ArticleLiterature Review

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

July 2013
Nutrition 29(10)

DOI:10.1016/j.nut.2013.01.012

Source
PubMed

Authors:

UND Life Sciences

Effects of Omega-3 Fatty Acids on Stereotypical Behavior and Social Interactions in Wistar Rats Prenatally Exposed to Lipopolysaccarides

Article

Nov 2016

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.

Microglia: Synaptic modulator in autism spectrum disorder

Article

Full-text available

Nov 2022

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable impairment of social communication and repetitive behaviors, highly restricted interests, and/or sensory behaviors beginning early in life. Many individuals with ASD have dysfunction of microglia, which may be closely related to neuroinflammation, making microglia play an important role in the pathogenesis of ASD. Mounting evidence indicates that microglia, the resident immune cells of the brain, are required for proper brain function, especially in the maintenance of neuronal circuitry and control of behavior. Dysfunction of microglia will ultimately affect the neural function in a variety of ways, including the formation of synapses and alteration of excitatory–inhibitory balance. In this review, we provide an overview of how microglia actively interact with neurons in physiological conditions and modulate the fate and functions of synapses. We put a spotlight on the multi-dimensional neurodevelopmental roles of microglia, especially in the essential influence of synapses, and discuss how microglia are currently thought to influence ASD progression.

Dietary strategies in Autism Spectrum Disorder (ASD)

Article

Full-text available

Jan 2018
PROG NUTR

Ayten Aylin Taş

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.

Interplay Between Peripheral and Central Inflammation in Autism Spectrum Disorders: Possible Nutritional and Therapeutic Strategies

Article

Full-text available

Mar 2018

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.

Relationship between Long Chain n-3 Polyunsaturated Fatty Acids and Autism Spectrum Disorder: Systematic Review and Meta-Analysis of Case-Control and Randomised Controlled Trials

Article

Full-text available

Feb 2017

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.

Identification of Biomarkers of Impaired Sensory Profiles among Autistic Patients

Article

Full-text available

Nov 2016
PLOS ONE

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.

Cysteinyl leukotriene correlated with 8-isoprostane levels as predictive biomarkers for sensory dysfunction in autism

Article

Full-text available

Aug 2016
LIPIDS HEALTH DIS

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.

Brain-Derived Neurotrophic Factor: A Novel Dynamically Regulated Therapeutic Modulator in Neurological Disorders

Article

Full-text available

Oct 2022
NEUROCHEM RES

The growth factor brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin-related kinase receptor type B (TrkB) play an active role in numerous areas of the adult brain, where they regulate the neuronal activity, function, and survival. Upregulation and downregulation of BDNF expression are critical for the physiology of neuronal circuits and functioning in the brain. Loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric disorders. This article reviews the BDNF gene structure, transport, secretion, expression and functions in the brain. This article also implicates BDNF in several brain-related disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, major depressive disorder, schizophrenia, epilepsy and bipolar disorder.

Genomic Insights into Omega-3 Polyunsaturated Fatty Acid Producing Shewanella sp. N2AIL from Fish Gut

Article

Full-text available

Apr 2022

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.

Docosahexaenoic and Eicosapentaenoic Intervention Modifies Plasma and Erythrocyte Omega-3 Fatty Acid Profiles But Not the Clinical Course of Children With Autism Spectrum Disorder: A Randomized Control Trial

Article

Full-text available

Mar 2022

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].

Dietary Fat Effect on the Gut Microbiome, and Its Role in the Modulation of Gastrointestinal Disorders in Children with Autism Spectrum Disorder

Article

Full-text available

Oct 2021

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.

Criss‐crossing Autism Spectrum Disorder and Adult Neurogenesis

Article

Full-text available

Sep 2021

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 lifelong 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 post‐natal 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. image

Newly marketed seed oils. What we can learn from the current status of authentication of edible oils

Article

Jun 2021
FOOD CONTROL

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.

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Article

Full-text available

Feb 2021

Undurti Das

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.

