Publications by authors named "Richard C Deth"

29 Publications

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Nutritional interventions for autism spectrum disorder.

Nutr Rev 2020 07;78(7):515-531

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, USA.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder with considerable clinical heterogeneity. With no cure for the disorder, treatments commonly center around speech and behavioral therapies to improve the characteristic social, behavioral, and communicative symptoms of ASD. Gastrointestinal disturbances are commonly encountered comorbidities that are thought to be not only another symptom of ASD but to also play an active role in modulating the expression of social and behavioral symptoms. Therefore, nutritional interventions are used by a majority of those with ASD both with and without clinical supervision to alleviate gastrointestinal and behavioral symptoms. Despite a considerable interest in dietary interventions, no consensus exists regarding optimal nutritional therapy. Thus, patients and physicians are left to choose from a myriad of dietary protocols. This review, summarizes the state of the current clinical and experimental literature on nutritional interventions for ASD, including gluten-free and casein-free, ketogenic, and specific carbohydrate diets, as well as probiotics, polyunsaturated fatty acids, and dietary supplements (vitamins A, C, B6, and B12; magnesium and folate).
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http://dx.doi.org/10.1093/nutrit/nuz092DOI Listing
July 2020

Methylation-related metabolic effects of D4 dopamine receptor expression and activation.

Transl Psychiatry 2019 11 12;9(1):295. Epub 2019 Nov 12.

Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, 33328, USA.

D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine synthase (MS). We evaluated the impact of D4R expression on folate-dependent phospholipid methylation (PLM) and MS activity, as well as cellular redox and methylation status, in transfected CHO cells expressing human D4R variants containing 2, 4, or 7 exon III repeats (D4.2R, D4.4R, D4.7R). Dopamine had no effect in non-transfected CHO cells, but increased PLM to a similar extent for both D4.2R- and D4.4R-expressing cells, while the maximal increase was for D4.7R was significantly lower. D4R expression in CHO cells decreased basal MS activity for all receptor subtypes and conferred dopamine-sensitive MS activity, which was greater with a higher number of repeats. Consistent with decreased MS activity, D4R expression decreased basal levels of methylation cycle intermediates methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), as well as cysteine and glutathione (GSH). Conversely, dopamine stimulation increased GSH, SAM, and the SAM/SAH ratio, which was associated with a more than 2-fold increase in global DNA methylation. Our findings illustrate a profound influence of D4R expression and activation on MS activity, coupled with the ability of dopamine to modulate cellular redox and methylation status. These previously unrecognized signaling activities of the D4R provide a unique link between neurotransmission and metabolism.
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http://dx.doi.org/10.1038/s41398-019-0630-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851363PMC
November 2019

Folate/Vitamin B12 Supplementation Combats Oxidative Stress-Associated Carcinogenesis in a Rat Model of Colon Cancer.

Nutr Cancer 2019 29;71(1):100-110. Epub 2018 Oct 29.

e Department of Pharmaceutical Sciences, College of Pharmacy , Nova Southeastern University , Fort Lauderdale , Florida , USA.

Folate and vitamin B12 deficiency is associated with depletion of the major intracellular antioxidant glutathione, and oxidative stress is emerging as an etiological mechanism for colon cancer. Azoxymethane (AOM), a potent carcinogen, induces colon cancer in rats by causing pathophysiological changes and oxidative stress. We investigated the synergistic effect of folate and vitamin B12 supplementation against AOM-induced carcinogenesis and oxidative stress in rat colon. Adult male rats were distributed into four groups: 1) Basal diet only; 2) AOM injection (15 mg/kg once per week in weeks 5 and 6); 3) Folate and vitamin B12 supplemented diet; 4) Folate and B12 diet with AOM injection. After 16 weeks, rats were sacrificed, colon tissue dissected, indicators of oxidative stress were measured, and immunohistochemical and ultrastructural changes were evaluated. AOM-injected rats showed oxidative stress, evident by glutathione depletion, oxidation of cellular proteins, and DNA oxidative damage. AOM increased mucosal levels of antiapoptotic and proapoptotic proteins Bcl2 and Bax and caused ultrastructure changes in colonic cell organelles. Folate and vitamin B12 supplementation decreased the level of oxidative stress and ameliorated the cytotoxic effects of AOM. In this in vivo experimental model of colon cancer, folate and vitamin B12 supplementation combats carcinogen-induced oxidative stress.
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http://dx.doi.org/10.1080/01635581.2018.1513047DOI Listing
May 2020

Early Disruption of the Microbiome Leading to Decreased Antioxidant Capacity and Epigenetic Changes: Implications for the Rise in Autism.

Front Cell Neurosci 2018 15;12:256. Epub 2018 Aug 15.

Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL, United States.

