Systemic oxidative stress in classic Rett syndrome
Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, is a leading cause of mental retardation with autistic features in females. However, its pathog...
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| Veröffentlicht in: | Free radical biology & medicine 2009-08, Vol.47 (4), p.440-448 |
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| creator | De Felice, Claudio Ciccoli, Lucia Leoncini, Silvia Signorini, Cinzia Rossi, Marcello Vannuccini, Laura Guazzi, Gianni Latini, Giuseppe Comporti, Mario Valacchi, Giuseppe Hayek, Joussef |
| description | Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal
MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, is a leading cause of mental retardation with autistic features in females. However, its pathogenesis remains incompletely understood, and no effective therapy is available to date. We hypothesized that a systemic oxidative stress may play a key role in the pathogenesis of classic RS. Patients with classic RS (
n
=
59) and control subjects (
n
=
43) were evaluated. Oxidative stress markers included intraerythrocyte non-protein-bound iron (NPBI; i.e., free iron), plasma NPBI, F
2-isoprostanes (F
2-IsoPs, as free, esterified, and total forms), and protein carbonyls. Lung ventilation/perfusion (
V/
Q) ratio was assessed using a portable gas analyzer, and RS clinical severity was evaluated using standard scales. Significantly increased intraerythrocyte NPBI (2.73-fold), plasma NPBI (×
6.0), free F
2-IsoP (×
1.85), esterified F
2-IsoP (×
1.69), total F
2-IsoP (×
1.66), and protein carbonyl (×
4.76) concentrations were evident in RS subjects and associated with reduced (−
10.53%) arterial oxygen levels compared to controls. Biochemical evidence of oxidative stress was related to clinical phenotype severity and lower peripheral and arterial oxygen levels. Pulmonary
V/
Q mismatch was found in the majority of the RS population. These data identify hypoxia-induced oxidative stress as a key factor in the pathogenesis of classic RS and suggest new therapeutic approaches based on oxidative stress modulation. |
| doi_str_mv | 10.1016/j.freeradbiomed.2009.05.016 |
| format | Article |
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MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, is a leading cause of mental retardation with autistic features in females. However, its pathogenesis remains incompletely understood, and no effective therapy is available to date. We hypothesized that a systemic oxidative stress may play a key role in the pathogenesis of classic RS. Patients with classic RS (
n
=
59) and control subjects (
n
=
43) were evaluated. Oxidative stress markers included intraerythrocyte non-protein-bound iron (NPBI; i.e., free iron), plasma NPBI, F
2-isoprostanes (F
2-IsoPs, as free, esterified, and total forms), and protein carbonyls. Lung ventilation/perfusion (
V/
Q) ratio was assessed using a portable gas analyzer, and RS clinical severity was evaluated using standard scales. Significantly increased intraerythrocyte NPBI (2.73-fold), plasma NPBI (×
6.0), free F
2-IsoP (×
1.85), esterified F
2-IsoP (×
1.69), total F
2-IsoP (×
1.66), and protein carbonyl (×
4.76) concentrations were evident in RS subjects and associated with reduced (−
10.53%) arterial oxygen levels compared to controls. Biochemical evidence of oxidative stress was related to clinical phenotype severity and lower peripheral and arterial oxygen levels. Pulmonary
V/
Q mismatch was found in the majority of the RS population. These data identify hypoxia-induced oxidative stress as a key factor in the pathogenesis of classic RS and suggest new therapeutic approaches based on oxidative stress modulation.</description><identifier>ISSN: 0891-5849</identifier><identifier>EISSN: 1873-4596</identifier><identifier>DOI: 10.1016/j.freeradbiomed.2009.05.016</identifier><identifier>PMID: 19464363</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Autism spectrum disorders ; Autistic Disorder ; Child ; Child, Preschool ; Disease Progression ; Erythrocytes - metabolism ; Erythrocytes - pathology ; F2-Isoprostanes - metabolism ; Female ; Free radicals ; Genetic Predisposition to Disease ; Humans ; Hypoxia ; Intellectual Disability ; Iron - metabolism ; Isoprostanes ; MeCP2 ; Methyl-CpG-Binding Protein 2 - genetics ; Mutation ; Oxidative Stress ; Oxygen - metabolism ; Pathogenesis ; Protein Carbonylation ; Rett syndrome ; Rett Syndrome - genetics ; Rett Syndrome - pathology ; Rett Syndrome - physiopathology ; Ventilation-Perfusion Ratio</subject><ispartof>Free radical biology & medicine, 2009-08, Vol.47 (4), p.440-448</ispartof><rights>2009 