|Year : 2015 | Volume
| Issue : 2 | Page : 113-119
Oxidative stress, thyroid dysfunction & Down syndrome
Carlos Campos, ┴ngela Casado
Department of Cellular & Molecular Medicine, Centre for Biological Research - Spanish National Research Council (CIB-CSIC), Madrid, Spain
|Date of Submission||17-Apr-2014|
|Date of Web Publication||3-Sep-2015|
Department of Cellular & Molecular Medicine, Centre for Biological Research, CSIC. C/ Ramiro de Maeztu, 9. E-28040 Madrid
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Down syndrome (DS) is one of the most common chromosomal disorders, occurring in one out of 700-1000 live births, and the most common cause of mental retardation. Thyroid dysfunction is the most typical endocrine abnormality in patients with DS. It is well known that thyroid dysfunction is highly prevalent in children and adults with DS and that both hypothyroidism and hyperthyroidism are more common in patients with DS than in the general population. Increasing evidence has shown that DS individuals are under unusual increased oxidative stress, which may be involved in the higher prevalence and severity of a number of pathologies associated with the syndrome, as well as the accelerated ageing observed in these individuals. The gene for Cu/Zn superoxide dismutase (SOD1) is coded on chromosome 21 and it is overexpressed (~50%) resulting in an increase of reactive oxygen species (ROS) due to overproduction of hydrogen peroxide (H 2 O 2 ). ROS leads to oxidative damage of DNA, proteins and lipids, therefore, oxidative stress may play an important role in the pathogenesis of DS.
Keywords: Down syndrome - oxidative stress - reactive oxygen species - thyroid dysfunction
|How to cite this article:|
Campos C, Casado ┴. Oxidative stress, thyroid dysfunction & Down syndrome. Indian J Med Res 2015;142:113-9
Down syndrome (DS) or trisomy 21 is one of the most important human congenital diseases. The syndrome is associated with mental retardation, congenital heart disease, immune system disorders, digestive problems, endocrine system deficits and different biochemical disorders. It could be speculated that the chromosome abnormality led to impaired formation of the thyroid and other organs  . The association of DS with thyroid disorders has been known for decades. Thyroid dysfunction is highly prevalent in DS ,,, . Patients with DS have an increased prevalence of autoimmune disorders affecting both endocrine and non-endocrine organs  . Thyroid disorders have been reported to have a prevalence rate of 3-54 per cent in individuals with DS and these increase in frequency with increasing age of the individual  . Another risk factor is the female sex  . It has been suggested that individuals with DS are under unusual oxidative stress, which has been proposed to be caused by an excess of Cu/Zn superoxide dismutase (SOD1) activity, an enzyme coded on HSA21 (21q22.1) ,,,, . SOD1 enhances the production of hydrogen peroxide (H 2 O 2 ), an important precursor of hydroxyl radical, being one of the at least 16 genes or predicted genes on HSA21 with a role in mitochondrial energy generation and reactive oxygen species (ROS) metabolism  . H 2 O 2 is then neutralized to water and oxygen through the actions of either glutathione peroxidase (GPx) and/or catalase (CAT). Hence, the increased ratio of SOD1 to catalase plus glutathione peroxidase can lead to increased oxidative stress in DS  . The aim of this article was to critically review the scientific literature concerning the link between oxidative stress and thyroid dysfunction in Down syndrome.
DS or trisomy 21 is known to occur in one out of 700-1000 live births  . Clinical symptoms were first described by John Langdon Down in 1866  , but the association with one extra copy of chromosome 21 was first reported by Lejeune et al . Trisomy 21 is now accepted to be the major cause of DS, accounting about 90-95 per cent of cases. The other 5-10 per cent are caused by other genetic abnormalities including chromosomal translocations (2 to 6%) and mosaicism (2 to 4%) , .