Currently, 1 out of every 59 children in the United States is diagnosed with autism. While initial research to find the possible causes for autism were mostly focused on the genome, more recent studies indicate a significant role for epigenetic regulation of gene expression and the microbiome. In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress. We propose that these autism-associated biological mechanisms may be caused and/or sustained by dysbiosis, an alteration to the composition of resident commensal communities relative to the community found in healthy individuals and its redox and epigenetic consequences, changes that in part can be due to early use and over-use of antibiotics across generations. Further studies are warranted to clarify the contribution of oxidative stress and gut microbiome in the pathophysiology of autism. A better understanding of the microbiome and gastrointestinal tract in relation to autism will provide promising new opportunities to develop novel treatment modalities.
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http://dx.doi.org/10.3389/fncel.2018.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104136PMC
August 2018

Aluminum Adjuvant-Containing Vaccines in the Context of the Hygiene Hypothesis: A Risk Factor for Eosinophilia and Allergy in a Genetically Susceptible Subpopulation?

Int J Environ Res Public Health 2018 05 3;15(5). Epub 2018 May 3.

College of Pharmacy, Department of Pharmaceutical Sciences, Nova Southeastern University, 1382 Terry Bldg, 3200 South University Drive, Fort Lauderdale, FL 33328, USA.

There are similarities between the immune response following immunization with aluminum adjuvants and the immune response elicited by some helminthic parasites, including stimulation of immunoglobulin E (IgE) and eosinophilia. Immunization with aluminum adjuvants, as with helminth infection, induces a Th2 type cell mediated immune response, including eosinophilia, but does not induce an environment conducive to the induction of regulatory mechanisms. Helminths play a role in what is known as the hygiene hypothesis, which proposes that decreased exposure to microbes during a critical time in early life has resulted in the increased prevalence and morbidity of asthma and atopic disorders over the past few decades, especially in Western countries. In addition, gut and lung microbiome composition and their interaction with the immune system plays an important role in a properly regulated immune system. Disturbances in microbiome composition are a risk factor for asthma and allergies. We propose that immunization with aluminum adjuvants in general is not favorable for induction of regulatory mechanisms and, in the context of the hygiene hypothesis and microbiome theory, can be viewed as an amplifying factor and significant contributing risk factor for allergic diseases, especially in a genetically susceptible subpopulation.
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http://dx.doi.org/10.3390/ijerph15050901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981940PMC
May 2018

Systematic Assessment of Research on Autism Spectrum Disorder (ASD) and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research.

Sci Eng Ethics 2017 12;23(6):1691-1718

Institute of Chronic Illnesses, Inc, 14 Redgate Court, Silver Spring, MD, 20905, USA.

Historically, entities with a vested interest in a product that critics have suggested is harmful have consistently used research to back their claims that the product is safe. Prominent examples are: tobacco, lead, bisphenol A, and atrazine. Research literature indicates that about 80-90% of studies with industry affiliation found no harm from the product, while only about 10-20% of studies without industry affiliation found no harm. In parallel to other historical debates, recent studies examining a possible relationship between mercury (Hg) exposure and autism spectrum disorder (ASD) show a similar dichotomy. Studies sponsored and supported by industry or entities with an apparent conflict of interest have most often shown no evidence of harm or no "consistent" evidence of harm, while studies without such affiliations report positive evidence of a Hg/autism association. The potentially causal relationship between Hg exposure and ASD differs from other toxic products since there is a broad coalition of entities for whom a conflict of interest arises. These include influential governmental public health entities, the pharmaceutical industry, and even the coal burning industry. This review includes a systematic literature search of original studies on the potential relationship between Hg and ASD from 1999 to August 2015, finding that of the studies with public health and/or industry affiliation, 86% reported no relationship between Hg and ASD. However, among studies without public health and/or industry affiliation, only 21% find no relationship between Hg and ASD. The discrepancy in these results suggests a bias indicative of a conflict of interest.
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http://dx.doi.org/10.1007/s11948-017-9983-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705731PMC
December 2017

Comparison of Protein N-Homocysteinylation in Rat Plasma under Elevated Homocysteine Using a Specific Chemical Labeling Method.

Molecules 2016 Sep 8;21(9). Epub 2016 Sep 8.

Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.