Behavioral changes and brain epigenetic alterations induced by maternal deficiencies of B vitamins in a mouse model

Article

Full-text available

Apr 2021
PSYCHOPHARMACOLOGY

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.

Dietary regulation for children with autism: Is it important?

Article

Full-text available

Nov 2020

Tungki Pratama Umar

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.

Understanding Abnormal SMO-SHH Signaling in Autism Spectrum Disorder: Potential Drug Target and Therapeutic Goals

Article

Full-text available

May 2022
CELL MOL NEUROBIOL

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

Enhanced Physical and Cognitive Performance in Active Duty Airmen: Evidence from a Randomized Multimodal Physical Fitness and Nutritional Intervention

Article

Full-text available

Oct 2020

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.

The Role of Microbiome, Dietary Supplements, and Probiotics in Autism Spectrum Disorder

Article

Full-text available

Apr 2020

The Role of Microbiome, Dietary Supplements, and Probiotics in Autism Spectrum Disorder

Article

Full-text available

Apr 2020
Int J Environ Res Publ Health

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.

Molecular Basis of the Beneficial Actions of Resveratrol

Article

Full-text available

Feb 2020
ARCH MED RES

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.

Metabolomics Biomarkers for Precision Psychiatry

Chapter

Full-text available

Sep 2019
ADV EXP MED BIOL

Pei-an Betty Shih

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.

Abnormal social behaviors and dysfunction of autism-related genes associated with daily agonistic interactions in mice

Preprint

Full-text available

Apr 2017

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.

Regional patterning of co-expressed genes in autistic brains

Article

Full-text available

Dec 2019

Fereshteh Izadi

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.

Comparative study on the independent and combined effects of omega-3 and vitamin B12 on phospholipids and phospholipase A2 as phospholipid hydrolyzing enzymes in PPA-treated rats as a model for autistic traits

Article

Full-text available

Aug 2018
LIPIDS HEALTH DIS

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.

Impaired lipid metabolism markers to assess the risk of neuroinflammation in autism spectrum disorder

Article

Full-text available

Aug 2018
METAB BRAIN DIS

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.

Maternal and fetal benefits of DHA supplementation during pregnancy

Article

Jan 2017

Neuroprotection through Flavonoid: Enhancement of the Glyoxalase Pathway

Article

Full-text available

Oct 2017

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.

Role of the gut-brain axis in the eating behavior of children with autism spectrum disorders

Article

Full-text available

Jan 2017

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.

High predictive values of RBC membrane-based diagnostics by biophotonics in an integrated approach for Autism Spectrum Disorders

Article

Full-text available

Dec 2017

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.

Developmental Disorders of the Cerebellum and Neurotrophic Factors

Chapter

Jul 2017

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.

Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions

Article

Full-text available

Oct 2016

Undurti Das

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.

Maternal Malnutrition in the Etiopathogenesis of Psychiatric Diseases: Role of Polyunsaturated Fatty Acids

Article

Full-text available

Jul 2016
BSRCCS

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.

Alzheimer's Disease and Autistic Spectrum Disorder: Is there any Association?

Article

Mar 2016
CNS NEUROL DISORD-DR

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.

Brain-derived neurotrophic factor and its clinical Implications

Article

Full-text available

Dec 2015

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.

Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen-activated protein kinase: Possible molecular approach

