplemented with ω-3 PUFA or saline solution by gavage at a dose of 0.8 g/kg orally for 21 d. On PND 52, the animals underwent behavioral tests; then, they were sacrificed, and the brain structures were dissected and analyzed by levels: neuron-specific enolase (NSE), brain-derived neurotrophic factor, and transforming growth factor (TGF)-β. Result: Prenatal exposure to LPS significantly increased the episodes of stereotyped movements and decreased social interaction in the offspring (P = 0.009 and P = 0.001, respectively), after ω-3 PUFA supplementation these parameters reversed (P = 0.005 and P = 0.013, respectively). Significant changes also were identified in the biochemical analysis in NSE and TGF-β in the brain structures; these conditions were reversed after ω-3 PUFA supplementation. Conclusion: Supplementation with ω-3 PUFA reversed animal behaviors that often are observed in autism and other mental disorders in rats prenatally exposed to LPS, and also exerted neuroprotective effects in marker levels of neuronal damage and expression of TGF-β.
... These compounds have been associated with brain edema formation and disruption of the BBB [70]. The obtained alteration in 8-isoprostane and CysLTs reported in the present study, can find support in the record of Das [71] showing that changes in the metabolism of AA and other PUFAs result in excess production of proinflammatory cytokines and inflammatory lipid mediators and less production of anti-inflammatory cytokines and bioactive lipids that ultimately induce the development of autism. ...
... The significant positive correlations discovered herein between 8-isoprostane and CysLTs (Table 2) confirmed an association between impaired phospholipid metabolism, inflammation, nutritional status and oxidative stress in the etiopathology of autism [68][69][70][71][72]. The discovered negative correlation between 8-isoprostane as a marker of oxidative stress and age may explain the remarkable improvement of autistic patients near adulthood. ...
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Background Autism is a neurodevelopmental disorder that clinically presented as cognitive deficits, social impairments and sensory dysfunction. An increasing body of evidence has shown that oxidative stress and inflammation are involved in the pathophysiology of autism. Recording biomarkers as measure of the severity of autistic features might help in understanding the pathophysiology of autism. Methods This study investigates the plasma levels of 8-isoprostane and Cysteinyl leukotrienes (CysLTs) in 44 autistic children and 40 healthy controls. The recruited autistic patients were assessed for behavior, cognitive and sensory deficits by using different autism severity rating scales, including the Childhood Autism Rating Scales (CARS), Social responsiveness scale (SRS) and Short Sensory Profile (SSP). Receiver Operating Characteristics analysis (ROC) of the obtained data was performed to measure the predictive value of 8-isoprostane and Cysteinyl leukotrienes (CysLTs) as oxidative stress- related parameters. Pearson’s correlations between the measured parameters was also performed. ResultsThe concentrations of 8-isoprostane and CysLTs in autistic patients were significantly higher than those in controls. While cognitive and social impairments did not show any significant differences, the SSP results were strongly correlated with the levels of both of the biomarkers assessed. However, autistic children showed improvements in oxidative stress status (as determined by 8-isoprostane levels) at increasing ages. Conclusion This study indicates that 8-isoprostane and CysLTs can be used as markers for the early recognition of autistic patients through sensory deficits phenotypes which might help early intervention.
... PUFA, namely arachidonic acid (AA, 20:4 ω-6), eicosapentaenoic acid (EPA, 20:5 ω-3), and docosahexaenoic acid (DHA, 22:6 ω-3), are crucial for brain development and cognitive and memory functions (Das, 2013). ...
... Intriguingly, metabolism of PUFAs, involving several cofactors such as antioxidants, minerals, trace elements, and various vitamins seems to be compromised (Das, 1985). AA, EPA, and DHA are precursors to anti-inflammatory bioactive lipids, such as lipoxins, resolvins, and protectins, involved in wound healing, and neuroprotection from various endogenous and exogenous insults (Das, 2013). It has been suggested that in some autistic patients, the metabolism of PUFAs is deficient or abnormal therefore anti-inflammatory lipids are lower, in spite of an increase of proinflammatory cytokines, oxidative stress, an alteration of various neurotransmitters (dopamine, serotonin, catecholamines, and BDNF), leading to ASD onset and progression, despite PUFA administration. ...
Article
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Pre- and post-natal factors can affect brain development and function, impacting health outcomes with particular relevance to neurodevelopmental diseases, such as autism spectrum disorders (ASDs). Maternal obesity and its associated complications have been related to the increased risk of ASDs in offspring. Indeed, animals exposed to maternal obesity or high fat diets are prone to social communication impairment and repetitive behavior, the hallmarks of autism. During development, fatty acids and sugars, as well as satiety hormones, like insulin and leptin, and inflammatory factors related to obesity-induced low grade inflammation, could play a role in the impairment of neuroendocrine system and brain neuronal circuits regulating behavior in offspring. On the other side, post-natal factors, such as mode of delivery, stress, diet or antibiotic treatment are associated to a modification of gut microbiota composition, perturbing microbiota-gut-brain axis. Indeed, the interplay between the gastrointestinal tract and the central nervous system not only occurs through neural, hormonal, and immune pathways, but also through microbe-derived metabolic products. The modification of unhealthy perinatal and postnatal environment, manipulation of gut microbiota, nutritional and dietary interventions could represent possible strategies in preventing or limiting ASDs, through targeting inflammatory process and gut microbiota.
... There are, though not very well understood, several potential biological pathways for a role of LCPUFA in ASD [88,89]. Approximately 60% of the brain's dry weight is fat, with DHA comprising 60% and 40% of the PUFA in the retina and brain, respectively [90], suggesting that it is structurally important. ...
... The development of axons and dentrites as well as myelination in multiple brain areas (involved in social behaviours, emotions, and RRB) has been reported to be impaired in individuals with ASD [105,106]. Similarly, an abnormal level of brain derived neurotrophic factor (BDNF, a protein that promotes the survival of neurons) in the circulation has been reported in children with ASD, which was associated with the severity of condition [88,107,108]. Docosahexaenoic acid administration normalised BDNF in the hippocampus, increased the growth of uninjured corticospinal and serotonergic fibres, and enhanced synaptic plasticity in an animal model of spinal cord injury [101,109]. ...
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Omega-3 long chain polyunsaturated fatty acid supplementation (n-3 LCPUFA) for treatment of Autism Spectrum Disorder (ASD) is popular. The results of previous systematic reviews and meta-analyses of n-3 LCPUFA supplementation on ASD outcomes were inconclusive. Two meta-analyses were conducted; meta-analysis 1 compared blood levels of LCPUFA and their ratios arachidonic acid (ARA) to docosahexaenoic acid (DHA), ARA to eicosapentaenoic acid (EPA), or total n-6 to total n-3 LCPUFA in ASD to those of typically developing individuals (with no neurodevelopmental disorders), and meta-analysis 2 compared the effects of n-3 LCPUFA supplementation to placebo on symptoms of ASD. Case-control studies and randomised controlled trials (RCTs) were identified searching electronic databases up to May, 2016. Mean differences were pooled and analysed using inverse variance models. Heterogeneity was assessed using I² statistic. Fifteen case-control studies (n = 1193) were reviewed. Compared with typically developed, ASD populations had lower DHA (−2.14 [95% CI −3.22 to −1.07]; p < 0.0001; I² = 97%), EPA (−0.72 [95% CI −1.25 to −0.18]; p = 0.008; I² = 88%), and ARA (−0.83 [95% CI, −1.48 to −0.17]; p = 0.01; I² = 96%) and higher total n-6 LCPUFA to n-3 LCPUFA ratio (0.42 [95% CI 0.06 to 0.78]; p = 0.02; I² = 74%). Four RCTs were included in meta-analysis 2 (n = 107). Compared with placebo, n-3 LCPUFA improved social interaction (−1.96 [95% CI −3.5 to −0.34]; p = 0.02; I² = 0) and repetitive and restricted interests and behaviours (−1.08 [95% CI −2.17 to −0.01]; p = 0.05; I² = 0). Populations with ASD have lower n-3 LCPUFA status and n-3 LCPUFA supplementation can potentially improve some ASD symptoms. Further research with large sample size and adequate study duration is warranted to confirm the efficacy of n-3 LCPUFA.
... Finally, Sensation Avoidance is a combination of low thresholds and active responding [36] The significant negative correlations observed among the tested 6 lipid mediators and sensory profile (Fig 7) is supported by the high area under the curve, specificity and sensitivity recorded for these markers through the use of receiver operating characteristic (ROC) analysis (Unpublished Data). Role of the measured parameters in the etiology of abnormal sensory profile in autistic patients is supported by the work of Das [37,38], who suggested that an alteration in the metabolism of PUFAs plays a significant role in ASD. It was proposed that formation of excess of pro-inflammatory cytokines and eicosanoids derived from AA (such as PGE2, thromboxanes and leukotrienes) and simultaneously reduced formation of anti-inflammatory cytokines and anti-inflammatory bioactive lipids such as lipoxin A4 (LXA4) (from AA), resolvins (from EPA and DHA) and protectins (from DHA) may have a significant role in ASD. ...
... It was suggested that PUFAs and their anti-inflammatory metabolites enhance neurite outgrowth, respectively. Biomarkers used in the identification process were set 1: PE, PS, PC, MAP2K1, IL-10, IL-12, and NFκB; set 2: PGE2, PGE2-EP2, PGES, cPLA2, 8-isoprostane, and COX-2; set 3: PGE2, PGES, cPLA2, 8-isoprostane, COX-2, and PE; and set 4 promote neuronal survival, and modulate actions of neurotransmitters [37,38]. It is likely that when there is an imbalance between pro-and anti-inflammatory metabolites of PUFAs and their precursors (between n-6 AA and n-3 EPA and DHA) it may result in oxidative stress that leads neuronal damage leading to the development of autism. ...
Article
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Background Autism is a neurodevelopmental disorder that displays significant heterogeneity. Comparison of subgroups within autism, and analyses of selected biomarkers as measure of the variation of the severity of autistic features such as cognitive dysfunction, social interaction impairment, and sensory abnormalities might help in understanding the pathophysiology of autism. Methods and Participants In this study, two sets of biomarkers were selected. The first included 7, while the second included 6 biomarkers. For set 1, data were collected from 35 autistic and 38 healthy control participants, while for set 2, data were collected from 29 out of the same 35 autistic and 16 additional healthy subjects. These markers were subjected to a principal components analysis using either covariance or correlation matrices. Moreover, libraries composed of participants categorized into units were constructed. The biomarkers used include, PE (phosphatidyl ethanolamine), PS (phosphatidyl serine), PC (phosphatidyl choline), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1), IL-10 (interleukin-10), IL-12, NFκB (nuclear factor-κappa B); PGE2 (prostaglandin E2), PGE2-EP2, mPGES-1 (microsomal prostaglandin synthase E-1), cPLA2 (cytosolic phospholipase A2), 8-isoprostane, and COX-2 (cyclo-oxygenase-2). Results While none of the studied markers correlated with CARS and SRS as measure of cognitive and social impairments, six markers significantly correlated with sensory profiles of autistic patients. Multiple regression analysis identifies a combination of PGES, mPGES-1, and PE as best predictors of the degree of sensory profile impairment. Library identification resulted in 100% correct assignments of both autistic and control participants based on either set 1 or 2 biomarkers together with a satisfactory rate of assignments in case of sensory profile impairment using different sets of biomarkers. Conclusion The two selected sets of biomarkers were effective to separate autistic from healthy control subjects, demonstarting the possibility to accurately predict the severity of autism using the selected biomarkers. The effectiveness of the identified libraries lied in the fact that they were helpful in correctly assigning the study population as control or autistic patients and in classifying autistic patients with different degree of sensory profile impairment.