Elevated blood concentrations of homocysteine have been well established as a risk factor for cardiovascular diseases and neuropsychiatric diseases, yet the etiologic relationship of homocysteine to these disorders remains poorly understood. Protein N-homocysteinylation has been hypothesized as a contributing factor; however, it has not been examined globally owing to the lack of suitable detection methods. We recently developed a selective chemical method to label N-homocysteinylated proteins with a biotin-aldehyde tag followed by Western blotting analysis, which was further optimized in this study. We then investigated the variation of protein N-homocysteinylation in plasma from rats on a vitamin B12 deficient diet. Elevated "total homocysteine" concentrations were determined in rats with a vitamin B12 deficient diet. Correspondingly, overall levels of plasma protein N-homocysteinylation displayed an increased trend, and furthermore, more pronounced and statistically significant changes (e.g., 1.8-fold, p-value: 0.03) were observed for some individual protein bands. Our results suggest that, as expected, a general metabolic correlation exists between "total homocysteine" and N-homocysteinylation, although other factors are involved in homocysteine/homocysteine thiolactone metabolism, such as the transsulfuration of homocysteine by cystathionine β-synthase or the hydrolysis of homocysteine thiolactone by paraoxonase 1 (PON1), may play more significant or direct roles in determining the level of N-homocysteinylation.
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http://dx.doi.org/10.3390/molecules21091195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292613PMC
September 2016

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

PLoS One 2016 22;11(1):e0146797. Epub 2016 Jan 22.

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, United States of America.

Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723262PMC
July 2016

Epigenetic effects of casein-derived opioid peptides in SH-SY5Y human neuroblastoma cells.

Nutr Metab (Lond) 2015 9;12:54. Epub 2015 Dec 9.

Department of Pharmaceutical Sciences, Nova Southeastern University, Rm # 3103, HPD building, Fort Lauderdale, FL USA.

Background: Casein-free, gluten-free diets have been reported to mitigate some of the inflammatory gastrointestinal and behavioral traits associated with autism, but the mechanism for this palliative effect has not been elucidated. We recently showed that the opioid peptide beta-casomorphin-7, derived from bovine (bBCM7) milk, decreases cysteine uptake, lowers levels of the antioxidant glutathione (GSH) and decreases the methyl donor S-adenosylmethionine (SAM) in both Caco-2 human GI epithelial cells and SH-SY5Y human neuroblastoma cells. While human breast milk can also release a similar peptide (hBCM-7), the bBCM7 and hBCM-7 vary greatly in potency; as the bBCM-7 is highly potent and similar to morphine in it's effects. Since SAM is required for DNA methylation, we wanted to further investigate the epigenetic effects of these food-derived opioid peptides. In the current study the main objective was to characterize functional pathways and key genes responding to DNA methylation effects of food-derived opioid peptides.

Methods: SH-SY5Y neuroblastoma cells were treated with 1 μM hBCM7 and bBCM7 and RNA and DNA were isolated after 4 h with or without treatment. Transcriptional changes were assessed using a microarray approach and CpG methylation status was analyzed at 450,000 CpG sites. Functional implications from both endpoints were evaluated via Ingenuity Pathway Analysis 4.0 and KEGG pathway analysis was performed to identify biological interactions between transcripts that were significantly altered at DNA methylation or transcriptional levels (p < 0.05, FDR <0.1).

Results: Here we show that hBCM7 and bBCM7, as well as morphine, cause epigenetic changes affecting gene pathways related to gastrointestinal disease and inflammation. These epigenetic consequences exhibited the same potency order as opiate inhibition of cysteine uptake insofar as hBCM7 was less potent than bBCM7, which was less potent than morphine.

Conclusion: Our findings indicate that epigenetic effects of milk-derived opiate peptides may contribute to GI dysfunction and inflammation in sensitive individuals. While the current study was performed using SH-SY5Y neuronal cellular models, similar actions on other cells types might combine to cause symptoms of intolerance. These actions may provide a potential contributing mechanism for the beneficial effects of a casein-free diet in alleviating gastrointestinal symptoms in neurological conditions including autism and other conditions. Lastly, our study also contributes to the evolving awareness of a "gut-brain connection".
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http://dx.doi.org/10.1186/s12986-015-0050-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673759PMC
December 2015

A role for impaired regulatory T cell function in adverse responses to aluminum adjuvant-containing vaccines in genetically susceptible individuals.

Vaccine 2014 Sep 25;32(40):5149-55. Epub 2014 Jul 25.

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.

Regulatory T cells play a critical role in the immune response to vaccination, but there is only a limited understanding of the response of regulatory T cells to aluminum adjuvants and the vaccines that contain them. Available studies in animal models show that although induced T regulatory cells may be induced concomitantly with effector T cells following aluminum-adjuvanted vaccination, they are unable to protect against sensitization, suggesting that under the Th2 immune-stimulating effects of aluminum adjuvants, Treg cells may be functionally compromised. Allergic diseases are characterized by immune dysregulation, with increases in IL-4 and IL-6, both of which exert negative effects on Treg function. For individuals with a genetic predisposition, the beneficial influence of adjuvants on immune responsiveness may be accompanied by immune dysregulation, leading to allergic diseases. This review examines aspects of the regulatory T cell response to aluminum-adjuvanted immunization and possible genetic susceptibility factors related to that response.
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http://dx.doi.org/10.1016/j.vaccine.2014.07.052DOI Listing
September 2014

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences.