DS patients present different morphological characteristics such as short height, obesity and bilateral epicanthic eyefolds. Furthermore, muscular hypotonia may be noted during life  . The syndrome is associated with mental retardation, congenital heart disease, immune system disorders, digestive problems, endocrine system deficits and different biochemical disorders , . The clinical manifestations of hypothyroidism are so non-specific that it may be attributed to the DS itself. Thyroid hormones are necessary with respect to brain development, and therefore, thyroid disorders should be detected immediately  . Besides, DS patients have an increased risk of leukaemia and Alzheimer's
disease ,,, .
The extra copy of chromosome 21 (HSA21) or part of it, affecting more than 300 genes, is associated with a variety of manifestations, including pathologies which are possibly related to ageing such as Alzheimer's disease, visual impairment, senile cataracts, leukaemia, diabetes mellitus, hypogonadism, vascular disease, amyloidosis and premature graying or loss of hair, and skin changes ,, . Besides, there is evidence of accelerated ageing in individuals with DS, this disorder being considered as a progeroid syndrome  , and it has been postulated that it may be the result of an increased oxidative stress. The prevalence of clinical disorders in individuals with DS is higher than in the general population, and has a negative impact on their quality of life and life expectancy ,, .
There is well-established evidence from in vivo, in vitro studies and animal models that oxidative stress is involved in DS. Thus, it has been proposed that the increased oxidative stress observed in these subjects is mainly caused to an excessive activity of SOD1, an enzyme coded on HSA21 (21q22.1)  . Besides, several abnormalities in mitochondrial function have been found in DS and also in mouse models of this pathology , . In addition to SOD1, there are several genes or predicted genes on HSA21 with a role in mitochondrial energy generation and ROS metabolism , .
A free radical is any species capable of independent existence, containing one or more unpaired electrons  , the most important ones being those derived from either oxygen and/or nitrogen. Both the radicals and the non-radical species generated via interaction with free radicals, are referred to as reactive oxygen/nitrogen species (RONS)  . RONS, formed in the human body in the cytosol, mitochondria, lysosomes, peroxisomes and plasma membranes under both physiological and pathological conditions  , are highly reactive and extremely short-lived agents mainly generated as by-products of aerobic metabolism, playing a dual role as both deleterious and beneficial species. When the generation of RONS exceeds the ability of antioxidant defence systems to remove them, an imbalance between RONS formation and antioxidant defence can cause oxidative/nitrosative damage to cellular constituents (DNA, proteins, lipids and sugars), which is defined as oxidative/nitrosative stress , . Thus, the degree of balance between ROS or reactive nitrogen species (RNS) determines the degree of oxidative or nitrosative stress, respectively. When the system becomes unbalanced (free radicals > antioxidant defences) a change in the intracellular redox balance towards a more oxidizing environment, may result in direct DNA damage (DNA mutations), changes in the structure and function of proteins, and peroxidative damage to cell membrane lipids with the possibility to cause illness and disease. Though an excess leads to oxidative/nitrosative stress, RONS are also involved in several important biological processes, including cell signalling, redox regulation of gene transcription, cellular immunity and apoptosis, being essential for normal physiological function  .
Oxidative stress is a process induced by endogenous as well as exogenous factors. Endogenous factors include normal physiological processes, such as oxidative phosphorylation or cytochrome P450 metabolism. Several environmental factors, including smoking, diet or exposure to ambient air pollution, represent exogenous sources of RONS  . Increasing evidence suggests that oxidative stress is linked to the primary or secondary pathophysiologic mechanisms of multiple human diseases, including DS , .
The biological effects of these highly reactive compounds are controlled in vivo by a wide spectrum of antioxidative defence mechanisms such as vitamins E and C, carotenoids, metabolites such as uric acid or glutathione and antioxidant enzymes. Cells have developed an enzymatic antioxidant pathway against free radicals and ROS which are generated during oxidative metabolism: firstly, SOD1 catalyzes the formation of hydrogen peroxide from superoxide radicals  . An excess of the enzyme SOD1 activity has been considered to be responsible for the increased oxidative stress found in this condition. The gene encoding SOD1 is located on HSA21, so DS individuals are trisomic for SOD1. SOD1 is overexpressed in about 50 per cent of these individuals , . This enzyme plays a key role in the metabolism of ROS, being part of the first line of antioxidant defence by catalyzing the dismutation of superoxide radical (O-2, mainly generated by oxidative metabolism, into oxygen plus H 2 O 2 . SOD1 is the major cytoplasmic superoxide scavenger, also located in the intermembrane space of the mitochondria  .