... Omega-3 longchain poly unsaturated fatty acids (PUFAs), namely docosahexaenoic acid (DHA, C22:6) and eicosapentaenoic acid (EPA, C20:5), are conditionally essential nutrients with important physiological roles and potential health benefits (such as being part of cell membranes, having anti-inflammatory and cardio-protective properties and taking part in neurotransmission) (46)(47)(48). DHA, in particular, is fundamental for brain function and development and normal visual development in infants (49,50) and EPA has been reported to be more influential on behaviour and mood (49). ...
... The rationale for supplementing diet with longchain omega-3 PUFAs came from studies that investigated children with ASD, who were reported to have low levels of omega-3 fatty acids in their blood tissue and/or a higher total omega-6 PUFA to omega-3 PUFA ratio when compared to typically developing children (51)(52)(53)(54)(55)(56)(57)(58)(59). In individuals with ASD, the metabolism of PUFAs is thought to be deficient or abnormal, leading to increased production of pro-inflammatory cytokines, increased oxidative stress and an imbalance in the formation and action of neurotransmitters (50). ...
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Many children with Autism Spectrum Disorders (ASDs) have been reported to suffer from conditions (i.e. gastrointestinal distress, abnormal sensory processing, etc.) that may interfere with their nourishment. To compensate for possible deficiencies stemming from food selectivity and idiosyncratic eating habits and to alleviate some of the symptoms of A S D, a number of dietary strategies have been implemented by caregivers. Such strategies may include supplementation of diets with probiotics, omega-3 fatty acids, antioxidants, vitamins and minerals. Exclusion of certain nutrients from the diet (such as gluten, casein, carbohydrates, etc.) has also been resorted to. There are a vast number of studies conducted on dietary interventions in children with A S D, however, the results of these studies are confusing and inconclusive.Thispaper aims to critically review scientific studies on dietary strate¬ gies as applied to children with A S D and deduce practical implications from existing researches.
... The protective action of BDNF against benzo(a)pyrene is especially interesting because it is a common mutagen and carcinogen found in coal tar, automobile exhaust fumes, cigarette smoke, cooked meat products, fried chicken, overcooked charcoal-barbecued beef, and hamburgers. Because resveratrol is able to prevent BPA-induced autism, type 2 diabetes mellitus, and metabolic syndrome [43][44][45], it is likely that it may have the ability to augment BDNF synthesis and action, as BDNF also has similar beneficial actions in these diseases [42,46]. BDNF levels are low in subjects with type 2 diabetes mellitus in a recent study [47], and BDNF interacts and enhances the production of an antiinflammatory bioactive lipid, namely, lipoxin A4, whose levels are also low in diabetes mellitus [47][48][49]. ...
... Lipoxin A4 is a potent suppressor of proinflammatory prostaglandin E2 synthesis [50]. This raises the possibility that resveratrol may augment the production of lipoxin A4 and block that of prostaglandin E2, and thus it is able to bring about its beneficial actions in several diseases, including autism, obesity, diabetes mellitus, metabolic syndrome, depression, schizophrenia, and cancer [22,24,[43][44][45][46][47][48][49][50][51]. ...
... From a neurochemical point of view, alterations in GABAergic transmission have been postulated in ASD [195][196][197] and modulation of GABAegic receptor functions has been described for DHA [198][199][200]. Furthermore, alterations in neurotrophins, and in particular BDNF, and alterations in PUFA metabolism have also been reported in ASD [201]. Deficiency in n-3 PUFA intake, especially in perinatal period, is linked to decreased BDNF content [52], thus more studies focused on the role of maternal low PUFA consumption and the risk of ASD development are surely warranted. ...
Article
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Evidence from human studies indicates that maternal metabolic state and malnutrition dramatically influence the risk for developing psychiatric complications in later adulthood. In this regard, the central role of polyunsaturated fatty acids (PUFAs), and particularly n-3 PUFAs, is emerging considering that epidemiological evidences have established a negative correlation between n-3 PUFA consumption and development of mood disorders. These findings were supported by clinical studies indicating that low content of n-3 PUFAs in diet is linked to an increased susceptibility to psychiatric disorders. PUFAs regulate membrane fluidity and exert their central action by modulating synaptogenesis and neurotrophic factor expression, neurogenesis, and neurotransmission. Moreover, they are precursors of molecules implicated in modulating immune and inflammatory processes in the brain. Importantly, their tissue concentrations are closely related to diet intake, especially to maternal consumption during embryonal life, considering that their synthesis from essential precursors has been shown to be inefficient in mammals. The scope of this review is to highlight the possible mechanisms of PUFA functions in the brain during pre- and post-natal period and to evaluate their role in the pathogenesis of psychiatric diseases.
... This could probably be due to dysfunctions in the blood-brain barrier system [133]. Increases in concentrations of cytokines and other inflammatory markers such as arachidonic, involved in neuronal functions, are observed [134] giving rise to prostaglandins. Presence of microglial cells in the immature CNS are considered to be a feature of main immune competency. ...
Article
Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders respectively, with devastating effects not only on the individual but also on the society. Collectively, a number of factors contribute to the expression of ASD and AD. It is of utmost curiosity that these disorders express at different stages of life and there is an involvement of certain susceptible genes. This genetic basis makes the background of common associations like memory deficits, cognition changes, demyelination, oxidative stress and inflammation, an integral part of both disorders. Modern technology resulting in genetically modified crops and increase in gadgets emitting electromagnetic frequencies have resulted in enhanced risks for neurological dysfunctions and disorders like ASD and AD. Subsequent advances in the psychological, pharmacological, biochemical and nutritional aspects of the disorders have resulted in the development of newer therapeutic approaches. The common clinical features like language impairment, executive functions, and motor problems have been discussed along with the patho-physiological changes, role of DNA methylation, myelin development, and heavy metals in the expression of these disorders. Psycho-pharmacological and nutritional approaches towards the reduction and management of risk factors have gained attention from the researchers in recent years. Current major therapies either target the inflammatory pathways or reduce cellular oxidative stress. This contribution focuses on the commonalities of the two disorders.
... It is interesting to note that PUFAs, especially LXA 4 and AA, augmented the production of BDNF (brain-derived neurotrophic factor), a neurotrophic factor that is needed for the survival of retinal neuronal cells [128,129] (Das UN, unpublished data). In addition, BDNF binds to LXA 4 and AA and other PUFAs rather avidly and thus bring about some of its beneficial actions [130]. ...
Article
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Diabetic macular edema (DME) and diabetic retinopathy (DR) are complications affecting about 25% of all patients with long-standing type 1 and type 2 diabetes mellitus and are a major cause of significant decrease in vision and quality of life. Age-related macular degeneration (AMD) is not uncommon, and diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. Recent studies suggest that DME, DR and AMD are inflammatory conditions characterized by a breakdown of the blood-retinal barrier, inflammatory processes and an increase in vascular permeability. Key factors that seem to have a dominant role in DME, DR and AMD are angiotensin II, prostaglandins and the vascular endothelial growth factor and a deficiency of anti-inflammatory bioactive lipids. The imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DME, DR and AMD. This implies that bioactive lipids that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DME, DR and AMD.
... A significant decrease in the levels of BDNF-BCl2-Akt (genes involved in anti-apoptotic signaling pathways of BDNF) was observed in autism disorder [141]. Thus, plasma levels of BDNF may be used as a bio-marker for detection of autism disorder during early stages [142][143][144][145]. As already discussed above, BDNF has an important role in energy homeostasis that accounts for its role in obesity, type 2 diabetes mellitus and metabolic syndrome. ...
Article
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Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus.
... Supplementary table 3). Literature analysis of the obtained pathways revealed that the majority of these significantly enriched pathways including glutathione conjugation(Zhou et al. 2013;Bowers et al. 2011;Main et al. 2012), bile acid and bile salt metabolism(Laake and Compart 2013), GABA A receptor activation(Cellot and Cherubini 2014), prolonged ERK activation events(Faridar et al. 2014), eicosanoid ligand-binding receptors(Das 2013;Tassoni et al. 2008), G1/S-specific transcription(Mbadiwe and Millis 2013), ARMS-mediated activation(Correia et al. 2010;Gupta et al. 2013), metabolism of angiotensinogen to angiotensins(Guimond and Gallo-Payet 2012) and interleukin-1 signaling(Huang et al. 2011;Suzuki et al. 2011) are linked to molecular mechanisms associated with autism. ...
Article
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Autism spectrum disorders (ASDs) are a family of neurodevelopmental disorders that affect different regions of the brain. Therefore, knowing which part of the brain is severely affected by ASDs needs to be more clear. Moreover, transcriptome data analysis in ASDs is mainly performed on brain samples, but the restricted availability of human ASDs brain tissues has remained as a large challenge. We were then interested in examining whether blood can compensate for brain samples in transcriptomic researches of the etiology of ASDs when brain tissue is not available. Herein, to identify key characteristic genes which potentially trigger the development of autism, a total of 563 samples covering different tissues/regions of brain obtained from GEO database were re-analyzed. The varied genes which passed the pre-processing filters were subjected to a network-driven integrative workflow to explore significant modules and underlying pathways. Expression profiles of 15,524 common genes obtained among all the mentioned data sets were parsed into 10-gene modules. A functional enrichment analysis of brain module preservation revealed basic functional pathways preserved between the blood and brain samples. The preserved intra-modular hub genes were significantly enriched in copper ion and chiefly mitochondrial functions including oxidation, ATP synthesis and TCA pathways. The blood-derived networks shared a number of top hub genes with cerebellum network. Additionally, genes involved in mitochondrial metabolism have been indicated as top hub genes in selected modules.
... Die entsprechende Neuroinflammation zeichnet sich durch die erhöhte Synthese zahlreicher proinflammatorischer Zytokine, Neurotransmitter und freier Radikale aus [15,44]. Umgekehrt ist die Bildung antiinflammatorischer Lipide wie Lipoxine, Resolvine und Protektine reduziert, was auch auf eine zu geringe Zufuhr an Omega-3-Fettsäuren zurückgehen könnte, da diese die biologischen Vorstufen der antiinflammatorischen Mediatoren darstellen [14]. körper) [50], Lactoferrin [17] und Vitamin C, das sich positiv auf den oxidativen Stress im Rahmen der Neuroinflammation auswirken könnte [8]. ...