J Nutr Biochem 2014 Oct 6;25(10):1011-8. Epub 2014 Jun 6.

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA. Electronic address:

Dietary interventions like gluten-free and casein-free diets have been reported to improve intestinal, autoimmune and neurological symptoms in patients with a variety of conditions; however, the underlying mechanism of benefit for such diets remains unclear. Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be modulated by nutritional factors such as milk and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat-derived protein) releases peptides with opioid activity, and in the present study, we demonstrate that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine. Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis was also observed. These results illustrate the potential of milk- and wheat-derived peptides to exert antioxidant and epigenetic changes that may be particularly important during the postnatal transition from placental to GI nutrition. Differences between peptides derived from human and bovine milk may contribute to developmental differences between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by wheat- and milk-derived opioid peptides, may predispose susceptible individuals to inflammation and systemic oxidation, partly explaining the benefits of gluten-free or casein-free diets.
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http://dx.doi.org/10.1016/j.jnutbio.2014.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157943PMC
October 2014

Potential Role of Selenoenzymes and Antioxidant Metabolism in relation to Autism Etiology and Pathology.

Autism Res Treat 2014 5;2014:164938. Epub 2014 Mar 5.

Energy & Environmental Research Center, University of North Dakota, 15 North 23rd Street, Stop 9018, Grand Forks, ND 58202, USA.

Autism and autism spectrum disorders (ASDs) are behaviorally defined, but the biochemical pathogenesis of the underlying disease process remains uncharacterized. Studies indicate that antioxidant status is diminished in autistic subjects, suggesting its pathology is associated with augmented production of oxidative species and/or compromised antioxidant metabolism. This suggests ASD may result from defects in the metabolism of cellular antioxidants which maintain intracellular redox status by quenching reactive oxygen species (ROS). Selenium-dependent enzymes (selenoenzymes) are important in maintaining intercellular reducing conditions, particularly in the brain. Selenoenzymes are a family of ~25 genetically unique proteins, several of which have roles in preventing and reversing oxidative damage in brain and endocrine tissues. Since the brain's high rate of oxygen consumption is accompanied by high ROS production, selenoenzyme activities are particularly important in this tissue. Because selenoenzymes can be irreversibly inhibited by many electrophiles, exposure to these organic and inorganic agents can diminish selenoenzyme-dependent antioxidant functions. This can impair brain development, particularly via the adverse influence of oxidative stress on epigenetic regulation. Here we review the physiological roles of selenoproteins in relation to potential biochemical mechanisms of ASD etiology and pathology.
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http://dx.doi.org/10.1155/2014/164938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966422PMC
June 2014

Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman.

Exp Biol Med (Maywood) 2014 Jun;239(6):697-706

Genetic, nutrition, and environmental factors have each been implicated as sources of risk for autism. Oxidative stress, including low plasma levels of the antioxidant glutathione, has been reported by numerous autism studies, which can disrupt methylation-dependent epigenetic regulation of gene expression with neurodevelopmental consequences. We investigated the status of redox and methylation metabolites, as well as the level of protein homocysteinylation and hair mercury levels, in autistic and neurotypical control Omani children, who were previously shown to exhibit significant nutritional deficiencies in serum folate and vitamin B₁₂. The serum level of glutathione in autistic subjects was significantly below control levels, while levels of homocysteine and S-adenosylhomocysteine were elevated, indicative of oxidative stress and decreased methionine synthase activity. Autistic males had lower glutathione and higher homocysteine levels than females, while homocysteinylation of serum proteins was increased in autistic males but not females. Mercury levels were markedly elevated in the hair of autistic subjects vs. control subjects, consistent with the importance of glutathione for its elimination. Thus, autism in Oman is associated with decreased antioxidant resources and decreased methylation capacity, in conjunction with elevated hair levels of mercury.
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http://dx.doi.org/10.1177/1535370214527900DOI Listing
June 2014

Autism: a redox/methylation disorder.

Authors:
Richard C Deth

Glob Adv Health Med 2013 Nov;2(6):68-73

Northeastern University, Boston, Massachusetts, United States.

While autism is still a mysterious developmental disorder, expansion of research efforts over the past 10 to 15 years has yielded a number of important clues implicating both genetic and environmental factors. We can now assert with a measure of confidence that contemporary autism reflects the combined impact of multiple environmental factors on the processes that regulate development in genetically vulnerable individuals. Since epigenetic regulation of gene expression is acknowledged as the most critical factor in development and DNA methylation (the addition of a carbon atom at discrete locations) is the fundamental event for epigenetic regulation, dysfunctional methylation can be considered as a likely cause of autism. Since methylation activity is highly sensitive to oxidative stress (an abnormal redox state) and many environmental factors promote oxidative stress, we have proposed a redox/methylation hypothesis for autism causation. The narrative herein describes the evolution of this hypothesis, which is essentially a series of linked discoveries about how the brain uniquely relies on oxidation and methylation to guide its development and to carry out its cognitive functions.
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http://dx.doi.org/10.7453/gahmj.2013.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865376PMC
November 2013

Impact of nutrition on serum levels of docosahexaenoic acid among Omani children with autism.

