title: Oxidative and nitrative stress and pro-inflammatory cytokines in Mucopolysaccharidosis type II patients: effect of long-term enzyme replacement therapy and relation with glycosaminoglycan accumulation.
abstract: Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a deficient activity of iduronate-2-sulfatase, leading to abnormal accumulation of glycosaminoglycans (GAG). The main treatment for MPS II is enzyme replacement therapy (ERT). Previous studies described potential benefits of six months of ERT against oxidative stress in patients. Thus, the aim of this study was to investigate oxidative, nitrative and inflammatory biomarkers in MPS II patients submitted to long term ERT. It were analyzed urine and blood samples from patients on ERT (mean time: 5.2years) and healthy controls. Patients presented increased levels of lipid peroxidation, assessed by urinary 15-F2t-isoprostane and plasmatic thiobarbituric acid-reactive substances. Concerning to protein damage, urinary di-tyrosine (di-Tyr) was increased in patients; however, sulfhydryl and carbonyl groups in plasma were not altered. It were also verified increased levels of urinary nitrate+nitrite and plasmatic nitric oxide (NO) in MPS II patients. Pro-inflammatory cytokines IL-1β and TNF-α were increased in treated patients. GAG levels were correlated to di-Tyr and nitrate+nitrite. Furthermore, IL-1β was positively correlated with TNF-α and NO. Contrastingly, we did not observed alterations in erythrocyte superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, in reduced glutathione content and in the plasmatic antioxidant capacity. Although some parameters were still altered in MPS II patients, these results may suggest a protective role of long-term ERT against oxidative stress, especially upon oxidative damage to protein and enzymatic and non-enzymatic defenses. Moreover, the redox imbalance observed in treated patients seems to be GAG- and pro-inflammatory cytokine-related.
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRGS, Av. Ipiranga, 2752, CEP 90610-000 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: carloseduardo.jacques@hotmail.com.
authors.forename: Carlos Eduardo Diaz
authors.initials: CE
authors.lastname: Jacques
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, R. Ramiro Barcelos, 2600, CEP 90035-003 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: donida.bruna@gmail.com.
authors.forename: Bruna
authors.initials: B
authors.lastname: Donida
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: carolmescka@yahoo.com.br.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Mescka
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRGS, Av. Ipiranga, 2752, CEP 90610-000 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: daianegbr@hotmail.com.
authors.forename: Daiane G B
authors.initials: DG
authors.lastname: Rodrigues
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, R. Ramiro Barcelos, 2600, CEP 90035-003 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: desireepmarchetti@gmail.com.
authors.forename: Desirèe P
authors.initials: DP
authors.lastname: Marchetti
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular, Instituto de Biociências, UFRGS, Av. Bento Gonçalves, 9500, CEP 90650-001 Porto Alegre, RS, Brazil. Electronic address: nandahbitencourt@gmail.com.
authors.forename: Fernanda H
authors.initials: FH
authors.lastname: Bitencourt
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: mburin@hcpa.edu.br.
authors.forename: Maira G
authors.initials: MG
authors.lastname: Burin
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: cfsouza@hcpa.edu.br.
authors.forename: Carolina F M
authors.initials: CF
authors.lastname: de Souza
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular, Instituto de Biociências, UFRGS, Av. Bento Gonçalves, 9500, CEP 90650-001 Porto Alegre, RS, Brazil. Electronic address: rgiugliani@hcpa.edu.br.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRGS, Av. Ipiranga, 2752, CEP 90610-000 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, R. Ramiro Barcelos, 2600, CEP 90035-003 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: crvargas@hcpa.edu.br.
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D016207:Cytokines / Q000378:metabolism*; D056947:Enzyme Replacement Therapy; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007066:Iduronate Sulfatase / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D016532:Mucopolysaccharidosis II / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D000073039:Nitrosative Stress / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D006025:Glycosaminoglycans; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007066:Iduronate Sulfatase; C517982:idursulfase
keywords: Enzyme replacement therapy; Mucopolysaccharidosis type II; Oxidative stress; Pro-inflammatory cytokines; Reactive nitrogen species; Reactive oxygen species