Article
Hintergrund: Autismus-Spektrum-Störungen (ASS) zählen zu den tiefgreifenden Entwicklungsstörungen des Kindes- und Jugendalters. Neben genetischen Einflüssen scheinen auch Umweltfaktoren zur ASS-Pathogenese beizutragen. Angehörige von Kindern und Jugendlichen mit ASS fragen oft nach bestimmten Diätformen, um die ASS-Symptomatik zu lindern. Ziel dieser Übersichtsarbeit ist die evidenzbasierte Bewertung der verfügbaren Daten zu ernährungstherapeutischen Interventionen bei Kindern und Jugendlichen mit ASS; die behandelnden Ärzte sollen so in die Lage versetzt werden, entsprechende Diäten fundiert beurteilen zu können. Methodik: Unter Anwendung definierter Ein- und Ausschlusskriterien wurde eine systematische Literaturrecherche in PubMed, Cinahl und The Cochrane Library durchgeführt; eingeschlossen wurden nur Studien, die nach 1999 publiziert wurden. Die Studienqualität wurde entsprechend mit CONSORT-, STROBE- und PRISMA-Checklisten bewertet. Ergebnisse: Es konnten 12 randomisiert-kontrollierte Studien und 2 nicht-kontrollierte Studien in die Auswertung einbezogen werden (n=971). Die Wirksamkeit der häufig angewendeten Gluten-/Casein-freien Diäten (GFCF) ist nicht belegt, und entsprechende valide prädiktive Parameter existieren ebenfalls nicht. Schlussfolgerung: Auf Grundlage der verfügbaren Daten lassen sich keine evidenzbasierten Empfehlungen für ernährungstherapeutische Interventionen bei Kindern und Jugendlichen mit ASS ableiten. Zukünftige Studien müssen klären, ob einzelne Patienten-Subgruppen dennoch von bestimmten Diätformen profitieren könnten.
... Therefore, BDNF has been proposed as a critical factor that is involved in ASD and is a therapeutic targeted that is being studied [Reviewed in [73]]. Conversely, another review proposed a decreased blood level of BDNF as a marker for ASD prediction and prognosis [Reviewed in [74]]. Sadakata et al. reported that transgenic knockout mice that are missing Ca 2+dependent activator protein for secretion 2 (CAPS2), a protein that is involved in NT release, were susceptible to autistic features [12,75]. ...
Chapter
The cerebellum plays a main role in motor control and also in cognition features such as attention. Thus, a disturbance in cerebellar development results in neurological disorders such as attention deficit hyperactivity disorder (ADHD), congenital ataxia, and autism. Because neurotrophic factors have established effects on the growth, proliferation, differentiation, and arborization of neurons, their role in the neurodevelopmental disorders has been investigated for decades. Results of numerous studies have shown changes in serum or tissue neurotrophic factor levels, as well as alterations in their receptors and components of their signaling pathways in these types of the neurodevelopmental diseases. In this chapter, we provide a brief overview of neurotrophic factors and their role in cerebellar development and then focus on the roles of the neurotrophin system in developmental disorders and diseases of the cerebellum.
... This highlights its relevance as a consequential factor. Recently, DHA deficit was also found in coeliac patients and has been correlated to deficiency of the brain-derived neurotrophic factor (BDNF) 31 , a well-known biomarker in mood disorders and autism 32,33 . It must also be taken into account that a high saturated fat diet reduces both DHA and BDNF levels, as reported in animal models 34 , and that the DHA decrease in RBC membrane of ASD patients could also recall the influence of maternal dietary fats on autism onset 35 . ...
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Membranes attract attention in medicine, concerning lipidome composition and fatty acid correlation with neurological diseases. Hyperspectral dark field microscopy (HDFM), a biophotonic imaging using reflectance spectra, provides accurate characterization of healthy adult RBC identifying a library of 8 spectral end-members. Here we report hyperspectral RBC imaging in children affected by Autism Spectrum Disorder (ASD) (n = 21) compared to healthy age-matched subjects (n = 20), investigating if statistically significant differences in their HDFM spectra exist, that can comprehensively map a membrane impairment involved in disease. A significant difference concerning one end-member (spectrum 4) was found (P value = 0.0021). A thorough statistical treatment evidenced: i) diagnostic performance by the receiving operators curve (ROC) analysis, with cut-offs and very high predictive values (P value = 0.0008) of spectrum 4 for identifying disease; ii) significant correlations of spectrum 4 with clinical parameters and with the RBC membrane deficit of the omega-3 docosahexaenoic acid (DHA) in ASD patients; iii) by principal component analysis, very high affinity values of spectrum 4 to the factor that combines behavioural parameters and the variable "cc" discriminating cases and controls. These results foresee the use of biophotonic methodologies in ASD diagnostic panels combining with molecular elements for a correct neuronal growth.
... Because of the variety of symptoms occurring with this disorder, it is more common currently to use the term "autism spectrum disorders" (ASD). It is because it may represent a broader concept that covers various groups of autistic symptom types [1,2]. In the past two decades, the occurrence of ASD rose rapidly; however, the reason for this phenomenon has not been identified yet despite numerous studies on this topic, and the etiology of it remains still unknown [3]. ...
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Introduction The occurrence of autism spectrum disorders (ASD) has significantly increased in the last few years. One of the common problems in this group are eating disorders and ailments from the gastrointestinal systems. According to some studies, these problems have a significant impact on the occurrence and severity of symptoms in the neurological system, so it is crucial to increase the attention paid on the role of diet in the treatment of this disease. One of the theories connects ASD with disorders of the digestive system and the intestinal bacterial flora. This theory is based on the gut-brain axis, which means the interaction between the gastrointestinal and nervous systems. Objectives To demonstrate the differences in behavior habits, interest in nutrition, and frequency of consumption of food products between children suffering from ASD and healthy children. Materials and methods The study was conducted among 44 children suffering from ASD and 33 healthy children as a control group. Data were collected using a questionnaire that was specially designed for this study. The questionnaire contained questions about eating habits and the frequency of consumption of selected food products. Results Parents of healthy children showed more interest in their children’s way of feeding and nutritional recommendations compared to parents of children with ASD (4% and 11.3%, respectively). In addition, 24.3% more children with ASD consulted with a nutritionist compared to the control group. Complaints of the digestive system were 21.1% more likely by children with ASD. Children suffering from ASD were characterized by a higher intake of red meat and giblets and less frequent consumption of milk and milk products compared to the control group. There were no statistically significant differences between the study group and the control group in terms of frequency of consumption of products, which are the source of gluten, artificial food additives-preservatives, and artificial colors. Conclusions There are differences in the habits and eating behaviors and the frequency of consumption of selected food products between a group of children with ASD and a group of healthy children.
... These can cause impaired electron transport chain (ETC) and mitochondria function (membrane potential/polarization, molecule transport, mito protein translocation, and apoptosis) [102,103]. ASD is also categorized by an abnormal immune response; this can have negative effects on brain growth factors, development, and neural transmitters [52,104]. Patients with autism demonstrated activated micro/ astro glia and increased levels of proapoptotic cytokines [52]. ...
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The glyoxalase pathway functions to detoxify reactive dicarbonyl compounds, most importantly methylglyoxal. The glyoxalase pathway is an antioxidant defense mechanism that is essential for neuroprotection. Excessive concentrations of methylglyoxal have deleterious effects on cells, leading to increased levels of inflammation and oxidative stress. Neurodegenerative diseases - including Alzheimer's, Parkinson's, Aging and Autism Spectrum Disorder - are often induced or exacerbated by accumulation of methylglyoxal. Antioxidant compounds possess several distinct mechanisms that enhance the glyoxalase pathway and function as neuroprotectants. Flavonoids are well-researched secondary plant metabolites that appear to be effective in reducing levels of oxidative stress and inflammation in neural cells. Novel flavonoids could be designed, synthesized and tested to protect against neurodegenerative diseases through regulating the glyoxalase pathway.
... Micronutrients deficiency plays an important role on neurotrophic factors and neurotransmitters synthesis and effects. Even if the mechanism remains unclear, adverse events occurring prenatally such as malnutrition could also induce an excessive inflammatory response partly responsible for brain disorders [61]. ...
... In the very recent years, the potential interaction between fatty acid profile and neuroinflammation, as an etiological mechanism of ASD, has been found utmost interesting, worth studied by many authors as a promising diagnostic tool. Since fatty acids make up 60% of the dry weight of the brain, with 20% of long-chain polyunsaturated fatty acids (PUFAs), they should play a crucial role in the brain development (Innis 2000;Vancassel et al. 2001;Richardson 2004;Das 2013). Omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA) are the most abundant PUFA in the brain, and play a critical role in the composition of neural cell membrane phospholipids, membrane fluidity modulation, and G-coupled protein receptors function (GPCRs) (Schuchardt et al. 2010;Bradbury 2011). ...
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Autism spectrum disorder (ASD) is a multifactorial disorder caused by an interaction between environmental risk factors and a genetic background. It is characterized by impairment in communication, social interaction, repetitive behavior, and sensory processing. The etiology of ASD is still not fully understood, and the role of neuroinflammation in autism behaviors needs to be further investigated. The aim of the present study was to test the possible association between prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin PGE2 EP2 receptors and nuclear kappa B (NF-κB) and the severity of cognitive disorders, social impairment, and sensory dysfunction. PGE2, COX-2, mPGES-1, PGE2-EP2 receptors and NF-κB as biochemical parameters related to neuroinflammation were determined in the plasma of 47 Saudi male patients with ASD, categorized as mild to moderate and severe as indicated by the Childhood Autism Rating Scale (CARS) or the Social Responsiveness Scale (SRS) or the Short Sensory Profile (SSP) and compared to 46 neurotypical controls. The data indicated that ASD patients have remarkably higher levels of the measured parameters compared to neurotypical controls, except for EP2 receptors that showed an opposite trend. While the measured parameter did not correlate with the severity of social and cognitive dysfunction, PGE2, COX-2, and mPGES-1 were remarkably associated with the dysfunction in sensory processing. NF-κB was significantly increased in relation to age. Based on the discussed data, the positive correlation between PGE2, COX-2, and mPGES-1 confirm the role of PGE2 pathway and neuroinflammation in the etiology of ASD, and the possibility of using PGE2, COX-2 and mPGES-1 as biomarkers of autism severity. NF-κB as inflammatory inducer showed an elevated level in plasma of ASD individuals. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of biochemical correlates to ASD.
... The remarkable improvement in cPLA2 and phospholipid levels in groups treated with ω-3, vitamin B12, and ω-3 + vitamin B12 is consistent with a recent study by Rathod et al. [41] in which the combined supplementation of vitamin B12 and ω-3 fatty acids led to higher ω-3 and nerve growth factor (NGF) levels in the hippocampus, higher brain derived neurotrophic factor (BDNF) levels in the cortex and hippocampus, together with improvement of cognitive performance. Omega-3 as a precursor for active mediators can regulate various brain functions such as neurotransmission, inflammation, immune reaction and neuronal survival [42][43][44][45][46]. The present study is consistent with the recent work of Qasem et al. [47], which reported a remarkable reduction in phospholipids and an increase in cPLA2 protein levels as etiological mechanisms of autism; these findings might support the use of PPA postnatal exposure to induce persistent autistic features, similar to the mechanism that causes autism. ...
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Background: Abnormal phospholipid metabolism is a major component of many neurodevelopmental disorders including autism. Oral administration of propionic acid (PPA) can produce behavioral abnormalities and biochemical features in rodents similar to those observed in autism and can thus be used as a model to understand impaired brain fatty acid metabolism in autism. Methods: The present study was designed to understand alterations in phospholipid metabolism in the brain of a rodent model of autism and to explore omega-3 and vitamin B12 as remedies. Five groups of rats were selected: Group 1 was the control. Group 2 was the rodent model of autism treated with a neurotoxic dose of PPA. Group 3 was given vitamin B12 cobalamin (16.7 mg/kg/day) for 30 days after PPA treatment. Group 4 was given pharmaceutical grade Omega-3 (200 mg cholesterol free-DHA/kg body weight/day), a product of Madre lab, Germany, for 30 days after PPA treatment for 3 days. Group 5 was given a combined dose of ω-3 + Vitamin B12 for the same duration post-PPA treatment. Phospholipid levels and Phospholipase A2 were measured in the brain homogenates of all the groups. ELISA and western blotting were used to detect the cPLA2 protein level. Results: A significant decrease in phospholipid levels and a significant increase in cPLA2 were found in brain tissue of PPA-treated rats; however, both ω-3 and vitamin B12 were efficient in ameliorating the neurotoxic effect of PPA. Conclusion: Both ω-3 and vitamin B12 may play a role in ameliorating impaired phospholipid metabolism in autism; however, proper clinical trials are needed.