Nutrition 2013 Sep 22;29(9):1142-6. Epub 2013 Jun 22.

Department of Family Medicine and Public Health, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Sultanate of Oman.

Objectives: Autism is a lifelong neurodevelopmental disorder of early childhood. Dietary supplementation of the ω-3 fatty acid (docosahexaenoic acid [DHA]) during prenatal and postnatal life is considered a protective dietary intervention strategy to minimize the risk for autism spectrum disorder (ASD). To our knowledge, no relevant studies have been conducted in the Middle East investigating the status of DHA among children with autism during early childhood. The aim of this study was to investigate the serum levels and dietary intake status of DHA among Omani children recently diagnosed with ASD.

Methods: The present case-control study involved 80 Omani children (<5 y), 40 cases and 40 controls matched for age and sex. A semi-quantitative food frequency questionnaire was used to assess dietary intake of all the participants, while serum levels of DHA were measured using high-performance liquid chromatography.

Results: Our results showed that children with ASD had lower dietary consumption of foodstuff containing DHA, as well as lower serum levels of DHA than controls.

Conclusion: The present finding from Oman supports the view of other studies that there are low serum levels of DHA among children with ASD.
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http://dx.doi.org/10.1016/j.nut.2013.03.009DOI Listing
September 2013

Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism.

PLoS One 2013 20;8(2):e56927. Epub 2013 Feb 20.

Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA.

The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity. MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed. Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age-dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels. MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF-α, whose CSF levels are elevated in autism. These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056927PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577685PMC
August 2013

Low folate and vitamin B12 nourishment is common in Omani children with newly diagnosed autism.

Nutrition 2013 Mar 1;29(3):537-41. Epub 2013 Jan 1.

Department of Family Medicine and Public Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman.

Objective: Arab populations lack data related to nutritional assessment in children with autism spectrum disorders (ASDs), especially micronutrient deficiencies such as folate and vitamin B12.

Methods: To assess the dietary and serum folate and vitamin B12 statuses, a hospital-based case-control study was conducted in 80 Omani children (40 children with ASDs versus 40 controls).

Results: The ASD cases showed significantly lower levels of folate, vitamin B12, and related parameters in dietary intake and serum levels.

Conclusion: These data showed that Omani children with ASDs exhibit significant deficiencies in folate and vitamin B12 and call for increasing efforts to ensure sufficient intakes of essential nutrients by children with ASDs to minimize or reverse any ongoing impact of nutrient deficiencies.
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http://dx.doi.org/10.1016/j.nut.2012.09.014DOI Listing
March 2013

Levels of heavy metals and essential minerals in hair samples of children with autism in Oman: a case-control study.

Biol Trace Elem Res 2013 Feb 28;151(2):181-6. Epub 2012 Nov 28.

Department of Family Medicine and Public Health, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoudh, Oman.

Toxic levels of heavy metals and low levels of essential minerals have been suggested to play a critical role in the pathogenesis of autism spectrum disorders (ASD). This study documents the levels of heavy metals and essential minerals in hair samples of children with ASD in Muscat, the urbanized capital of Oman, Muscat. The study included 27 children with ASD and 27 matched non-ASD controls. Parental interviews were held and dietary intake questionnaires completed in conjunction with the collection of hair samples. Analysis of heavy metals and essential minerals was carried out by inductively coupled plasma mass spectrometry. Chi-square analysis and non-parametric Fisher's exact tests were used to assess statistical significance. Children with ASD had significantly higher levels of all 11 analyzed heavy metals in their hair samples (P < 0.05), ranging from 150 to 365 % of control levels. ASD children also had significantly higher levels of essential minerals sulfur, sodium, magnesium, potassium, zinc, and iron, but lower levels of calcium and copper in their hair samples. This study corroborates data from previous studies in different parts of the world indicating the presence of elevated levels of heavy metals and selective depletion of essential minerals in the hair of children with ASD.
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http://dx.doi.org/10.1007/s12011-012-9553-zDOI Listing
February 2013

Are ASD and ADHD a Continuum? A Comparison of Pathophysiological Similarities Between the Disorders.

J Atten Disord 2015 Sep 16;19(9):805-27. Epub 2012 Oct 16.

Northeastern University, Boston, MA, USA.

Objective: The objective of this study was to review and compare the similarities between autism spectrum disorder (ASD) and ADHD with regard to symptomatology, neurological deficits, metabolic and endocrine-related conditions, and brain pathology.