Article

Full-text available

Jun 2023
ENVIRON TOXICOL

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior followed by impairment in social, verbal, and non-verbal interaction and communication. Valproic acid (VPA) is a well-known anti-epileptic drug, but its prenatal exposure to animals causes social impairment, neurotransmitters imbalance, and neuroinflammation with ASD-like phenotypes. Syringic acid (SA) is a polyphenolic compound with anti-inflammatory, anti-apoptotic, antioxidant, and neuromodulator activity. The purpose of study was to investigate the protective effect of Syringic acid (SA) in prenatal VPA-treated rats through behavioral, neuroinflammation, oxidative stress, neurotransmitters, neuronal integrity, and apoptotic marker. Single dose of VPA was administered 600 mg/kg, i.p. on a gestational day (GD) 12th and SA was administrated from PnD 26th to 54th at the dose of 25, 50, and 100 mg/kg, p.o. On PnD 56th behavioral parameters (Pain sensitivity, open field test, narrow beam walks test and social impairment test) were performed and all animals were sacrificed, and brain tissue was isolated for oxidative stress (GSH, CAT, and LPO), neuroinflammation (TNF-α and IL-6) and neurotransmitters (GABA and Glutamate), histopathology (H&E, Nissl), immunohistochemistry (p38 MAPK) analysis. Rat treated with SA dose-dependently prevented behavioral alteration, restored antioxidant enzymes, neurotransmitters level, decreased neuroinflammatory markers, and improved neuronal integrity. Furthermore, immunohistochemistry confirmed the reduced p38 MAPK marker expression by SA in VPA induced autistic behavior.

Developmental Disorders of the Cerebellum and Neurotrophic Factors

Chapter

Feb 2023

The cerebellum plays a central role in motor control and 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. The role of neurotrophic factors on the growth, proliferation, differentiation, and arborization of neurons and thus neurodevelopmental disorders has been established and investigated for decades. Numerous studies have shown changes in the level of a neurotrophic factor in the serum or tissue and alterations in their receptors and components of their signaling pathways in these neurodevelopmental diseases. This chapter provides a brief overview of neurotrophic factors and their role in cerebellar development. We also focus on the functions of the neurotrophin system in developmental disorders and diseases of the cerebellum.

Effects of polyunsaturated fatty acid–rich diets and risk of non-communicable diseases

Chapter

Jan 2022

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.

Can bioactive lipids arachidonic and docosahexaenoic acids prevent autism and reduce its severity?

Chapter

Jan 2021

Undurti Das

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.

Potential importance of supplementation with zinc for autism spectrum disorder

Article

Apr 2021
ENCEPHALE

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.

Metabolomic profiling of fatty acid biomarkers for intracerebral hemorrhage stroke

Article

Jan 2021
TALANTA

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.

Role of nutritional deficiency in the development of autism spectrum disorders

Article

Full-text available

May 2020

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.

A perinatal strategy to prevent autism

Chapter

Jan 2020

Undurti Das

Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF); polyunsaturated fatty acids (PUFAs): arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, gamma-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines, and a deficiency of antiinflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Recent studies revealed that various PUFAs and their metabolites influence the synthesis, release, and action of various neurotransmitters, synapse formation, and information processing in the brain. We also noted that PUFAs and their antiinflammatory metabolites such as lipoxin A4 enhance the production of BDNF, a potent neurotrophic factor. In addition, PUFAs influence gut microbiota. These evidences suggest that altered PUFA metabolism has a significant role in the pathobiology of autism. In view of this, I propose that all pregnant women, especially those who are obese, as obesity is known to be associated with low-grade systemic inflammation, or those who are at high risk to have autistic children may be supplemented with AA, EPA, and DHA and co-factors needed for their optimum metabolism such that antiinflammatory lipoxin A4 and BDNF are produced in adequate amounts in the developing brain such that autism and other related disorders are prevented.

Article

Nov 2019

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.

The growth factors / neuropeptides axis in the pathogenesis of autism spectrum disorder and schizophrenia

Article

Jul 2019

Rami Bou Khalil

Perinatal and postweaning diets high in omega-3 fatty acids have age- and sex-specific effects on the fatty acid composition of the cerebellum and brainstem of C57BL/6 mice

Article

Jul 2019

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.

Abnormal Social Behaviors and Dysfunction of Autism-Related Genes Associated With Daily Agonistic Interactions in Mice

Chapter

Full-text available

Jan 2018

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.

Ácidos grasos omega-3 en el tratamiento de los trastornos del espectro autista

Article

Sep 2016

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.

Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia

Article

Feb 2016

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 77 : 53–72, 2016. © 2016 Wiley Periodicals, Inc.