Hydrogen peroxide can generate toxic hydroxyl radicals, but it is removed by a reaction catalyzed by CAT and GPx  . Glutathione reductase (GR) is a flavoprotein catalyzing the NADPH-dependent reduction of glutathione disulphide (GSSG) to glutathione (GSH), which is essential for the maintenance of glutathione levels. Any increase in SOD catalytic activity produces an excess of hydrogen peroxide that must be efficiently neutralized by CAT or GPx. The activity of the first and second step antioxidant enzymes must, therefore, be balanced to prevent oxidative damage in cells, which may contribute to various pathological processes  .
The trace element selenium (Se) is capable of exerting multiple actions on endocrine systems by modifying the expression of at least 30 selenoproteins, many of which have clearly defined functions. Well-characterized selenoenzymes are the families of glutathione peroxidases (GPx), thioredoxin reductases (TRs) and iodothyronine deiodinases (Ds). These selenoenzymes are capable of modifying cell function by acting as antioxidants and modifying redox status and thyroid hormone metabolism  . Se is also involved in cell growth, apoptosis and modifying the action of cell signaling systems and transcription factors. During thyroid hormone synthesis GPx1, GPx3 and TR1 are upregulated, providing the thyrocytes with considerable protection from peroxidative damage  .
The thyroid contains more Se per gram of tissue than any other organ  and Se, like iodine, is essential for normal thyroid function and thyroid hormone homeostasis. Synthesis of thyroid hormone requires iodination of tyrosyl residues on thyroglobulin which is stored in the lumen of the thyroid follicle. This iodination is catalyzed by thyroid peroxidase (TPO) and requires the generation of high H 2 O 2 concentrations which are potentially harmful to the thyrocyte  .
The thyrocyte is continually exposed to potentially toxic concentrations of H 2 O 2 and lipid hydroperoxides. The cytotoxic effects of H 2 O 2 on thyroid cells include caspase-3-dependent apoptosis that occurs at H 2 O 2 concentrations that are insufficient to induce necrosis. In Se deficiency the apoptotic response to H 2 O 2 is increased  . When Se intake is adequate, the intracellular GPx and TR systems protect the thyrocyte from these peroxides.
Oxidative damage can be monitored by the determination of different oxidative stress biomarkers. Several studies have shown higher levels of protein carbonyls, malondialdehyde, allantoin or 8-hydroxydeoxyguanosine in DS than in normal population ,,, .
Thyroid hormones (THs) are associated with oxidative stress and antioxidant status due to their capacity to accelerate the basal metabolism and change respiratory rate in mitochondria  . However, THs are related to oxidative stress not only by their stimulation of metabolism but also by their effects on antioxidant mechanisms  . These regulate proteins, vitamins and antioxidant enzymes synthesis and degradation  as well as oxygen consumption and mitochondria energy metabolism, playing an important role in free radical production  . It has been suggested that variations of thyroid hormones levels can be one of the main physiological modulators of in vivo cellular oxidative stress  . Thyroid dysfunction is the most frequent endocrine abnormality in subjects with DS, with a prevalence varying between 0 and 66 per cent, depending on variations in population size, age, laboratory assays or definitions of thyroid dysfunction used, the more common rates being >20 per cent  . Hypothyroidism is the most frequent thyroid abnormality in DS , . It can be either congenital, with an incidence in infants with DS of 1:141 live births  compared with an incidence ranging between 1:2,500 and <1:5,000 among newborns without DS  ,
or acquired at any age after birth. Claret et al have observed that the hypothyroidism characteristic of early infancy in DS usually presents as a subclinical disorder. The distribution of the disorder in this initial stage is similar between sexes, which contrasts with that found in the population without DS, where the hypothyroidism is clearly predominant in the female sex  . However, more evidence is required regarding the optimal course of treatment for subclinical hypothyroidism  . Hyperthyroidism is also more prevalent among people with DS than in the general population, though the gap is smaller , .