Method: A comprehensive review of the relevant research literature was carried out.

Results: A number of important similarities between ASD and ADHD were identified, including recent increases in prevalence, male-biased incidence, shared involvement of sensory processing, motor and impulse control, abnormal patterns of neural connectivity, and sleep disturbances. Studies suggest involvement of androgen metabolism, impaired methylation, and heavy metal toxicity as possible contributing factors for both disorders.

Conclusion: ASD and ADHD share a number of features and pathophysiological conditions, which suggests that the two disorders may be a continuum and have a common origin.
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http://dx.doi.org/10.1177/1087054712459886DOI Listing
September 2015

How aluminum adjuvants could promote and enhance non-target IgE synthesis in a genetically-vulnerable sub-population.

J Immunotoxicol 2013 Apr-Jun;10(2):210-22. Epub 2012 Sep 11.

Department of Pharmaceutical Sciences, Northeastern University, 148 TF, 360 Huntington Avenue, Boston, MA 02115, USA.

Aluminum-containing adjuvants increase the effectiveness of vaccination, but their ability to augment immune responsiveness also carries the risk of eliciting non-target responses, especially in genetically susceptible individuals. This study reviews the relevant actions of aluminum adjuvants and sources of genetic risk that can combine to adversely affect a vulnerable sub-population. Aluminum adjuvants promote oxidative stress and increase inflammasome activity, leading to the release of IL-1β, IL-18, and IL-33, but not the important regulatory cytokine IL-12. In addition, they stimulate macrophages to produce PGE₂, which also has a role in regulating immune responses. This aluminum-induced cytokine context leads to a T(H)2 immune response, characterized by the further release of IL-3, IL-4, IL-5, IL-9, IL-13, and IgE-potentiating factors such as sCD23. Genetic variants in cytokine genes, such as IL-4, IL-13, IL-33, and IL-18 influence the response to vaccines in children and are also associated with atopy. These genetic factors may therefore define a genetically-vulnerable sub-population, children with a family history of atopy, who may experience an exaggerated T(H)2 immune response to aluminum-containing vaccines. IL-4, sCD23, and IgE are common factors for both atopy and the immune-stimulating properties of aluminum adjuvants. IL-4 is critical in the production of IgE and total IgE up-regulation. IL-4 has also been reported to induce the production of sCD23 and trigger resting sIgM+, sIgD+ B-cells to switch to sIgE+ B-cells, making them targets for IgE-potentiating factors. Further, the actions of IgE-potentiating factors on sIgE+ B-cells are polyclonal and unrestricted, triggering their differentiation into IgE-forming plasma cells. These actions provide a mechanism for aluminum-adjuvant promotion and enhancement of non-target IgE in a genetically vulnerable sub-population. Identification of these individuals may decrease the risk of adverse events associated with the use of aluminum-containing vaccines.
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http://dx.doi.org/10.3109/1547691X.2012.708366DOI Listing
December 2013

Role of a redox-based methylation switch in mRNA life cycle (pre- and post-transcriptional maturation) and protein turnover: implications in neurological disorders.

Front Neurosci 2012 26;6:92. Epub 2012 Jun 26.

Department of Pharmaceutical Sciences, Northeastern University Boston, MA, USA.

Homeostatic synaptic scaling in response to neuronal stimulus or activation, and due to changes in cellular niche, is an important phenomenon for memory consolidation, retrieval, and other similar cognitive functions (Turrigiano and Nelson, 2004). Neurological disorders and cognitive disabilities in autism, Rett syndrome, schizophrenia, dementia, etc., are strongly correlated to alterations in protein expression (both synaptic and cytoplasmic; Cajigas et al., 2010). This correlation suggests that efficient temporal regulation of synaptic protein expression is important for synaptic plasticity. In addition, equilibrium between mRNA processing, protein translation, and protein turnover is a critical sensor/trigger for recording synaptic information, normal cognition, and behavior (Cajigas et al., 2010). Thus a regulatory switch, which controls the lifespan, maturation, and processing of mRNA, might influence cognition and adaptive behavior. Here, we propose a two part novel hypothesis that methylation might act as this suggested coordinating switch to critically regulate mRNA maturation at (1) the pre-transcription level, by regulating precursor-RNA processing into mRNA, via other non-coding RNAs and their influence on splicing phenomenon, and (2) the post-transcription level by modulating the regulatory functions of ribonucleoproteins and RNA binding proteins in mRNA translation, dendritic translocation as well as protein synthesis and synaptic turnover. DNA methylation changes are well recognized and highly correlated to gene expression levels as well as, learning and memory; however, RNA methylation changes are recently characterized and yet their functional implications are not established. This review article provides some insight on the intriguing consequences of changes in methylation levels on mRNA life-cycle. We also suggest that, since methylation is under the control of glutathione anti-oxidant levels (Lertratanangkoon et al., 1997), the redox status of neurons might be the central regulatory switch for methylation-based changes in mRNA processing, protein expression, and turnover. Lastly, we also describe experimental methods and techniques which might help researchers to evaluate the suggested hypothesis.
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http://dx.doi.org/10.3389/fnins.2012.00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382963PMC
October 2012

Genomics, intellectual disability, and autism.