Increased ω-3 polyunsaturated fatty acid/arachidonic acid ratios and upregulation of signaling mediator in individuals with autism spectrum disorders

Article

Dec 2015

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.

Autism: recent molecular genetic advances

Article

Full-text available

Apr 2000
HUM MOL GENET

Janine A Lamb

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.

Management of Children With Autism Spectrum Disorders

Article

Full-text available

Dec 2007

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.

Development of white matter and reading skills

Article

Full-text available

Oct 2012
P NATL ACAD SCI USA

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.

Improved Working Memory but No Effect on Striatal Vesicular Monoamine Transporter Type 2 after Omega-3 Polyunsaturated Fatty Acid Supplementation

Article

Full-text available

Oct 2012
PLOS ONE

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.

The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation

Article

Full-text available

May 2003

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.

Omega 3 polyunsaturated fatty acid improves spatial learning and hippocampal Peroxisome Proliferator Activated Receptors (PPARα and PPARγ) gene expression in rats

Article

Full-text available

Sep 2012
BMC NEUROSCI

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.

Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism

Article

Full-text available

Sep 2012
SCIENCE

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.

Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brain-derived neurotrophic factor (BDNF) through molecular docking simulation

Article

Full-text available

Sep 2012
LIPIDS HEALTH DIS

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.

The Screening and Diagnosis of Autistic Spectrum Disorders

Article

Full-text available

Dec 1999

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.

Acetylcholinesterase and butyrylcholinesterase as markers of low-grade systemic inflammation

Article

Full-text available

May 2012
ANN HEPATOL

Undurti Das

Role of polyunsaturated fatty acids in the management of Egyptian children with autism

Article

Full-text available

Sep 2008

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.

Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism

Article

Full-text available

Feb 2012
AM J PSYCHIAT

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.

Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients With Major Depressive Disorder

Article

Full-text available

Dec 2011
J CLIN PSYCHOPHARM

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.

Maternal Docosahexaenoic Acid Feeding Protects Against Impairment of Learning and Memory and Oxidative Stress in Prenatally Stressed Rats: Possible Role of Neuronal Mitochondria Metabolism

Article

Full-text available

Sep 2011
ANTIOXID REDOX SIGN

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.

Plasma Cytokine Profiles in Subjects with High-Functioning Autism Spectrum Disorders

Article

Full-text available

May 2011
PLOS ONE

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.

Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation

Article

Full-text available

May 2011

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.

IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation

Article

Full-text available

May 2011
J NEUROINFLAMM

Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively. In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses. Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.

A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder

Article

Full-text available

Sep 2009
J NEURODEV DISORD

Autism Spectrum Disorder (ASD) is associated with both (i) post-mortem and neuroimaging evidence of abnormal cortical development, and (ii) altered signalling in Brain Derived Neurotrophic Factor (BDNF) pathways - which regulate neuroproliferative and neuroplastic processes. In healthy controls genotype at a single nucleotide polymorphism that alters BDNF signalling (Val66met) has been related to regional cortical volume. It is not known however if this influence on brain development is intact in ASD. Therefore we compared the relationship between genotype and cortical anatomy (as measured using in vivo Magnetic Resonance Imaging) in 41 people with ASD and 30 healthy controls. We measured cortical volume, and its two sole determinants - cortical thickness and surface area - which reflect differing neurodevelopmental processes. We found "Group-by-Genotype" interactions for cortical volume in medial (caudal anterior cingulate, posterior cingulate) and lateral (rostral middle, lateral orbitofrontal, pars orbitalis and pars triangularis) frontal cortices. Furthermore, within (only) these regions "Group-by-Genotype" interactions were also found for surface area. No effects were found for cortical thickness in any region. Our preliminary findings suggest that people with ASD have differences from controls in the relationship between BDNF val66met genotype and regional (especially frontal) cortical volume and surface area, but not cortical thickness. Therefore alterations in the relationship between BDNF val66met genotype and surface area in ASD may drive the findings for volume. If correct, this suggests ASD is associated with a distorted relationship between BDNF val66met genotype and the determinants of regional cortical surface area - gyrification and/or sulcal positioning.

Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia

Article

Full-text available

Apr 2011
LIPIDS HEALTH DIS

Autism is a developmental disorder characterized by social and emotional deficits, language impairments and stereotyped behaviors that manifest in early postnatal life. This study aims to compare the relative concentrations of essential fatty acids (Linoleic and α- linolenic), their long chain polyunsaturated fatty acids and phospholipids in plasma of autistic patients from Saudi Arabia with age-matching controls. 25 autistic children aged 3-15 years and 16 healthy children as control group were included in this study. Relative concentration of essential fatty acids/long chain polyunsaturated fatty acids and omega-3/omega-6 fatty acid series together with phosphatidylethanolamine, phosphatidylserine and phosphatidylcholine were measured in plasma of both groups. Remarkable alteration of essential fatty acids/long chain polyunsaturated fatty acids, omeg-3/omega-6 and significant lower levels of phospholipids were reported. Reciever Operating characteristics (ROC) analysis of the measured parameters revealed a satisfactory level of sensitivity and specificity. Essential fatty acids/long chain polyunsaturated fatty acids and omeg-3/omega-6 ratios, phosphatidylethanolamine, phosphatidylserine and phosphatidylcholine could be used as potential biomarkers that point to specific mechanisms in the development of autism and may help tailor treatment or prevention strategies.

Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia

Article

Full-text available

Apr 2011
LIPIDS HEALTH DIS

Autism is a family of developmental disorders of unknown origin. The disorder is characterized by behavioral, developmental, neuropathological and sensory abnormalities, and is usually diagnosed between the ages of 2 and 10 with peak prevalence rates observed in children aged 5-8 years. Recently, there has been heightened interest in the role of plasma free fatty acids (FA) in the pathology of neurological disorders. The aim of this study is to compare plasma fatty acid profiles of Saudi autistic patients with those of age-matching control subjects in an attempt to clarify the role of FA in the etiology of autism. 26 autistic patients together with 26-age-matching controls were enrolled in the present study. Methyl esters of FA were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography. The obtained data proved that fatty acids are altered in the plasma of autistic patients, specifically showing an increase in most of the saturated fatty acids except for propionic acid, and a decrease in most of polyunsaturated fatty acids. The altered fatty acid profile was discussed in relation to oxidative stress, mitochondrial dysfunction and the high lead (Pb) concentration previously reported in Saudi autistic patients. Statistical analysis of the obtained data shows that most of the measured fatty acids were significantly different in autistic patients compared to age -matching controls. Receiver Operating Characteristic (ROC) curve analysis shows satisfactory values of area under the curve (AUC) which could reflect the high degree of specificity and sensitivity of the altered fatty acids as biomarkers in autistic patients from Saudi Arabia.

Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells

Article

Full-text available

May 2011
CARDIOVASC RES

Members of the growth factor family of neurotrophins [NTs; e.g. brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been localized to pulmonary artery (PA) in humans. However, their role is unclear. Based on previous findings of NTs and their receptors within the pulmonary endothelium, we tested the hypothesis that NTs induce nitric oxide (NO) production in pulmonary endothelial cells (ECs), thus contributing to vasodilation. In human pulmonary artery ECs loaded with the NO-sensitive fluorescent dye diaminofluorescein-2, both BDNF and NT3 (100 pM, 1 nM, and 10 nM) acutely (<10 min) and substantially increased fluorescence levels in a concentration-dependent fashion (to levels comparable to that induced by 1 μM acetylcholine). NT-induced elevation of NO levels was blunted by the tyrosine kinase inhibitor K252a, the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester, the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Suppression of TrkB or TrkC expression via siRNA as well as functional blockade of p75NTR prevented NT-induced NO elevation. Both BDNF and NT3 increased phosphorylation of Akt and endothelial NO synthase (eNOS). In endothelium-intact porcine PA rings, NTs increased cGMP and induced vasodilation in pre-contracted arteries. These results indicate that NTs acutely modulate pulmonary endothelial NO production and contribute to relaxation of the pulmonary vasculature.