The available data concerning oxidative stress in both hypothyroidism and hyperthyroidism are scarce and controversial. In hypothyroidism, a low free radical generation is expected because of the metabolic suppression brought about by the decrease in thyroid hormone levels  . However, there are some studies reporting an increased oxidative stress in patients with hyperthyroidism as well as with hypothyroidism ,,,, , even in subclinical hypothyroid states. In addition, thyroid hormone (T3 ) has been shown to downregulate the expression of SOD1 and, conversely, progressive hypothyroidism leads to an increase in SOD1 activity in the brain of rats  .
Only a few investigations have been conducted addressing the link between thyroid dysfunction and oxidative stress in DS, all of these in hypothyroid subjects. Kanavin et al were the first studying the link between oxidative stress and thyroid dysfunction in DS, suggesting that hypothyroidism is linked to decreased levels of selenium in DS subjects. Oxidative and nitrosative stress have been assessed in hypothyroid DS subjects receiving levothyroxine for treatment of hypothyroidism by measuring a set of urinary biomarkers: 8-hydroxy-2'-deoxyguanosine (8-OHdG), isoprostane 15-F2t-IsoP, thiobarbituric acid-reacting substances (TBARS), advanced glycation end-products (AGEs), dityrosine (diTyr), hydrogen peroxide and total nitrite and nitrate (NOx), in children  and in adolescents and adults  . In these studies, significantly higher levels of diTyr in children with DS receiving levothyroxine for hypothyroidism have been found compared to their healthy siblings. Besides, subjects with DS receiving levothyroxine showed increased levels of diTyr in the early adulthood (from 15 to 19 yr) and increased levels of diTyr, AGEs and TBARS in the adulthood (from 20 to 40 yr) than in those without hypothyroidism. Both hypothyroid and hyperthyroid patients are characterized by higher levels of low density lipoprotein (LDL) oxidation when compared with healthy normolipidemic control subjects  , which may explain the increased levels of urinary TBARS. In hyperthyroid patients increased lipid peroxidation was strictly related to free thyroxine levels, while in hypothyroidism it was strongly influenced by serum lipids  . Therefore, lipid composition must be studied in hypothyroid DS subjects before any conclusion can be reached.
Decreased urinary levels of creatinine (Cr) were observed in DS children receiving levothyroxine compared to their non-DS healthy siblings , . Besides, lower levels of urinary Cr have been found in the early adulthood (from 15 to 19 yr) of DS subjects receiving levothyroxine compared with DS subject without diagnosed hypothyroidism  . Hence, renal impairment due to hypothyroidism may bias the results in these patients as has been suggested by the authors  . It is well known that levels of Cr are influenced by thyroid hormones. Hypothyroidism enhances serum Cr levels because it reduces the glomerular filtration rate and increases production of Cr  . Impaired renal function has been reported in subjects with hypothyroidism  . It has also been reported that non-DS children with congenital hypothyroidism have an increased prevalence of congenital renal and urologic anomalies  , and renal impairment has also been described in DS based on decreased Cr clearance , .
Reduced Cr clearance in non-DS patients with hypothyroidism had been reported, but normal values were obtained when they were treated with thyroid hormones  . However, the same has not been found in DS , , suggesting that factors contributing to the aetiology of hypothyroidism may be different in DS than in non-DS individuals.