Authors:
Richard C Deth

N Engl J Med 2012 06;366(23):2231-2; author reply 2232

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http://dx.doi.org/10.1056/NEJMc1204397DOI Listing
June 2012

Effect of suboptimal breast-feeding on occurrence of autism: a case-control study.

Nutrition 2012 Jul 26;28(7-8):e27-32. Epub 2012 Apr 26.

Department of Family Medicine and Public Health, Sultan Qaboos University, Al-Khoudh, Sultanate of Oman.

Objective: To evaluate the association between suboptimal breast-feeding practices and autism spectrum disorders (ASDs).

Methods: A case-control study was conducted in 102 ASD cases and 102 matched healthy controls.

Results: Based on adjusted odds ratios from logistic regression models, ASD was found to be associated with the late initiation of breast-feeding (odds ratio 1.48, 95% confidence interval 1.01-3.1), a non-intake of colostrum (odds ratio 1.7, 95% confidence interval 1.03-4.3), prelacteal feeding, and bottle-feeding. The risk of ASD was found to decrease in a dose-response fashion over increasing periods of exclusive breast-feeding (P for trend = 0.04) and continued breast-feeding (P for trend = 0.001).

Conclusion: The study indicates that increased ASD risk is generally associated with suboptimal breast-feeding practices.
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http://dx.doi.org/10.1016/j.nut.2012.01.007DOI Listing
July 2012

Hyperhomocysteinemia among Omani autistic children: a case-control study.

Acta Biochim Pol 2011 20;58(4):547-51. Epub 2011 Dec 20.

Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Oman.

High serum homocysteine (Hcy) level is regarded as an indicator for impairment of folate-dependent methionine cycle and is associated with oxidative stress. In a case control study, we evaluated eighty 3-5 years old Omani children (40 diagnosed with Autism Spectrum Disorder and 40 their age and gender matched controls) for their fasting serum homocysteine levels as a biomarker of Autism Spectrum Disorder (ASD). Serum folate and vitamin B(12) status were also evaluated. The serum homocysteine was measured using an enzyme immunoassay (EIA) technique whereas folate and vitamin B(12) were measured using an automated random access immune-assay system. The results indicated that mean serum Hcy levels were significantly (P < 0.05) higher in autistic children (20.1 ± 3.3 µmol/L) as compared to controls (9.64 ± 2.1 µmol/L). Significantly (P < 0.05) lower serum folate (1.8 ± 0.4 µg/L) and vitamin B(12) (191.1 ± 0.9 pg/mL) levels were observed in autistic children as compared to controls (6.1 ± 0.6 µg/L and 288.9 ± 1.3 pg/mL, respectively). The levels of homocysteine in autistic children were also much higher as compared to normal reference values (5-15 µmol/L). The results suggest that high fasting serum homocysteine and low folate and vitamin B(12) levels could be used as clinical biomarkers for an early diagnosis and management of ASD.
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May 2012

Ethanol lowers glutathione in rat liver and brain and inhibits methionine synthase in a cobalamin-dependent manner.

Alcohol Clin Exp Res 2011 Feb 1;35(2):277-83. Epub 2010 Dec 1.

Department of Food Science and Nutrition, Sultan Qaboos University, Muscat, Sultanate of Oman.

Background: Methionine synthase (MS) is a ubiquitous enzyme that requires vitamin B12 (cobalamin) and 5-methyl-tetrahydrofolate for the methylation of homocysteine to methionine. Previous studies have shown that acute or chronic ethanol (ETOH) administration results in the inhibition of MS and depletion of glutathione (GSH), and it has been proposed that GSH is required for the synthesis of methylcobalamin (MeCbl).

Methods: We measured GSH levels and investigated the ability of different cobalamin cofactors [cyano- (CNCbl), glutathionyl- (GSCbl), hydroxo- (OHCbl), and MeCbl] to support MS activity in liver and brain cortex from control and ETOH-treated rats.

Results: In control animals, MS activity was higher in liver than in cortex for all cobalamins and MeCbl-based activity was higher than for other cofactors. S-adenosylmethionine (SAM) was required for OHCbl, CNCbl, and GSCbl-based activity, but not for MeCbl. Feeding an ETOH-containing diet for four weeks caused a significant decrease in liver MS activity, in a cobalamin-dependent manner (OHCbl ≥ CNCbl > GSCbl > MeCbl). In brain cortex, OHCbl, CNCbl, and GSCbl-based activity was reduced by ETOH treatment, but MeCbl-based activity was unaffected. GSH levels were reduced by ETOH treatment in both liver and cortex homogenates, and addition of GSH restored OHCbl-based MS activity to control levels. Betaine administration had no significant effect on GSH levels or MS activity in either control or ETOH-fed groups.