Effects of Altered Maternal Folic Acid, Vitamin B12 and Docosahexaenoic Acid on Placental Global DNA Methylation Patterns in Wistar Rats

Article

Full-text available

Mar 2011
PLOS ONE

Potential adverse effects of excess maternal folic acid supplementation on a vegetarian population deficient in vitamin B(12) are poorly understood. We have previously shown in a rat model that maternal folic acid supplementation at marginal protein levels reduces brain omega-3 fatty acid levels in the adult offspring. We have also reported that reduced docosahexaenoic acid (DHA) levels may result in diversion of methyl groups towards DNA in the one carbon metabolic pathway ultimately resulting in DNA methylation. This study was designed to examine the effect of normal and excess folic acid in the absence and presence of vitamin B(12) deficiency on global methylation patterns in the placenta. Further, the effect of maternal omega 3 fatty acid supplementation on the above vitamin B(12) deficient diets was also examined. Our results suggest maternal folic acid supplementation in the absence of vitamin B(12) lowers plasma and placental DHA levels (p<0.05) and reduces global DNA methylation levels (p<0.05). When this group was supplemented with omega 3 fatty acids there was an increase in placental DHA levels and subsequently DNA methylation levels revert back to the levels of the control group. Our results suggest for the first time that DHA plays an important role in one carbon metabolism thereby influencing global DNA methylation in the placenta.

Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus?

Article

Full-text available

Jan 2011
LIPIDS HEALTH DIS

Undurti Das

Acetylcholine, the principal vagus neurotransmitter, inhibits inflammation by suppressing the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic acetylcholine receptor subunit (alpha7nAChR) that explains why vagus nerve stimulation is anti-inflammatory in nature. Strong expression of alpha7nAChR in the synovium of rheumatoid arthritis and psoriatic arthritis patients was detected. Peripheral macrophages and synovial fibroblasts respond in vitro to specific alpha7nAChR cholinergic stimulation with potent inhibition of proinflammatory cytokines. Fibroblasts balance inflammatory mechanisms and arthritis development through feedback cholinergic stimulation by nearby immune cells. Collagen induced arthritis in alpha7nAChR(-/-) mice was significantly severe and showed increased synovial inflammation and joint destruction compared to the wild-type mice. Similar to vagal nerve stimulation and alpha7nAChR agonists, polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also suppress inflammation. In view of their similar anti-inflammatory actions, it is proposed that vagal nerve stimulation, alpha7nAChR agonists and EPA and DHA may augment the formation of anti-inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins. This implies that therapies directed at regulation of the cholinergic and alpha7nAChR mediated mechanisms and enhancing the formation of lipoxins, resolvins, protectins and maresins may halt and/or ameliorate rheumatoid arthritis, lupus and other rheumatological conditions.

Molecular Basis of Health and Disease

Book

Jan 2011

Undurti Das

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.

A perinatal strategy to prevent adult diseases: The role of long-chain polyunsaturated fatty acids

Chapter

Jan 2002

Undurti Das

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.

Minerals, trace elements, and vitamins interact with essential fatty acids and prostaglandins to prevent hypertension, thrombosis, hypercholesteremia and atherosclerosis and their attendant complications

Article

Jan 1985

Undurti Das

Neuroprotective Actions of Polyunsaturated Fatty Acids with Particular Reference to Alzheimer’s Disease

Article

Jan 2011

Undurti Das

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.

Metabolic Syndrome Pathophysiology: The Role of Essential Fatty Acids

Article

Jan 2010

Undurti Das

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.

Semantics of the MibML Conceptual Modeling Grammar

Article

Jul 2009

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 >

Molecular Basis of Health and Disease

Chapter

Apr 2011

Undurti Das

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.

Long-chain polyunsaturated fatty acids in growth and development of brain and memory

Article

Feb 2003
NUTRITION

Undurti Das

Metabolic syndrome is a low-grade systemic inflammatory condition

Article

Jul 2010

Undurti Das

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.

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

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