... The role of FA in the membranes of different cells and in the neurotransmitters supports the hypothesis that DHA supplements would improve the symptoms of ASD (15). The different mechanisms of involvement of n-3 PUFA levels in the etiology of ASD have been suggested as defects in enzymes involved in the DHA and EPA production from α-linolenic acid (ALA), known as FA desaturases (FADS), by deficiencies in its process of cell membrane incorporation, or an alteration in its metabolism, e.g., through a possible dysfunction in mitochondrial PUFA oxidation (49,50). These FA alterations would justify the higher incidence of ASD in boys, because girls appear to have a higher conversion rate of ALA into DHA, associated with the higher hepatic expression of PUFA desaturase enzymes, and probably longer DHA half-life in plasma compared with boys (51). ...
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Background The pathogenesis of autism spectrum disorder (ASD) is under investigation and one of the main alterations relates to the metabolic and inflammatory system dysfunctions. Indeed, based on a possible deficit of omega-3 fatty acids (FAs) of patients with ASD and looking for an anti-inflammatory effect, dietary supplements with omega-3 fatty acids have been proposed. We aimed to evaluate differences in plasma and erythrocyte FA profiles and plasma cytokines in patients with infantile ASD after supplementation with docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids or placebo and both compared at baseline with a reference healthy group. Methods A double-blind, randomized placebo-controlled intervention with DHA/EPA for 6 months was carried out in 54 children between 2 and 6 years diagnosed with ASD. They were selected and randomly assigned into two groups: 19 children received 800 mg/day of DHA and 25 mg/day of EPA, or placebo. In addition, another reference group of 59 healthy children of the same age was included. Plasma lipids and cytokines, and FA profiles in plasma and erythrocytes were measured at baseline and after 6 months of treatment in ASD children, and at baseline in the reference group. Results There were no differences in demographic, anthropometric characteristics, and omega-3 intake between the healthy reference group and the ASD children at baseline. Children with ASD showed the higher plasma percentages of palmitic acid and total saturated FA and lower total omega-6 polyunsaturated FA (PUFA) compared with healthy children. An increased level of DHA and reduced EPA level in erythrocytes were detected in the ASD group vs. the reference group. After 6 months of treatment, the ASD group that received DHA enriched product significantly increased the plasma and erythrocyte percentages of DHA, but no differences were observed in the clinical test scores and other parameters as plasma cytokines between the two groups of ASD related to the intervention. Conclusion Spanish children with ASD exhibit an appropriate omega-3 FA status in plasma and erythrocytes. Neither a clinical improvement of ASD children nor a better anti-inflammatory or fatty acid state has been found after an intervention with DHA/EPA for 6 months. So, the prescription of n-3 LC-PUFA and other dietary supplements in ASD should be only indicated after a confirmed alteration of FA metabolism or omega-3 LC-PUFA deficiency evaluated by specific erythrocyte FA. Clinical Trial Registration [ www.ClinicalTrials.gov ], identifier [NCT03620097].
... The strains of Shewanella, including S. violacea, S. benthica, S. peizotolerans, have been reported to produce EPA, which is associated with adaptation under extreme cold and high hydrostatic pressure [27][28][29]. These omega-3 fatty acids are associated with beneficial health effects related to maternal and fetal health, prevention of cardiovascular diseases, preventing blood circulatory disorders due to the anti-aggregatory feature of EPA, and prevention of neurological disorders [30][31][32][33]. Due to the above salient features, the Shewanella genus has been of research interest in environmental and applied microbiology. ...
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The genus Shewanella is widely distributed in niches ranging from an aquatic environment to spoiled fish and is loaded with various ecologically and commercially important metabolites. Bacterial species under this genus find application in bioelectricity generation and bioremediation due to their capability to use pollutants as the terminal electron acceptor and could produce health-beneficial omega-3 fatty acids, particularly eicosapentaenoic acid (EPA). Here, the genome sequence of an EPA-producing bacterium, Shewanella sp. N2AIL, isolated from the gastrointestinal tract of Tilapia fish, is reported. The genome size of the strain was 4.8 Mb with a GC content of 46.3% containing 4385 protein-coding genes. Taxonogenomic analysis assigned this strain to the genus Shewanella on the basis of average nucleotide identity (ANI) and in silico DNA-DNA hybridization (DDH), phylogenetically most closely related with S. baltica NCTC 10735T. The comparative genome analysis with the type strain of S. baltica revealed 693 unique genes in the strain N2AIL, highlighting the variation at the strain level. The genes associated with stress adaptation, secondary metabolite production, antibiotic resistance, and metal reduction were identified in the genome suggesting the potential of the bacterium to be explored as an industrially important strain. PUFA synthase gene cluster of size ~20.5 kb comprising all the essential domains for EPA biosynthesis arranged in five ORFs was also identified in the strain N2AIL. The study provides genomic insights into the diverse genes of Shewanella sp. N2AIL, which is particularly involved in adaptation strategies and prospecting secondary metabolite potential, specifically the biosynthesis of omega-3 polyunsaturated fatty acids.
... Research evidence indicates that BDNF (brain-derived neurotrophic factor) promotes the survival and differentiation of serotonergic neurons [66]. Similar to these data, the involvement of BDNF in symptoms of ASDs in animal models [67][68][69][70] and autistic patients [71][72][73] has been demonstrated. In the current and previous studies [41-42], decreased Bdnf gene expression was identified in the raphe nuclei of the midbrain in the losers and winners. ...
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Background The ability of people to communicate with each other is a necessary component of social behavior and the normal development of individuals who live in a community. An apparent decline in sociability may be the result of a negative social environment or the development of affective and neurological disorders, including autistic spectrum disorders. The behavior of these humans may be characterized by the deterioration of socialization, low communication, and repetitive and restricted behaviors. This study aimed to analyze changes in the social behaviors of male mice induced by daily agonistic interactions and investigate the involvement of genes, related with autistic spectrum disorders in the process of the impairment of social behaviors. Methods Abnormal social behavior is induced by repeated experiences of aggression accompanied by wins (winners) or chronic social defeats (losers) in daily agonistic interactions in male mice. The collected brain regions (the midbrain raphe nuclei, ventral tegmental area, striatum, hippocampus, and hypothalamus) were sequenced at JSC Genoanalytica ( http://genoanalytica.ru/ , Moscow, Russia). The Cufflinks program was used to estimate the gene expression levels. Bioinformatic methods were used for the analysis of differentially expressed genes in male mice. Results The losers exhibited an avoidance of social contacts toward unfamiliar conspecific, immobility and low communication on neutral territory. The winners demonstrated aggression and hyperactivity in this condition. The exploratory activity (rearing) and approaching behavior time towards the partner were decreased, and the number of episodes of repetitive self-grooming behavior was increased in both social groups. These symptoms were similar to the symptoms observed in animal models of autistic spectrum disorders. In an analysis of the RNA-Seq database of the whole transcriptome in the brain regions of the winners and losers, we identified changes in the expression of the following genes, which are associated with autism in humans: Tph2, Maoa, Slc6a4, Htr7,Gabrb3, Nrxn1, Nrxn2, Nlgn1, Nlgn2, Nlgn3, Shank2, Shank3, Fmr1, Ube3a, Pten, Cntn3, Foxp2, Oxtr, Reln, Cadps2, Pcdh10, Ctnnd2, En2, Arx, Auts2, Mecp2 , and Ptchd1 .Common and specific changes in the expression of these genes in different brain regions were identified in the winners and losers. Conclusions This research demonstrates for the first time that abnormalities in social behaviors that develop under a negative social environment in adults may be associated with alterations in expression of genes, related with autism in the brain.
... Long chain polyunsaturated fatty acids, or PUFAs, like DHA and EPA, are found in high concentrations in the brain's gray matter. PUFAs in the brain are known to promote neuronal growth and synapse formation and facilitate neural transmission 47 . Long chain omega-6 polyunsaturated fatty acids are important for brain and cognitive health; but this effect is most pronounced when they are in a balanced ratio with the omega-3 polyunsaturated fats 48,49 . ...
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Achieving military mission objectives requires high levels of performance from Airmen who operate under extreme physical and cognitive demands. Thus, there is a critical need to establish scientific interventions to enhance physical fitness and cognitive performance –promoting the resilience of Airmen and aiding in mission success. We therefore conducted a comprehensive, 12-week randomized controlled trial in active-duty Air Force airmen (n=148) to compare the efficacy of a multimodal intervention comprised of high-intensity interval aerobic fitness and strength training paired with a novel nutritional supplement (comprised of β-hydroxy β-methylbutyrate (HMB), lutein, phospholipids, DHA and selected micronutrients including B12 and folic acid) to high-intensity interval aerobic fitness and strength training paired with a standard of care placebo beverage. The exercise intervention alone improved several dimensions of physical fitness (power (+0.85%), strength and endurance (+8.3%), mobility and stability (+22%), heart rate (-1.1%) and lean muscle mass (+1.4%)) and cognitive function (episodic memory (+9.5%), processing efficiency (+7.5%), executive function reaction time (-4.8%) and fluid intelligence accuracy (+19.5%)). Relative to exercise training alone, the multimodal fitness and nutritional intervention further improved working memory (+9.0%), fluid intelligence reaction time (-7.7%), processing efficiency (+1.8%), heart rate (-2.4%) and lean muscle mass (+1.5%). These findings establish the efficacy of a multimodal intervention that incorporates aerobic fitness and strength training with a novel nutritional supplement to enhance military performance objectives and to provide optimal exercise training and nutritional support for the modern warfighter.
... Menni et al. (2017) noted that increased serum DHA was associated with bacterial groups that were negatively correlated with intestinal inflammation and Crohn's disease [153]. In addition, low omega-3 levels can lead to the malfunction of neurotransmitters, as EFA can modulate the expression and action of neurotransmitters including serotonin, dopamine, and acetylcholine [154]. ...
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Children with autism spectrum disorder (ASD) report a higher frequency and severity of gastrointestinal disorders (GID) than typically developing (TD) children. GID-associated discomfort increases feelings of anxiety and frustration, contributing to the severity of ASD. Emerging evidence supports the biological intersection of neurodevelopment and microbiome, indicating the integral contribution of GM in the development and function of the nervous system, and mental health, and disease balance. Dysbiotic GM could be a contributing factor in the pathogenesis of GID in children with ASD. High-fat diets may modulate GM through accelerated growth of bile-tolerant bacteria, altered bacterial ratios, and reduced bacterial diversity, which may increase the risk of GID. Notably, saturated fatty acids are considered to have a pronounced effect on the increase of bile-tolerant bacteria and reduction in microbial diversity. Additionally, omega-3 exerts a favorable impact on GM and gut health due to its anti-inflammatory properties. Despite inconsistencies in the data elaborated in the review, the dietary fat composition, as part of an overall dietary intervention, plays a role in modulating GID, specifically in ASD, due to the altered microbiome profile. This review emphasizes the need to conduct future experimental studies investigating the effect of diets with varying fatty acid compositions on GID-specific microbiome profiles in children with ASD.