Some abnormalities reported in DS may influence the thyroid function: (i) decreased levels of selenium  , which is required for thyroid hormone synthesis and metabolism, acts as an antioxidant protecting the thyrocyte against peroxides and is part of selenium-dependent antioxidant enzymes (e.g. GPx and thioredoxin reductase), (ii) an impairment in the activity of phenylalanine hydroxylase  , which converts the phenylalanine in tyrosine, and (iii) overexpression of DYRK1A kinase  , which could reduce availability of tyrosine. These factors may lead to several anomalies related to thyroid disorders, even in DS subjects with "normal" thyroid hormones levels. However, further investigation is required to ascertain the mechanisms underlying these findings. On the other hand, signs and symptoms of hypothyroidism can be difficult to discriminate from those found in the natural course of DS itself. These are overlapped to some extent in both DS and hypothyroidism (e.g. hypotonia, lethargy, mental retardation, growth failure, prolonged neonatal jaundice, delayed closure of fontanelles, macroglossia, obesity, etc.)  . Although it has been reported that mild plasma thyroid stimulating hormone (TSH) elevation is prevalent in DS: 80-90 per cent in early infancy and 30-50 per cent thereafter  , untreated subclinical hypothyroidism is present in DS at birth and persists throughout life  . In summary, more studies linking thyroid disorders and oxidative stress in DS are clearly needed.
| Conclusions|| |
Thyroid dysfunction is the most frequent endocrine abnormality in patients with DS. There are studies reporting an increased oxidative stress in patients with hyperthyroidism as well as with hypothyroidism, even in subclinical hypothyroid state. In addition, thyroid hormone (T3 ) has been shown to downregulate the expression of SOD1. Some abnormalities reported in DS may influence the thyroid function: viz. decreased levels of selenium, impairment in the activity of phenylalanine hydroxylase, and overexpression of DYRK1A kinase. However, many aspects that are crucial for the health and well-being of people with this condition remain to be elucidated and require further research.
| Acknowledgment|| |
The authors thank María Burgos for English correction of the manuscript, and Nieves Fonturbel for her help with bibliographic compilation.This study was supported in part by FundaciÓn Inocente, Inocente, Madrid, Spain.
| References|| |
Gruñeiro de Papendieck L, Chiesa A, Bastida MG, Alonso G, Finkielstain G, Heinrich, JJ. Thyroid dysfunction and high thyroid stimulating hormone levels in children with Down's syndrome. J Pediatr Endocrinol Metabol
Fort P, Lifshitz F, Bellisario R, Davis J, Lanes R, Pugliese M, et al
. Abnormalities of thyroid function in infants with Down syndrome. J Pediatr
Karlsson B, Gustafsson J, Hedov G, Ivarsson S, Anneren G. Thyroid dysfunction in Down syndrome: related to age and thyroid autoimmunity. Arch Dis Child
Tuysuz B, Beker DB. Thyroid dysfunction in children with Down's syndrome. Acta Paediatr
Kennedy RL, Jonest TH, Cukle HS. Down's syndrome and the thyroid. Clin Endocrinol
(Oxf) 1992; 37
Waller DK, Anderson JL, Lorey F, Cunningham GC. Risk factors for congenital hypothyroidism: an investigation of infant's birth weight, ethnicity, and gender in California, 1990-1998. Teratology
Sinet PM, Couturier J, Dutrillaux B, Poissonnier M, Raoul O, Rethoré MO, et al
. Trysomy 21 and superoxide dismutase 1 (IPO-A). Tentative of location in 21q221 bande. Exp Cell Res
Sherman L, Dafni N, Lieman-Hurwitz J, Groner Y. Nucleotide sequence and expression of human chromosome 21-encoded superoxide dismutase mRNA. Proc Natl Acad Sci USA
De la Torre MR, Casado A, López-Fernández ME, Carrascosa D, Ramírez MV, Sáez J. Overexpression of copper-zinc superoxide dismutase in trisomy 21. Experientia
Roizen N, Patterson D. Down's syndrome. Lancet
Gardiner KJ. Molecular basis of pharmacotherapies for cognition in Down syndrome. Trends Pharmacol Sci
Jovanovic SV, Clements D, MacLeod K. Biomarkers of oxidative stress are significantly elevated in Down syndrome. Free Rad Biol Med
Hook EB. Down´s syndrome-frequency in human populations and factors pertinent to variation in rates. In: de la Cruz FF, Gerald PS, editors. Trisomy 21 (Down´s Syndrome): Research perspectives
. Baltimore: University Park Press; 1981. p. 3-68.