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-4014c1ff167149b40d491ec79a4955e47c798af375e63e7a132937f962b8e25c3</citedby><cites>FETCH-LOGICAL-c413t-4014c1ff167149b40d491ec79a4955e47c798af375e63e7a132937f962b8e25c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.freeradbiomed.2009.05.016$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19464363$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De Felice, Claudio</creatorcontrib><creatorcontrib>Ciccoli, Lucia</creatorcontrib><creatorcontrib>Leoncini, Silvia</creatorcontrib><creatorcontrib>Signorini, Cinzia</creatorcontrib><creatorcontrib>Rossi, Marcello</creatorcontrib><creatorcontrib>Vannuccini, Laura</creatorcontrib><creatorcontrib>Guazzi, Gianni</creatorcontrib><creatorcontrib>Latini, Giuseppe</creatorcontrib><creatorcontrib>Comporti, Mario</creatorcontrib><creatorcontrib>Valacchi, Giuseppe</creatorcontrib><creatorcontrib>Hayek, Joussef</creatorcontrib><title>Systemic oxidative stress in classic Rett syndrome</title><title>Free radical biology & medicine</title><addtitle>Free Radic Biol Med</addtitle><description>Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal
MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, is a leading cause of mental retardation with autistic features in females. However, its pathogenesis remains incompletely understood, and no effective therapy is available to date. We hypothesized that a systemic oxidative stress may play a key role in the pathogenesis of classic RS. Patients with classic RS (
n
=
59) and control subjects (
n
=
43) were evaluated. Oxidative stress markers included intraerythrocyte non-protein-bound iron (NPBI; i.e., free iron), plasma NPBI, F
2-isoprostanes (F
2-IsoPs, as free, esterified, and total forms), and protein carbonyls. Lung ventilation/perfusion (
V/
Q) ratio was assessed using a portable gas analyzer, and RS clinical severity was evaluated using standard scales. Significantly increased intraerythrocyte NPBI (2.73-fold), plasma NPBI (×
6.0), free F
2-IsoP (×
1.85), esterified F
2-IsoP (×
1.69), total F
2-IsoP (×
1.66), and protein carbonyl (×
4.76) concentrations were evident in RS subjects and associated with reduced (−
10.53%) arterial oxygen levels compared to controls. Biochemical evidence of oxidative stress was related to clinical phenotype severity and lower peripheral and arterial oxygen levels. Pulmonary
V/
Q mismatch was found in the majority of the RS population. These data identify hypoxia-induced oxidative stress as a key factor in the pathogenesis of classic RS and suggest new therapeutic approaches based on oxidative stress modulation.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Autism spectrum disorders</subject><subject>Autistic Disorder</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Disease Progression</subject><subject>Erythrocytes - metabolism</subject><subject>Erythrocytes - pathology</subject><subject>F2-Isoprostanes - metabolism</subject><subject>Female</subject><subject>Free radicals</subject><subject>Genetic Predisposition to Disease</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Intellectual Disability</subject><subject>Iron - metabolism</subject><subject>Isoprostanes</subject><subject>MeCP2</subject><subject>Methyl-CpG-Binding Protein 2 - genetics</subject><subject>Mutation</subject><subject>Oxidative Stress</subject><subject>Oxygen - metabolism</subject><subject>Pathogenesis</subject><subject>Protein Carbonylation</subject><subject>Rett syndrome</subject><subject>Rett Syndrome - genetics</subject><subject>Rett Syndrome - pathology</subject><subject>Rett Syndrome - physiopathology</subject><subject>Ventilation-Perfusion Ratio</subject><issn>0891-5849</issn><issn>1873-4596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkF1LwzAUhoMobk7_ghQEvWpNmq8Gr2TMDxgIflyHND2FjHadSTbcvzdjQ_BGvDoH3uecFx6ErgguCCbidlG0HsCbpnZDD01RYqwKzIuUHaExqSTNGVfiGI1xpUjOK6ZG6CyEBcaYcVqdohFRTDAq6BiVb9sQoXc2G75cY6LbQBaihxAyt8xsZ0JI2SvEmIXtsvGp8RydtKYLcHGYE_TxMHufPuXzl8fn6f08t4zQmDNMmCVtS4QkTNUMN0wRsFIZpjgHJtNamZZKDoKCNISWispWibKuoOSWTtDN_u_KD59rCFH3LljoOrOEYR20pJQKprBM5PWfZIlJRSVRCbzbg9YPIXho9cq73vitJljv5OqF_iVX7-RqzHXK0vXloWZd77Kf24PNBMz2ACQtGwdeB-tgaaFxHmzUzeD-VfQNUpqRRw</recordid><startdate>20090815</startdate><enddate>20090815</enddate><creator>De Felice, Claudio</creator><creator>Ciccoli, Lucia</creator><creator>Leoncini, Silvia</creator><creator>Signorini, Cinzia</creator><creator>Rossi, Marcello</creator><creator>Vannuccini, Laura</creator><creator>Guazzi, Gianni</creator><creator>Latini, Giuseppe</creator><creator>Comporti, Mario</creator><creator>Valacchi, Giuseppe</creator><creator>Hayek, Joussef</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20090815</creationdate><title>Systemic oxidative stress in classic Rett syndrome</title><author>De Felice, Claudio ; Ciccoli, Lucia ; Leoncini, Silvia ; Signorini, Cinzia ; Rossi, Marcello ; Vannuccini, Laura ; Guazzi, Gianni ; Latini, Giuseppe ; Comporti, Mario ; Valacchi, Giuseppe ; Hayek, Joussef</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-4014c1ff167149b40d491ec79a4955e47c798af375e63e7a132937f962b8e25c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Autism spectrum disorders</topic><topic>Autistic Disorder</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Disease Progression</topic><topic>Erythrocytes - metabolism</topic><topic>Erythrocytes - pathology</topic><topic>F2-Isoprostanes - metabolism</topic><topic>Female</topic><topic>Free radicals</topic><topic>Genetic Predisposition to Disease</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Intellectual Disability</topic><topic>Iron - metabolism</topic><topic>Isoprostanes</topic><topic>MeCP2</topic><topic>Methyl-CpG-Binding Protein 2 - genetics</topic><topic>Mutation</topic><topic>Oxidative Stress</topic><topic>Oxygen - metabolism</topic><topic>Pathogenesis</topic><topic>Protein Carbonylation</topic><topic>Rett syndrome</topic><topic>Rett Syndrome - genetics</topic><topic>Rett Syndrome - pathology</topic><topic>Rett Syndrome - physiopathology</topic><topic>Ventilation-Perfusion Ratio</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Felice, Claudio</creatorcontrib><creatorcontrib>Ciccoli, Lucia</creatorcontrib><creatorcontrib>Leoncini, Silvia</creatorcontrib><creatorcontrib>Signorini, Cinzia</creatorcontrib><creatorcontrib>Rossi, Marcello</creatorcontrib><creatorcontrib>Vannuccini, Laura</creatorcontrib><creatorcontrib>Guazzi, Gianni</creatorcontrib><creatorcontrib>Latini, Giuseppe</creatorcontrib><creatorcontrib>Comporti, Mario</creatorcontrib><creatorcontrib>Valacchi, Giuseppe</creatorcontrib><creatorcontrib>Hayek, Joussef</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Free radical biology & medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Felice, Claudio</au><au>Ciccoli, Lucia</au><au>Leoncini, Silvia</au><au>Signorini, Cinzia</au><au>Rossi, Marcello</au><au>Vannuccini, Laura</au><au>Guazzi, Gianni</au><au>Latini, Giuseppe</au><au>Comporti, Mario</au><au>Valacchi, Giuseppe</au><au>Hayek, Joussef</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Systemic oxidative stress in classic Rett syndrome</atitle><jtitle>Free radical biology & medicine</jtitle><addtitle>Free Radic Biol Med</addtitle><date>2009-08-15</date><risdate>2009</risdate><volume>47</volume><issue>4</issue><spage>440</spage><epage>448</epage><pages>440-448</pages><issn>0891-5849</issn><eissn>1873-4596</eissn><abstract>Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal
MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, is a leading cause of mental retardation with autistic features in females. However, its pathogenesis remains incompletely understood, and no effective therapy is available to date. We hypothesized that a systemic oxidative stress may play a key role in the pathogenesis of classic RS. Patients with classic RS (
n
=
59) and control subjects (
n
=
43) were evaluated. Oxidative stress markers included intraerythrocyte non-protein-bound iron (NPBI; i.e., free iron), plasma NPBI, F
2-isoprostanes (F
2-IsoPs, as free, esterified, and total forms), and protein carbonyls. Lung ventilation/perfusion (
V/
Q) ratio was assessed using a portable gas analyzer, and RS clinical severity was evaluated using standard scales. Significantly increased intraerythrocyte NPBI (2.73-fold), plasma NPBI (×
6.0), free F
2-IsoP (×
1.85), esterified F
2-IsoP (×
1.69), total F
2-IsoP (×
1.66), and protein carbonyl (×
4.76) concentrations were evident in RS subjects and associated with reduced (−
10.53%) arterial oxygen levels compared to controls. Biochemical evidence of oxidative stress was related to clinical phenotype severity and lower peripheral and arterial oxygen levels. Pulmonary
V/
Q mismatch was found in the majority of the RS population. These data identify hypoxia-induced oxidative stress as a key factor in the pathogenesis of classic RS and suggest new therapeutic approaches based on oxidative stress modulation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19464363</pmid><doi>10.1016/j.freeradbiomed.2009.05.016</doi><tpages>9</tpages></addata></record> |
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| subjects | Adolescent Adult Autism spectrum disorders Autistic Disorder Child Child, Preschool Disease Progression Erythrocytes - metabolism Erythrocytes - pathology F2-Isoprostanes - metabolism Female Free radicals Genetic Predisposition to Disease Humans Hypoxia Intellectual Disability Iron - metabolism Isoprostanes MeCP2 Methyl-CpG-Binding Protein 2 - genetics Mutation Oxidative Stress Oxygen - metabolism Pathogenesis Protein Carbonylation Rett syndrome Rett Syndrome - genetics Rett Syndrome - pathology Rett Syndrome - physiopathology Ventilation-Perfusion Ratio |
| title | Systemic oxidative stress in classic Rett syndrome |
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