... Intriguingly, the down-regulation of BDNF, together with anti-apoptotic signaling, is one of the hallmarks of ASD (Sheikh et al. 2010;Das 2013). These findings suggest that ASD patients could benefit from elevated BDNF levels, induced either by physical activity and coordinative exercise or by external administration. ...
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Autism spectrum disorder (ASD) comprises a group of multifactorial neurodevelopmental disorders primarily characterized by deficits in social interaction and repetitive behavior. Although the onset is typically in early childhood, ASD poses a life-long challenge for both patients and caretakers. Adult neurogenesis (AN) is the process by which new functional neurons are created from neural stem cells existing in the postnatal brain. The entire event is based on a sequence of cellular processes such as proliferation, specification of cell fate, maturation and, ultimately, synaptic integration into the existing neural circuits. Hence, AN is implicated in structural and functional brain plasticity throughout life. Accumulating evidence shows that impaired AN may underlie some of the abnormal behavioral phenotypes seen in ASD. In this review, we approach the interconnections between the molecular pathways related to AN and ASD. We also discuss existing therapeutic approaches targeting such pathways both in preclinical and clinical studies. A deeper understanding of how ASD and AN reciprocally affect one another could reveal important converging pathways leading to the emergence of psychiatric disorders.
... Replacement of dietary saturated fatty acids with n-6 PUFA, for example, has been shown to lower total blood cholesterol, and, according to the American Heart Association, long-chain n-3 PUFA supplementation may help reduce mortality in patients with prevalent coronary heart disease and in those with heart failure without preserved ventricular function (Siscovick et al., 2017). Moreover, docosahexaenoic acid (DHA) from the n-3 PUFA group is important for the development of the nervous system, in particular fetus optic nerves (Das, 2013). Wide observational studies have also revealed that a diet rich in fish is associated with a lower risk of neurological disorders such as cognitive deterioration and Alzheimer's disease. ...
Article
The actual concerns regarding the quality and authenticity of newly-marketed seed oils are based on a high risk of identity theft, tampering with purity, and adulteration. Seed oils are a rich source of dietary fat and various phytochemicals, and as such are an object of health-related and commercial interest. However, the lipid composition of these oils is poorly investigated and there is a lack of information on what methods are appropriate for detecting adulteration in this kind of oils. Therefore, in this review, the current knowledge on the problem of detecting adulteration of well-known edible oils was collected and systematized. Most methods of identification and determination of lipidomic profiles of oils are based on infrared and Raman spectroscopy as well as chromatographic separation combined with mass spectrometry. Quantitative and qualitative determination of fatty acids, tri- and di-glycerols, phospholipids, glycolipids, sterols and tocopherols can contribute to overcoming the problem of food adulteration.
... Furthermore, deficiency of these PUFAs seem to have a role in disorders like schizophrenia and attention deficit hyperactivity disorder (ADHD). Perinatal supplementation of AA and DHA is critical for normal brain growth and development in humans and seem to improve cognition and sensorimotor integration [189][190][191][192][193]. In view of these important functions of AA and DHA, it is possible that they are involved in the pathobiology of AD and Parkinson's disease. ...
Article
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Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.
... Additionally, the BDNF can induce a lasting potentiation of synaptic efficacy at the mossy fibers projection accompanied by a structural reorganization at the CA3 area (Martinez-Moreno et al. 2020). Previous research on BDNF revealed that this neurotrophin was highly expressed in the central nervous system (particularly in the hippocampus), which has essential functions in neuronal development and neuroplasticity that are related to social behavior disorders (Brondino et al. 2018;Das 2013;Hing et al. 2018). Preclinical studies have shown that levels and expression of BDNF are altered in the brain due to an unbalanced maternal diet low in micronutrients (Sable et al. 2014). ...
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RationaleB vitamins play essential roles in brain development and functionality; however, the effects of their deficiency during early life on mental health are not thoroughly understood.Objectives The objective of this study is to investigate the effects of a maternal deficiency of vitamin B6, B9 (folate), and B12 on behavioral changes in adult offspring.Methods Female C57BL/6 J mice were put on a diet lacking vitamin B6, B9, B12, or the above three vitamins from pregnancy to weaning. The growth and developmental characteristics of both the pregnant mothers and offspring were collected. In the adult offspring, the serum levels of neuroactive substances were measured using an enzyme-linked immunosorbent assay. The level of BDNF and dimethylated lysine 9 on histone H3 (H3K9me2) was detected by immunohistochemical staining. In addition, their depressive-like behaviors, anxiety-like behaviors, and sociability were recorded using sucrose preference, a forced swim, social interaction, tail suspension, and open field tests.ResultsThe maternal deficiency of the three B vitamins delayed offspring development. Compared to the controls, all of the groups showed decreased serum levels of 5-HT and neuropeptide Y. In the groups with deficiency of B9 or the three B vitamins, there were significant changes in sociability and social novelty preference. In groups with deficiencies in B9, B12, or all three B vitamins, the expression levels of BDNF and H3K9me2 in the hippocampus were significantly decreased.Conclusions Maternal deficiencies of the major B vitamins caused changes in social behaviors in adult mice accompanied with epigenetic alterations in the brain and changes in the serum levels of neuroactive substances.
... In the event of autism triggered by the disruption of mitochondrial chain structure, the amount of ROS appears to be elevated and ends with excessive oxidative stress (Surapaty et al. 2020). The downregulation of the BDNF-Akt-Bcl2 anti-apoptotic signaling pathway in the autistic brain is one of the underlying mechanisms responsible for autism (Das 2013). Activation of SHH signaling is beneficial for various neurological and cardiovascular disorders. ...
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Autism is a multifactorial neurodevelopmental condition; it demonstrates some main characteristics, such as impaired social relationships and increased repetitive behavior. The initiation of autism spectrum disorder is mostly triggered during brain development by the deregulation of signaling pathways. Sonic hedgehog (SHH) signaling is one such mechanism that influences neurogenesis and neural processes during the development of the central nervous system. SMO-SHH signaling is also an important part of a broad variety of neurological processes, including neuronal cell differentiation, proliferation, and survival. Dysregulation of SMO-SHH signaling leads to many physiological changes that lead to neurological disorders such as ASD and contribute to cognitive decline. The aberrant downregulation of SMO-SHH signals contributes to the proteolytic cleavage of GLI (glioma-associated homolog) into GLI3 (repressor), which increases oxidative stress, neuronal excitotoxicity, neuroinflammation, and apoptosis by suppressing target gene expression. We outlined in this review that SMO-SHH deregulation plays a crucial role in the pathogenesis of autism and addresses the current status of SMO-SHH pathway modulators. Additionally, a greater understanding of the SHH signaling pathway is an effort to improve successful treatment for autism and other neurological disorders. This is a preview of subscription content, log in to check access. Access options
... PUFA deficiency is hypothesized to induce autistic behavior (hyperactivity, aggression, and stereotypic habits) associated with proinflammatory cytokine cumulation, escalation of oxidative process and neurotransmitter imbalance (cholinergic, GABAergic, and dopaminergic neurotransmission in conjunction with a diminished level of serotonin in the prefrontal cortex) [29][30][31]. Omega-3 PUFA supplementation is also related to neuroinflammation regulation, microglia activity, and synaptic plasticity although future research with a longer period of follow-up is still needed [32]. ...
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Autism is a kind of pervasive developmental disorder that is related to many behavioral problems including perception, communication, motor development, and social disorder. World Health Organization (WHO) estimates that about six in 1,000 children worldwide are affected by an autism spectrum disorder. Nutritional regulation is one of the main concerns of children with autism due to many problems in the biochemical process, digestion process, and food allergy. Food selection in autistic children is not different from any other normal children, following standard requirement of a balanced diet, by implementing specific elimination and supplementation diet. There are many indications for dietary regulation in autistic children including developmental disorder, obvious digestion problems, and atopic signs. Implementing dietary regulation is not free from problems, inclusive of child factor, parent factor, and external factor.
... Omega-3 long-chain polyunsaturated fatty acids (PUFAs), especially docosahexaenoic and eicosapentaenoic acids, are necessary for the normal brain and visual development and function and regulation of behavior and mood [83]. The defective metabolism of PUFAs has been observed in ASD children, which was associated with an increase in inflammatory cytokines, oxidative stress and the malfunctioning of neurotransmitters [84]. A low level of ω-3, altered ω-3 and ω-6 ratio have been detected in ASD children compared to that of the normal children [85]. ...
... Omega-3 long-chain polyunsaturated fatty acids (PUFAs), especially docosahexaenoic and eicosapentaenoic acids, are necessary for the normal brain and visual development and function and regulation of behavior and mood [83]. The defective metabolism of PUFAs has been observed in ASD children, which was associated with an increase in inflammatory cytokines, oxidative stress and the malfunctioning of neurotransmitters [84]. A low level of ω-3, altered ω-3 and ω-6 ratio have been detected in ASD children compared to that of the normal children [85]. ...
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Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder characterized by the impairment of the cognitive function of a child. Studies suggested that the intestinal microbiota has a critical role in the function and regulation of the central nervous system, neuroimmune system and neuroendocrine system. Any adverse changes in the gut-brain axis may cause serious disease. Food preferences and dietary patterns are considered as key in influencing the factors of ASD development. Several recent reviews narrated the importance of dietary composition on controlling or reducing the ASD symptoms. It has been known that the consumption of probiotics confers several health benefits by positive amendment of gut microbiota. The influence of probiotic intervention in children with ASD has also been reported and it has been considered as an alternative and complementary therapeutic supplement for ASD. The present manuscript discusses the role of microbiota and diet in the development of ASD. It also summarizes the recent updates on the influence of dietary supplements and the beneficial effect of probiotics on ASD symptoms. An in-depth literature survey suggested that the maternal diet and lifestyle are greatly associated with the development of ASD and other neurodevelopmental disorders. Mounting evidences have confirmed the alteration in the gut microbial composition in children suffering from ASD. However, the unique profile of microbiome has not yet been fully characterized due to the heterogeneity of patients. The supplementation of probiotics amended the symptoms associated with ASD but the results are inconclusive. The current study recommends further detailed research considering the role of microbiome, diet and probiotics in the development and control of ASD.
... This cytoprotective action of BDNF is somewhat similar to the observed cytoprotective action of RSV against bisphenol A-induced autism, type 2 diabetes mellitus and metabolic syndrome (52e54). This suggest that in all probability RSV may augment BDNF synthesis (6,55). ...
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Resveratrol modulates the transcription factor NF-κB, cytochrome P450 isoenzyme CYP1A1, expression and activity of cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR and cyclins and various phospho-diesterases resulting in an increase in cytosolic cAMP levels. Cyclic AMP, in turn, activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway that facilitates increased oxidation of fatty acids, mitochondrial respiration and their biogenesis and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) and other pro-inflammatory molecules and inhibits expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) that may explain its anti-inflammatory actions. Polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites lipoxin A4, resolvins, protectins and maresins have a significant role in obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome and cancer. We observed that PUFAs (especially arachidonic acid, AA) and BDNF (brain-derived neurotrophic factor) protect against the cytotoxic actions of alloxan, streptozotocin, benzo(a)pyrene (BP) and doxorubicin. Thus, there is an overlap in the beneficial actions of resveratrol, PUFAs and BDNF suggesting that these molecules may interact and augment synthesis and action of each other. This is supported by the observation that resveratrol and PUFAs modulate gut microbiota and influence stem cell proliferation and differentiation. Since resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve.