Langdon-Down J. Observations on an ethnic classification of idiots. London Hosp Clin Lect Reports
Lejeune J, Gautier M, Turpin R. Study of somatic choromosomes in 9 Down syndrome children. Comptes rend Acad Sci Paris
Mikkelsen M. Down syndrome: cytogenetical epidemiology. Hereditas
Tolksdorf M, Wiedemann HR. Clinical aspects of Down's syndrome from infancy to adult life. Hum Genet
(Suppl) : 3-31.
Carroll KN, Arbogast PG, Dudley JA, Cooper WO. Increase in incidence of medically treated thyroid disease in children with Down syndrome after re-release of American Academy of Pediatrics Health Supervision Guidelines. Pediatrics
Murphy J, Hoey HM, Philip M, Roche EF, Macken S, Mayne P, et al
. Guidelines for the medical management of Irish children and adolescent with Down syndrome. Irish Med J
Sarici D, Akin MA, Kurtoglu S, Gunes T, Ozturk MA, Akcakus M. Thyroid functions of neonates with Down síndrome. Ital J Pediatr
2012; 38 :
Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet
Bruwier A, Chantrain CF. Hematological disorders and leukemia in children with Down syndrome. Eur J Pediatr
Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk. Mental Retard Develop Disabilit Res Reviews
Strydom A, Chan T, King M, Hassiotis A, Livingston G. Incidence of dementia in older adults with intellectual disabilities. Res Dev Disabil
Pueschel SM. Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Gen
(Suppl) : 52-6.
Puri BK, Singh I. Prevalence of cataract in adult Down's syndrome patients aged 28 to 83 years. Clin Pract Epidemiol Ment Health
Bokov A, Chaudhuri A, Richardson A. The role of oxidative damage and stress in aging. Mech Ageing Dev
Martin GM. Genetic syndrome in man with potential relevance to the pathology of aging. In: Bergsma D, Harrison DE, editors. Genetic effects on aging
. New York, USA: Liss; 1978. p. 3-39.
Claret C, Corretger JM, Goday A. Hypothyroidism and Down's syndrome. Rev Med Int Sindr Down
Salmon AB, Richardson A, Páez VI. Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med
Pallardó FV, Degan P, d'Ischia M, Kelly FJ, Zatterale A, Calzone R, et al
. Multiple evidence for an early age pro-oxidant state in Down Syndrome patients. Biogerontology
Casado A, López-Fernández ME, Ruiz R. Oxidative stress markers in Down síndrome. Rev Med Inter Syndr Down
Schuchmann S, Heinemann U. Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: a model of Down's syndrome. Free Radic Biol Med
Ishihara K, Amano K, Takaki E, Ebrahim AS, Shimohata A, Shibazaki N, et al.
