Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis / A. ANWAR in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 3p. Titre : Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis Type de document : Texte imprimé et/ou numérique Auteurs : A. ANWAR, Auteur ; P. M. ABRUZZO, Auteur ; S. PASHA, Auteur ; K. RAJPOOT, Auteur ; A. BOLOTTA, Auteur ; A. GHEZZO, Auteur ; M. MARINI, Auteur ; A. POSAR, Auteur ; Paola VISCONTI, Auteur ; P. J. THORNALLEY, Auteur ; N. RABBANI, Auteur Article en page(s) : 3p. Langues : Anglais (eng) Mots-clés : Advanced glycation endproducts (AGEs)  Amino acid metabolome  Autism spectrum disorder (ASD)  Machine learning  Oxidative stress  Ferrara (CE BIF) Index. décimale : PER Périodiques Résumé : Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 +/- 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 +/- 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), Nepsilon-carboxymethyl-lysine (CML) and Nomega-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs-CML, CMA-and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0183-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis [Texte imprimé et/ou numérique] / A. ANWAR, Auteur ; P. M. ABRUZZO, Auteur ; S. PASHA, Auteur ; K. RAJPOOT, Auteur ; A. BOLOTTA, Auteur ; A. GHEZZO, Auteur ; M. MARINI, Auteur ; A. POSAR, Auteur ; Paola VISCONTI, Auteur ; P. J. THORNALLEY, Auteur ; N. RABBANI, Auteur . - 3p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 3p. Mots-clés : Advanced glycation endproducts (AGEs)  Amino acid metabolome  Autism spectrum disorder (ASD)  Machine learning  Oxidative stress  Ferrara (CE BIF) Index. décimale : PER Périodiques Résumé : Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 +/- 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 +/- 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), Nepsilon-carboxymethyl-lysine (CML) and Nomega-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs-CML, CMA-and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0183-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

Na(+) , K(+) -ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells / A. BOLOTTA in Autism Research, 11-10 (October 2018)  

Public ISBD [article]  inAutism Research > 11-10 (October 2018) . - p.1388-1403 Titre : Na(+) , K(+) -ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells Type de document : Texte imprimé et/ou numérique Auteurs : A. BOLOTTA, Auteur ; Paola VISCONTI, Auteur ; G. FEDRIZZI, Auteur ; A. GHEZZO, Auteur ; M. MARINI, Auteur ; P. MANUNTA, Auteur ; E. MESSAGGIO, Auteur ; A. POSAR, Auteur ; A. VIGNINI, Auteur ; P. M. ABRUZZO, Auteur Article en page(s) : p.1388-1403 Langues : Anglais (eng) Mots-clés : Nrf2  Na+, K+-ATPase  autism spectrum disorders  beta-actin  endogenous ouabain  erythrocyte membrane  membrane lipids  metals  oxidative stress Index. décimale : PER Périodiques Résumé : Na(+) , K(+) -ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain-like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Res 2018, 11: 1388-1403. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD. En ligne : http://dx.doi.org/10.1002/aur.2002 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369 [article] Na(+) , K(+) -ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells [Texte imprimé et/ou numérique] / A. BOLOTTA, Auteur ; Paola VISCONTI, Auteur ; G. FEDRIZZI, Auteur ; A. GHEZZO, Auteur ; M. MARINI, Auteur ; P. MANUNTA, Auteur ; E. MESSAGGIO, Auteur ; A. POSAR, Auteur ; A. VIGNINI, Auteur ; P. M. ABRUZZO, Auteur . - p.1388-1403. Langues : Anglais (eng) in Autism Research > 11-10 (October 2018) . - p.1388-1403 Mots-clés : Nrf2  Na+, K+-ATPase  autism spectrum disorders  beta-actin  endogenous ouabain  erythrocyte membrane  membrane lipids  metals  oxidative stress Index. décimale : PER Périodiques Résumé : Na(+) , K(+) -ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain-like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Res 2018, 11: 1388-1403. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD. En ligne : http://dx.doi.org/10.1002/aur.2002 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369

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