... Patients with colon cancer who received fish oil supplementation had a significant reduction in IL-6 and TNF-alpha levels and an increase in the percentages of CD3+ and CD+ lymphocytes when compared with the control group [72]. These data suggest that n-3 PUFA might also benefit symptoms in psychiatric disorders [73], which are now recognized as disorders of neuronal inflammation [74][75][76]. ...
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The treatment of psychiatric disorders remains a significant challenge in part due to imprecise diagnostic criteria and incomplete understanding of the molecular pathology involved. Current diagnostic and pharmacological treatment guidelines use a uniform approach to address each disorder even though psychiatric clinical presentation and prognosis within a disorder are known to be heterogeneous. Limited therapeutic success highlights the need for a precision medicine approach in psychiatry, termed precision psychiatry. To practice precision psychiatry, it is essential to research and develop multiple omics-based biomarkers that consider environmental factors and careful phenotype determination. Metabolomics, which lies at the endpoint of the “omics cascade,” allows for detection of alterations in systems-level metabolites within biological pathways, thereby providing insights into the mechanisms that underlie various physiological conditions and pathologies. The eicosanoids, a family of metabolites derived from oxygenated polyunsaturated fatty acids, play a key role in inflammatory mechanisms and have been implicated in psychiatric disorders such as anorexia nervosa and depression. This review (1) provides background on the current clinical challenges of psychiatric disorders, (2) gives an overview of metabolomics application as a tool to develop improved biomarkers for precision psychiatry, and (3) summarizes current knowledge on metabolomics and lipidomic findings in common psychiatric disorders, with a focus on eicosanoids. Metabolomics is a promising tool for precision psychiatry. This research has great potential for both discovering biomarkers and elucidating molecular mechanisms underlying psychiatric disorders.
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Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well as in learned motor deficits, cognition impairments and perseverative tendencies that are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim of this study is to examine the effects of RORα deficiency on brain phospholipid fatty acid concentrations and compositions. Staggerer mice (Rorasg/sg) and wildtype littermates (Rora+/+) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were quantified by gas chromatography-flame ionization detection. In the cerebellum, all fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid concentrations were significantly different at 2-month-old, we examined changes in fatty acid composition. The composition of ARA was not significantly different between genotypes; though DHA composition remained significantly lowered. Despite cerebellar atrophy at >7-months-old, cerebellar fatty acid concentrations had recovered comparably to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific and age-dependent.
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Epidemiological studies indicate that the fatty acid composition of diets may be important in the pathogenesis of non-communicable diseases (NCDs). In previous studies, a high ratio of omega-6 fatty acids to omega-3 fatty acids in diets and tissues has been reported as a risk factor for NCDs, that is, coronary artery disease, hypertension, atherosclerosis, stroke, type 2 diabetes mellitus, cancer, and other chronic diseases The Western-type diet is generally proatherogenic, characterized by energy-dense, refined, ready-prepared foods with a high glycemic index and unhealthy lipids and poor in omega-3 fatty acids, phytochemicals, and fiber. A lower intake of polyunsaturated fatty acids in conjunction with a deficiency of flavonoids and polyphenolics, as found in today’s Western diets, may promote the risk of NCDs. These diets are rich in total fat, trans fat, and refined carbohydrates, and the omega-6/omega-3 fatty acid ratio varies from 20 to 50 in various countries. Recently, increased intake of the omega-6 fatty acids linoleic acid and arachidonic acid have been found to protect against cardiovascular diseases (CVDs) and all-cause mortality. Increased intake of such diets is associated with the antiinflammatory state in the human body, with a decline in oxidative stress resulting in a significant reduction in CVDs and other chronic diseases. Both omega-6 and omega-3 fatty acids influence gene expression and possess antiinflammatory effects, which may increase in the presence of flavonoids in the diets. Increased dietary intake of omega-6 fatty acid significantly reduces the apparent atherogenic effect of genotype, whereas increased dietary intake of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have similar effects. Recent studies indicate that both dietary omega-6 and omega-3 fatty acids, including marine omega-3 fatty acids, EPA, and DHA inhibit leukotriene-, thromboxane-, and prostaglandin-mediated tissue inflammation, thereby leading to a decreased risk of NCDs. It is possible that proinflammatory Western diets and inflammation in the tissue are the main issues for development of NCDs. New approaches include Mediterranean-type diets rich in fruits, vegetables, nuts, and fish with low consumption of red meat and poultry, along with high concentrations of linoleic acid– and alpha-linolenic acid–rich foods, such as rape seed oil, mustard oil, canola oil, and olive oil, which may modulate inflammation and may be protective against NCDs.
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Purpose: The global rate of diagnosis of autism spectrum disorder (ASD) is increasing and many parents are turning to complementary and alternative medicine (CAM) to help with the wide range of symptoms, including behavioural abnormalities. The aim of this review is to examine the efficacy of omega-3 supplementation, a popular CAM therapy for behavioural problems in children with ASD. Methods: The peer-reviewed literature published in the English language between 2007 and April 2015 was systematically searched using www.clinicaltrials.gov (US National Institute of Health database), CINAHL, Google scholar, PubMed (US National Library of Medicine) and Cochrane library databases, using a combination of the search terms Autism, ASD, Omega-3, fish oil, PUFA, EFA, EPA, DHA. Clinical studies examining the effects of omega-3 in ASD were considered. Results: Six studies were found to be relevant to this review (N = 168, ages 2 – 17). Two of these were open-label studies and four were randomised control trials. Conclusion: There is limited evidence supporting the use of omega-3 supplementation in clinical practice for the treatment of behavioural symptoms in children with ASD. However, some studies do show potential for this treatment option in a limited range of behavioural outcomes. Further studies are required.
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Aims: The investigation of links between the ratio of omega-3/omega-6 PUFAs and neuronal signaling is a research priority in autism spectrum disorders (ASD). Main methods: We examine the relationships between the plasma ratios of docosahexaenoid acid (DHA)/arachidonic acid (AA) and eicopentaenoic acid (EPA)/AA and biomarkers of AA-related signaling mediators such as ceruloplasmin, transferrin and superoxide dismutase, in the behavioral symptoms of 28 individuals with ASD (mean age 13.5 ± 4.6 years) and 21 age- and gender-matched normal healthy controls (mean age 13.9 ± 5.7 years). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). We conducted controlling for dietary intake and assessed the dietary intake of nutrients. Key findings: There were no significant differences in intake of nutrients such as omega-3 and omega-6 PUFAs, saturated and unsaturated fatty acid, DHA, AA, iron and copper. Plasma EPA, DHA, and arachidic acid levels, and plasma DHA/AA and EPA/AA ratios were significantly higher, while plasma AA and adrenic acid were significantly lower in the 28 individuals with ASD than in the 21 normal controls. The ABC scores were significantly higher in the ASD group compared to the control group. The plasma ceruloplasmin levels in the ASD group were significantly reduced compared to those in the control group. Significance: Increased plasma DHA/AA and EPA/AA ratios may be related to low plasma levels of ceruloplasmin which has neuroprotective protprties. Reduced plasma ceruloplasmin levels may diminish the protective capacity against brain damage, and may contribute to the pathophysiology of behavioral symptoms in individuals with ASD.
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Preclinical Research Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia. Drug Dev Res, 2016. © 2016 Wiley Periodicals, Inc.
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Zinc is an essential micronutrient for cellular proliferation and subsequent body and brain development. Zinc deficiency is becoming a major public health issue equally in under-developed and developed countries. The lack of sufficient zinc, whether related to environmental or internal factors, is an important environmental stressor that is eligible to become elucidated as a contributing factor for the pathogenesis of autism spectrum disorder (ASD). The aim of this manuscript is to briefly overview available data regarding the relationship of zinc deficiency with the development of ASD and to relate these data with currently known pathogenetic mechanisms of this disorder namely brain growth disturbances and neuropeptides secretion. Zinc deficiency impacts brain connectivity and growth and alters adequate neurotransmission. In addition, zinc deficiency may indirectly act on the brain by disturbing the immune system and by altering the normal gut-brain connection. Zinc seems to be important for the social effect of neuropeptides. Zinc supplementation in pregnant women and newborn children with the aim of preventing ASD needs further consideration.
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It is suggested that supplementation of a rational combination of arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3) to pregnant and lactating mothers and to newborns and children will prevent the development and severity of autism.
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Autism spectrum disorders (ASD) are characterized by behavioural abnormalities and impaired communication skills. Both genetic and environmental factors have been attributed as causative factors. It has been reported that there are alterations in the organization of functional networks in brain as well as in the balance between structural and functional net-works in brain in children and adolescents with ASD when compared to normal children. Various studies have shown that lower levels of micronutrients like magnesium, selenium, Vitamin A, Vitamin D and Vitamin E, Folic acid and iron are found in children with ASD. This narrative review was undertaken to highlight the role of nutritional deficiency in the development of ASD in children relevant literature was collected from Google scholar, Pubmed, Cross Ref and Scopus. This review also takes into consideration how nutritional deficiency during pregnancy, infancy and childhood can have a role in the development of ASD in children.
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Decline in socialization and communication may be the result of negative social environment, but can also be due to other environmental as well as genetic factors leading to the development of affective or neurological disorders, including autistic spectrum disorders. Animal models have been employed to study such disorders. In this chapter, we present a single experimental study as an example. We demonstrate how one can utilize environmental manipulation methods, including social defeat induced stress, to explore behavioral and gene expression changes as a model of abnormal social behavior. In our example, we induced changes in social behaviors be providing repeated experience with social defeat and aggression during daily agonistic interactions in male mice. In addition, we also study potential alterations in the expression of genes in five brain regions. Analysis of an RNA-Seq database of the whole transcriptome revealed changes in expression of the Tph2, Maoa, Slc6a4, Htr7, Gabrb3, Nrxn1, Nrxn2, Nlgn1, Nlgn2, Nlgn3, Shank2, Shank3, Fmr1, Ube3a, Pten, Cntn3, Foxp2, Oxtr, Reln, Cadps2, Pcdh10, Ctnnd2, En2, Arx, Auts2, Mecp2, and Ptchd1 genes. These genes have also been associated with autism in humans. Our research thus demonstrates for the first time that abnormalities in social behaviors induced by negative social environment in adult mice are associated with altered expression of autism-related genes in the brain. We argue that environmental manipulations may thus represent a potential way the human CNS disorders associated with abnormal social behavior could be modeled and analyzed.