Conclusions: The ETOH-induced decrease in OHCbl-based MS activity is secondary to decreased GSH levels and a decreased ability to synthesize MeCbl. The ability of MeCbl to completely offset ETOH inhibition in brain cortex, but not liver, suggests tissue-specific differences in the GSH-dependent regulation of MS activity.
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http://dx.doi.org/10.1111/j.1530-0277.2010.01343.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058891PMC
February 2011

A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation.

J Comput Neurosci 2008 Jun 11;24(3):314-29. Epub 2007 Oct 11.

Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier St., Suite D, New Orleans, LA 70112, USA.

We describe a new molecular mechanism of dopamine-induced membrane protein modulation that can tune neuronal oscillation frequency to attention-related gamma rhythm. This mechanism is based on the unique ability of D4 dopamine receptors (D4R) to carry out phospholipid methylation (PLM) that may affect the kinetics of ion channels. We show that by deceasing the inertia of the delayed rectifier potassium channel, a transition to 40 Hz oscillations can be achieved. Decreased potassium channel inertia shortens spike duration and decreases the interspike interval via its influence on the calcium-dependent potassium current. This mechanism leads to a transition to attention-related gamma oscillations in a pyramidal cell-interneuron network. The higher frequency and better synchronization is observed with PLM affecting pyramidal neurons only, and recurrent excitation between pyramidal neurons is important for synchronization. Thus dopamine-stimulated methylation of membrane phospholipids may be an important mechanism for modulating firing activity, while impaired methylation can contribute to disorders of attention.
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http://dx.doi.org/10.1007/s10827-007-0057-3DOI Listing
June 2008

Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats.

Anesth Analg 2007 Jul;105(1):83-8

Department of Anesthesiology Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

Background: Nitrous oxide is a commonly used anesthetic that inhibits the activity of methionine synthase, an enzyme involved in methylation reactions and DNA synthesis and repair. This inhibition triggers vacuole formation and degeneration of neurons in areas of the developing and mature brain that are important for spatial memory, raising the possibility that nitrous oxide might have sustained effects on learning.

Methods: To test this possibility, we randomized 18-month-old Fischer 344 rats (n = 13 per group) to 4 h of 70% nitrous oxide + 30% oxygen or 70% nitrogen + 30% oxygen (control) and assessed memory using a 12-arm radial maze for 14 days beginning 2 days after nitrous oxide inhalation. In separate, identically treated groups of rats, we measured methionine synthase activity in the cortex and liver at the end of nitrous oxide exposure and 2 days later (n = 3 rats per group per time point) using a standard assay.

Results: Liver and cortical methionine synthase was inhibited during nitrous oxide inhalation (6% and 23% of control in liver and cortex, respectively; P < 0.01). Liver enzyme activity remained depressed 2 days later, whereas cortical enzyme activity recovered. There was no difference in error rate between control and nitrous oxide treated rats. However, those exposed to nitrous oxide took more time to complete the maze and made fewer correct choices before first error (P < 0.05).

Conclusions: Sedation with 70% nitrous oxide profoundly, but transiently, reduces the activity of cortical methionine synthase but produces lasting impairment in spatial working memory in aged rats.
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http://dx.doi.org/10.1213/01.ane.0000266491.53318.20DOI Listing
July 2007

Protein kinase C regulates alpha(2A/D)-adrenoceptor constitutive activity.

Pharmacology 2004 Jun;71(2):80-90

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.

We investigated a possible role for protein kinases in the constitutive activity of alpha(2A/D) adrenoceptors in membranes from transfected PC12 cells, using a [35S]GTPgammaS binding assay. After treatment of intact cells with various protein kinase inhibitors, constitutive activity was assessed by the reduction in basal GTP binding caused by the inverse agonist rauwolscine (RAU). Inhibitors of protein kinase C (PKC) caused the loss of RAU-sensitive GTP binding, while inhibitors of other protein kinases were ineffective. Anti-G(alpha) antibody treatments showed that constitutive alpha(2A/D)-receptor activity is directed toward different G proteins than agonist-stimulated activity. T373A mutant receptors exhibited increased constitutive activity, including a component that was insensitive to PKC inhibition. Since T373 is located within a putative G(i/o) activator sequence, these results suggest that PKC-dependent phosphorylation of T373 increases alpha(2A/D)-adrenergic receptor constitutive activity and causes a switch in G protein preference.
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http://dx.doi.org/10.1159/000076944DOI Listing
June 2004