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Resumen Los trastornos del espectro autista incluyen un grupo heterogéneo de trastornos del neurodesarrollo que se caracterizan por deficiencias en la interacción social, comunicación y aprendizaje, así como patrones de conducta restrictivos y reiterativos. A pesar de su inicio en la infancia, estos pacientes presentan afectación clínica también en la edad adulta. Los tratamientos farmacológicos son empleados de forma muy habitual a pesar de presentar escasa evidencia de su efectividad en pacientes adultos con estos trastornos. En el contexto de una profundización en la etiopatogenia del autismo y la búsqueda de alternativas terapéuticas que puedan demostrar eficacia, recientemente se han llevado a cabo estudios en relación con el posible déficit y uso clínico de ácidos grasos omega-3 en pacientes con trastornos del espectro autista. A continuación se presenta el caso clínico de una paciente adulta con autismo a quien los tratamientos farmacológicos empleados durante años no habían resultado eficaces, apareciendo alteraciones analíticas como efectos adversos, planteándose entonces el tratamiento con ácidos grasos omega-3, con buen resultado posterior.
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The sex- and age-specific effects of omega (n)-3 polyunsaturated fatty acids (PUFA) enriched diets on brainstem and cerebellar fatty acid composition, and the expression of stearoyl-CoA desaturase (SCD)-1 and myelin basic protein (MBP) were investigated in C57BL/6 mice. Female mice were fed diets (20% fat, w/w) high or low in n-3 PUFA before mating, during pregnancy and lactation; and offspring (both males and females) were weaned onto their mother's designated diet for 16 weeks. A diet high in n-3 PUFA caused an accretion of docosahexaenoic acid in the cerebellum. Monounsaturated fatty acids increased from weaning to 16 weeks in the cerebellum. The changes in the cerebellar fatty acids were more pronounced in females, with a significant effect of diet. A diet high in n-3 PUFA increased cerebellar SCD-1 and MBP mRNA expression. These findings are novel and demonstrate that the effects of n-3 PUFA are brain region, age- and sex-specific.
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The identification of new biomarkers (e.g., metabolic biomarkers) will facilitate not only the diagnosis of stroke but also the differentiation of stroke subtypes, especially the discrimination of ischaemic stroke from intracerebral hemorrhage. Herein, we develop for the first time an ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS)-based targeted metabolomic method to screen the metabolic biomarkers of stroke and identify the fatty acid metabolite 20-hydroxy-leukotriene B4 (20-OH-LTB4) and its key enzyme cytochrome P450 family 4 subfamily F member 2 (CYP4F2) as the potential biomarkers for differentiating healthy persons, acute ischemic stroke (AIS) patients, and intracerebral hemorrhage stroke (ICH) patients. We evaluated 158 fatty acids and their metabolites in 177 serum samples obtained from 65 healthy volunteers, 70 AIS patients and 42 ICH patients, and identified the potential biomarkers associated with ICH by using multivariate statistical analysis. We found that 20-OH-LTB4 and arachidonic acid can be used to discriminate ICH patients from healthy individuals, and 20-OH-LTB4 and 17, 18-epoxy-eicosatetraenoic acid (7,18-EpETE) can be used to differentiate the subtypes of ICH and AIS. Especially, 20-OH-LTB4 may function as a potential biomarker for ICH diagnosis and risk assessment, and it can discriminate ICH patients from healthy individuals and AIS patients. Moreover, we identified CYP4F2 protein as a potential biomarker of ICH for prevention and treatment assessment. This method may provide a powerful platform for ICH diagnosis, prevention, and treatment assessment.
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Polyunsaturated fatty acids (PUFAs) are vital for normal growth and development and physiological function of various tissues in humans. PUFAs have immunomodulatory actions in addition to their ability to modulate inflammation, vascular reactivity, neurotransmission and stem cell biology. PUFAs and their metabolites possess both pro- and anti-inflammatory properties that underlie their actions and involvement in several diseases. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), possesses both cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitory action and enhances the production of anti-inflammatory lipoxin A4 {(called as epi-lipoxin A4, aspirin-triggered lipoxins (ATLs)}. In addition, at low doses aspirin may not interfere with the production of prostacyclin (PGI2). Both lipoxin A4 and PGI2 have vasodilator, platelet anti-aggregator and anti-inflammatory actions that may underlie the beneficial actions of aspirin. Paradoxically, other NSAIDs may not have the same actions as that of aspirin on PUFA metabolism. Similar anti-inflammatory compounds are formed from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by the action of aspirin termed as resolvins (from EPA and DHA) and protectins and maresins from DHA. PUFAs: arachidonic acid (AA), EPA and DHA and their various products modulate not only inflammation and immune response but also possess actions on various genes, nuclear factors, cyclic AMP and GMP, G-protein coupled receptors (GPRs), hypothalamic neurotransmitters, hormones, cytokines and enzymes, and interact with nitric oxide, carbon monoxide, and hydrogen sulfide to regulate their formation and action and to form new compounds that have several biological actions. These pleiotropic actions of PUFAs and their metabolites may explain their ability to play a role in several physiological actions and diseases. The big challenge is to harness these actions to prevent and manage clinical conditions..
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Autism (MIM 209850) is a severe neuropsychiatric disorder of unknown aetiology with profound consequences for patients and their families. Strong evidence from twin and family studies indicates the importance of genetic factors in the development of idiopathic autism, although it is clear that these influences are complex. This review focuses on recent molecular investigations to identify susceptibility loci implicated in autistic disorder.
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Pediatricians have an important role not only in early recognition and evaluation of autism spectrum disorders but also in chronic management of these disorders. The primary goals of treatment are to maximize the child's ultimate functional independence and quality of life by minimizing the core autism spectrum disorder features, facilitating development and learning, promoting socialization, reducing maladaptive behaviors, and educating and supporting families. To assist pediatricians in educating families and guiding them toward empirically supported interventions for their children, this report reviews the educational strategies and associated therapies that are the primary treatments for children with autism spectrum disorders. Optimization of health care is likely to have a positive effect on habilitative progress, functional outcome, and quality of life; therefore, important issues, such as management of associated medical problems, pharmacologic and nonpharmacologic intervention for challenging behaviors or coexisting mental health conditions, and use of complementary and alternative medical treatments, are also addressed.
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White matter tissue properties are highly correlated with reading proficiency; we would like to have a model that relates the dynamics of an individual’s white matter development to their acquisition of skilled reading. The development of cerebral white matter involves multiple biological processes, and the balance between these processes differs between individuals. Cross-sectional measures of white matter mask the interplay between these processes and their connection to an individual’s cognitive development. Hence, we performed a longitudinal study to measure white-matter development (diffusion-weighted imaging) and reading development (behavioral testing) in individual children (age 7–15 y). The pattern of white-matter development differed significantly among children. In the left arcuate and left inferior longitudinal fasciculus, children with above-average reading skills initially had low fractional anisotropy (FA) that increased over the 3-y period, whereas children with below-average reading skills had higher initial FA that declined over time. We describe a dual-process model of white matter development comprising biological processes with opposing effects on FA, such as axonal myelination and pruning, to explain the pattern of results.
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Studies in rodents indicate that diets deficient in omega-3 polyunsaturated fatty acids (n-3 PUFA) lower dopamine neurotransmission as measured by striatal vesicular monoamine transporter type 2 (VMAT2) density and amphetamine-induced dopamine release. This suggests that dietary supplementation with fish oil might increase VMAT2 availability, enhance dopamine storage and release, and improve dopamine-dependent cognitive functions such as working memory. To investigate this mechanism in humans, positron emission tomography (PET) was used to measure VMAT2 availability pre- and post-supplementation of n-3 PUFA in healthy individuals. Healthy young adult subjects were scanned with PET using [(11)C]-(+)-α-dihydrotetrabenzine (DTBZ) before and after six months of n-3 PUFA supplementation (Lovaza, 2 g/day containing docosahexaenonic acid, DHA 750 mg/d and eicosapentaenoic acid, EPA 930 mg/d). In addition, subjects underwent a working memory task (n-back) and red blood cell membrane (RBC) fatty acid composition analysis pre- and post-supplementation. RBC analysis showed a significant increase in both DHA and EPA post-supplementation. In contrast, no significant change in [(11)C]DTBZ binding potential (BP(ND)) in striatum and its subdivisions were observed after supplementation with n-3 PUFA. No correlation was evident between n-3 PUFA induced change in RBC DHA or EPA levels and change in [(11)C]DTBZ BP(ND) in striatal subdivisions. However, pre-supplementation RBC DHA levels was predictive of baseline performance (i.e., adjusted hit rate, AHR on 3-back) on the n-back task (y = 0.19+0.07, r(2) = 0.55, p = 0.009). In addition, subjects AHR performance improved on 3-back post-supplementation (pre 0.65±0.27, post 0.80±0.15, p = 0.04). The correlation between n-back performance, and DHA levels are consistent with reports in which higher DHA levels is related to improved cognitive performance. However, the lack of change in [(11)C]DBTZ BP(ND) indicates that striatal VMAT2 regulation is not the mechanism of action by which n-3 PUFA improves cognitive performance.
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This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.
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This study examined the effects of dietary polyunsaturated fatty acids (PUFA) as different n-6: n-3 ratios on spatial learning and gene expression of peroxisome- proliferator-activated receptors (PPARs) in the hippocampus of rats. Thirty male Sprague-Dawley rats were randomly allotted into 3 groups of ten animals each and received experimental diets with different n-6: n-3 PUFA ratios of either 65:1, 22:1 or 4.5:1. After 10 weeks, the spatial memory of the animals was assessed using the Morris Water Maze test. The expression of PPARα and PPARγ genes were determined using real-time PCR. Decreasing dietary n-6: n-3 PUFA ratios improved the cognitive performance of animals in the Morris water maze test along with the upregulation of PPARα and PPARγ gene expression. The animals with the lowest dietary n-6: n-3 PUFA ratio presented the highest spatial learning improvement and PPAR gene expression. It can be concluded that modulation of n-6: n-3 PUFA ratios in the diet may lead to increased hippocampal PPAR gene expression and consequently improved spatial learning and memory in rats.
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The genetic heterogeneity of autism poses a major challenge for identifying mechanism-based treatments. A number of rare mutations are associated with autism, and it is unclear whether these result in common neuronal alterations. Monogenic syndromes, such as fragile X, include autism as one of their multifaceted symptoms and have revealed specific defects in synaptic plasticity. We discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism with those in fragile X syndrome. Neuroligin-3 knockout mice (a model for nonsyndromic autism) exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor–dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development.
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Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that is implicated in the regulation of food intake and body weight. Polyunsaturated fatty acids (PUFAs) localised in cell membranes have been shown to alter the levels of BDNF in the brain, suggesting that PUFAs and BDNF could have physical interaction with each other. To decipher the molecular mechanism through which PUFAs modulates BDNF's activity, molecular docking was performed for BDNF with PUFAs and its metabolites, with 4-Methyl Catechol as a control. Inferring from molecular docking studies, lipoxin A4 (LXA4), and a known anti-inflammatory bioactive metabolite derived from PUFAs, with a binding energy of -3.98 Kcal/mol and dissociation constant of 1.2mM showed highest binding affinity for BDNF in comparison to other PUFAs and metabolites considered in the study. Further, the residues Lys 18, Thr 20, Ala 21, Val 22, Phe 46, Glu 48, Lys 50, Lys 58, Thr 75, Gln 77, Arg 97 and Ile 98 form hot point motif, which on interaction enhances BDNF's function. These results suggest that PUFAs and their metabolites especially, LXA4, modulate insulin resistance by establishing a physical interaction with BDNF. Similar interaction(s) was noted between BDNF and resolvins and protectins but were of lesser intensity compared to LXA4.
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The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.
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Objective: Estimation of free polyunsaturated fatty acids (PUFAs) in blood and evaluation of behavior of autistic children before and after taking fish oil (Efalex) were performed. Design and methods: 30 autistic children (18 males and 12 females) aged 3-11 years and 30 healthy children as control group were included in this study. Tandem mass spectrometry and CARS were used to estimate the free PUFAs from dried blood spot and to evaluate the autistic behavior respectively. Results: Before taking Efalex, linolenic acid showed a significant reduction (71%), followed by docosahexaenoic acid (65%) and arachidonic acid (45%), while linoleic acid was the least affected PUFA (32%). After taking Efalex, 66% of autistic children showed clinical and biochemical improvement, linolenic acid and docosahexaenoic acid showed the highest levels after Efalex supplementation. Conclusion: PUFA supplementation may play an important role in ameliorating the autistic behavior.
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Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months. The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity. The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values. These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.
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The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo (olive oil) in the initial treatment of individuals with major depressive disorder (MDD). We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response. Forty-two subjects participated in this 9-week randomized, masked, placebo-controlled study of combination therapy (two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid, 200 mg of and docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) treatment of MDD. The combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time (F = 7.32; df 1,177; P = 0.008) beginning at week 4 (t = -2.48; df 177; P = 0.014). Combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the 8 weeks of active treatment; however, combination therapy did not seem to enhance the speed of the initial antidepressant response. These findings suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD. A larger definitive study is warranted.
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Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, no study has been performed to investigate its preventive effect on prenatal stress-induced behavioral and molecular alterations in offspring. In the present study, rats were exposed to restraint stress on days 14-20 of pregnancy, three times a day, 2 hours each time; DHA was given at the doses of 100 and 300 mg/kg/day for two weeks. We showed that prenatal restraint stress caused (1) learning and memory impairment, (2) BDNF mRNA level decrease, (3) oxidative damage to proteins, (4) enhanced expression of nitric oxide synthase and apoptosis, and (5) abnormalities in mitochondrial metabolism that included changes in mitochondrial complexes I-V, and enhancement of expression of proteins involved in mitochondrial fusion/fission (Mfn-1, Mfn-2, Drp-1) and autophagy (Atg3, Atg7, Beclin-1, p-Akt, and p-mTOR) in the hippocampus of offspring. Besides the well-known role in child brain development, we reported the novel finding of DHA in protecting prenatal stress-induced cognitive dysfunction involving the modulation of mitochondrial function and dynamics. Maternal feeding of DHA significantly prevented prenatal stress-induced impairment of learning and memory and normalized the biomarkers of oxidative damage, apoptosis, and mitochondrial metabolism in the hippocampus of both male and female offspring. These results suggest that maternal feeding of DHA exerts preventive effects on prenatal stress-induced brain dysfunction and that modulation of mitochondrial metabolism may play critical role in DHA protection.
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Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD. A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons. The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD.
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Autism Spectrum Condition (ASC) is recognised as having an inflammatory component. Post mortem brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebro-spinal fluid, although little is known about the underlying molecular mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements and of NF-kB in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centres: London Brain Bank, Kings College London, UK (ASC: N=3, controls: N=4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: N=6, controls: N=5). The hypothesis was that concentrations of NF-kB would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e. acidification). Neurons, astrocytes and mircroglia all demonstrated increased extranuclear and nuclear translocated NF-kB p65 expression in samples of brain tissue from ASC donors relative to samples from matched controls. These between-groups differences were increased in astrocytes and microglia relative to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in homogenised samples demonstrated a 0.98 unit difference in means and a strong (F = 98.3; p = 0.00018) linear relationship to the expression of nuclear translocated NF-kB in mature microglia. Acridine orange staining localised pH reductions to lysosomal compartments. In summary, NF-κB is aberrantly expressed in orbitofrontal cortex in patients with ASC as part of a putative molecular cascade leading to inflammation that is potentially responsible for the associated behavioural and clinical symptoms.
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Book
About the Author.- Preface.- Dedication.- Chapter 1: Introduction.- Chapter 2: Health and Disease as two sides of the same coin.- Chapter 3: Inflammation.- Chapter 4: Essential fatty acids-Biochemistry, Physiology and Clinical Significance.- Chapter 5: Cell membrane organization.- Chapter 6: Low-grade systemic inflammation is common in iseases/disorders.- Chapter 7: Obesity.- Chapter 8: Hypertension.- Chapter 9: Insulin resistance, dyslipidemia, type 2 diabetes Mellitus and metabolic syndrome.- Chapter 10: Atherosclerosis.- Chapter 11: Osteoporosis.- Chapter 12: Alzheimer's disease, schizophrenia and depression.- Chapter 13: Rheumatological conditions.- Chapter 14: Cancer.- Chapter 15: Aging.- Chapter 16: Adult diseases and low-grade systemic inflammation have their origins in the perinatal period.- Chapter 17: Clinical implications.
Chapter
The theory that perinatal supplementation of LCPUFAs can or will prevent adult diseases has a number of components: the association of obesity, hypertension, type 2 diabetes mellitus and CHD (the major components of the Metabolic Syndrome X) with elevated serum levels of CRP, IL-6, TNF-α, and leptin; elevated inflammatory markers as high-risk indicators of cardiovascular and non-cardiovascular causes of death in diabetes and obesity; the high content of LCPUFAs in human breast milk which inhibit the production of pro-inflammatory cytokines and playing an important role in brain growth and development, food intake behaviour, and neurotransmitter production in the brain, strong correlation between breast- milk feeding periods in infancy and subsequent obesity, hypertension, type 2 diabetes mellitus and CHD in adults; and serotonin, dopamine, and neuropeptide Y influencing cytokines and brain aceylcholine, which act not only as neurotransmitters but also influence inflammation in the brain1-4. The conclusion is that obesity, hypertension, type 2 diabetes mellitus, CHD, and other components of the Metabolic Syndrome X are due to low-grade systemic inflammation and may be the result of a marginal or sub-clinical deficiency of LCPUFAs during the critical stages in the development of the brain.
Article
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are of benefit in Alzheimer's disease by virtue of their anti-inflammatory actions, ability to modulate neural function, including neurotransmission, membrane fluidity, ion channel, enzyme regulation and gene expression. EPA, DHA, and ω-6 arachidonic acid (AA) form precursors to anti-inflammatory compounds: lipoxins, resolvins, protectins and maresins that suppress leukocyte migration and activation, inhibit NF-κB activation, production of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6, free radical generation, and enhance endothelial nitric oxide generation and augment the healing process. In animal models, the protective action of EPA and DHA against Alzheimer's disease correlated with increased formation of lipoxins, resolvins, protectins and maresins. EPA, DHA and AA stimulate neurite outgrowth by activating syntaxin 3 that is specifically involved in fast calcium-triggered exocytosis of neurotransmitters. SNAP25 (synaptosomal-associated protein of 25 kDa), a syntaxin partner implicated in neurite outgrowth, interacted with syntaxin 3 only in the presence of AA that allowed the formation of the binary syntaxin 3-SNAP 25 complex. AA stimulated syntaxin 3 to form the ternary SNARE complex (soluble N-ethylmaleimide-sensitive factor attachment protein receptor), which is needed for the fusion of plasmalemmal precursor vesicles into the cell surface membrane that leads to membrane fusion that facilitates neurite outgrowth. These results imply that EPA, DHA, and AA when given in optimal amounts are of benefit in the prevention and treatment of Alzheimer's disease. PUFAs enhance the concentrations of neurotrophic factors in the brain that may provide additional protection to neurons. Thus, PUFAs by themselves or their stable synthetic analogues could be of benefit in Alzheimer's disease and other neurodegenerative diseases.
Article
Avoiding or controlling fatigue damage is a major issue in the design and inspection of welded structures subjected to dynamic loading. Life predictions are usually used for safe life analysis, i.e. for verifying that it is very unlikely that fatigue damage will occur during the target service life of a structure. Damage tolerance analysis is used for predicting the behavior of a fatigue crack and for planning of in-service scheduled inspections. It should be a high probability that any cracks appearing are detected and repaired before they become critical. In both safe life analysis and the damage tolerance analysis there may be large uncertainties involved that have to be treated in a logical and consistent manner by stochastic modeling. This book focuses on fatigue life predictions and damage tolerance analysis of welded joints and is divided into three parts. The first part outlines the common practice used for safe life and damage tolerance analysis with reference to rules and regulations. The second part emphasises stochastic modeling and decision-making under uncertainty, while the final part is devoted to recent advances within fatigue research on welded joints. Industrial examples that are included are mainly dealing with offshore steel structures. Spreadsheets which accompany the book give the reader the possibility for hands-on experience of fatigue life predictions, crack growth analysis and inspection planning. As such, these different areas will be of use to engineers and researchers.
Article
A conceptual modeling grammar should be based on the theory of ontology and possess clear ontological semantics to represent problem domain knowledge in a precise and consistent manner. In this paper, we follow the notion of ontological expressiveness and conduct an ontological analysis of a newly-developed conceptual modeling grammar termed MibML (Multiagent-based Integrative Business Modeling Language). The grammar is developed to respond to the emerging needs for a special-purpose conceptual modeling grammar for the MIBIS (multi-agent-based integrative business information systems) universe. We assign ontological semantics to the MibML constructs and their relationship using the BWW (Bunge Wand-Weber) model. This article provides a starting point to further develop ontological principles and step-by-step guidelines to ensure the straightforward mapping from domain knowledge into MibML modeling constructs. Purchase this article to continue reading all 19 pages >
Chapter
Inflammation is the complex biological response of vascular tissue to harmful stimuli such as pathogens, damaged cells or irritants [1] that consists of both vascular and cellular responses. Inflammation is a protective attempt by the organism to remove the injurious stimuli and initiate healing process and to restore both structure and function. It should be understood that infection and inflammation are not synonymous: infection is caused by an exogenous pathogen while inflammation is the response of the organism to the pathogen. Inflammation may be local or systemic, and it can be acute or chronic. During the inflammatory process, the reaction of blood vessels is unique that leads to the accumulation of fluid and leukocytes in extravascular tissues. The reaction of blood vessels can be in the form of vasodilatation that is seen in the form of hyperemia at the site(s) of injury, that increases blood supply to the injured tissue/organ so that cellular elements, antibodies and nutrients can reach the site of injury in adequate amounts to eliminate the inflammation-inducing agent and/or repair process can be initiated once inflammation subsides. Thus, both injury and repair are two sides of the inflammatory process that are very closely intertwined such that it is difficult to separate these two processes. In fact, in majority of the instances, both inflammation to injury and repair occur almost simultaneously.
Article
An increase in proinflammatory cytokines, a decrease in endothelial nitric oxide and adiponectin levels and an alteration in hypothalamic peptides and gastrointestinal hormones that regulate satiety, hunger and food intake all occur in metabolic syndrome. Consumption of a diet that is energy dense and rich in saturated and trans-fats by pregnant women and lactating mothers, in childhood and adult life may trigger changes in the hypothalamic and gut peptides and hormones. Such changes modulate immune response and inflammation and lead to alterations in the hypothalamic `bodyweight/appetite/satiety set point' and result in the initiation and development of the metabolic syndrome. Roux-en-gastric bypass induces weight loss, decreases the levels of cytokines and restores hypothalamic neuropeptides and gut hormones and the hypothalamic bodyweight/appetite/satiety set point to normal. Thus, metabolic syndrome is a low-grade systemic inflammatory condition with its origins in the perinatal period and childhood.