Increased lipid peroxidation in Down's syndrome mouse models. J Neurochem
Pagano G, Talamanca AA, Castello G, Cordero MD, d'Ischia M, Gadaleta MN, et al
. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: Toward mitochondria-targeted clinical strategies. Oxid Med Cell Longev
Pallardó FV, Lloret A, Lebel M, d'Ischia M, Cogger VC, Le Couteur DG, et al
. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down syndrome, Fanconi anaemia and Werner syndrome. Biogerontology
Halliwell B, Gutteridge JMC. Oxidative stress. In: Halliwell B. Gutteridge JMC, editors. Free radicals in biology and medicine
, 4 [th]
ed. New York, USA: Oxford University Press Inc. 2007. p. 888.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol
Hemnani T, Parihar MS. Reactive oxygen species and oxidative DNA damage. Indian J Physiol Pharmacol
Sies H. Oxidative stress: from basis research to clinical application. Am J Med
Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A. Biomarkers of oxidative damage in human disese. Clin Chem
Campos C, Guzmán R, López-Fernández E, Casado A. Urinary biomarkers of oxidative/nitrosative stress in healthy smokers. Inhalation Toxicology
Garaiová I, Muchová J, Sustrová M, Blazicek P, Sivonová M, Kvasnicka P, et al
. The relationship between antioxidant systems and some markers of oxidative stress in persons with Down syndrom. Biologia
De Haan JB, Wolvetang EJ, Cristiano F, Iannello R, Bladier C, Kelner MJ, et al
. Reactive oxygen species and their contribution to pathology in Down síndrome. Adv Pharmacol
Casado A, Castellanos A, López-Fernández ME, García-Aroca C, Noriega F. Relationship between oxidative and occupational stress and aging in nurses of an intensive care unit. Age
Anneren G, Edman B. Down syndrome - a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide-dismutase type 1 (SOD-1) gene. Acta Pathol Microbiol Immunolog Scandinavica (APMIS)
Liochev SI, Fridovich I. Mechanism of the peroxidase activity of Cu, Zn superoxide dismutase. Free Rad Biol Med
Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver. Cu, Zn-SOD in mitochondria. J Biol Chem
Michel C, Raes M, Toussaint O, Remacle J. Importance of Se-glutathione peroxidase, catalase and Cu/Zn SOD for cell survival against oxidative stress. Free Rad Biol Med
Sun AY, Chen YM. Oxidative stress and neurodegenerative disorders. J Biomed Sci
Beckett GJ, Arthur JR. Selenium and endocrine systems. J Endocrinol
Dickson RC, Tomlinson RH. Selenium in blood and human tissues. Clin Chim Acta
Demelash A, Karlsson JO, Nilsson M, Bjorkman U. Selenium has a protective role in caspase-3- dependent apoptosis induced by H 2
in primary cultured pig thyrocytes. Eur J Endocrinol
Zitnanová I, Korytár P, Sobotová H, Horáková L, Sustrová M, Pueschel S, et al
. Markers of oxidative stress in children with Down syndrome. Clin Chem Lab Med
Garcez ME, Peres W, Salvador M. Oxidative stress and hematologic and biochemical parameters in individuals with Down syndrome. Mayo Clinic Proc
Casado A, López-Fernández ME, Ruiz R. Lipid peroxidation in Down syndrome caused by regular trisomy 21, trisomy 21 by Robertsonian translocation and mosaic trisomy 21. Clin Chem Lab Med
Villanueva I, Alva-Sánchez C, Pacheco-Rosado J. The role of thyroid hormones as inductor of oxidative stress and neurodegeneration. Oxid Med Cell Longev
Pereira B, Rosa LF, Safi DA, Bechara EJ, Curi R. Control of superoxide dismutase, catalase and glutathione peroxidase activities in rat lymphoid organs by thyroid hormones. J Endocrinol
Torun AN, Kulaksizoglu S, Kulaksizoglu M, Pamuk BO, Isbilen E, Tutuncu NB. Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clin Endocrinol (Oxf)
Guerrero A, Pamplona R, Portero-Otin M, Barja G, Lopez-Torres M. Effect of thyroid status on lipid composition and peroxidation in the mouse liver. Free Rad Biol Med
Prasher VP. Prevalence of thyroid dysfunction and autoimmunity in adults with Down syndrome. Down Syndrom Res Practic
Murdoch JC, Ratcliffe WA, McLarty DG, Rodger JC, Ratcliffe JG. Thyroid function in adults with Down´s syndrome. J Clin Endocrinol
Medda E, Olivieri A, Stazi MA, Grandolfo ME, Fazzini C, Baserga M, et al
. Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003). Eur J Endocrinol Metab
King K, O'Gorman C, Gallagher S. Thyroid dysfunction in children with Down syndrome: a literature review. Ir J Med Sci
Loudon MM, Day RA, Duke MC. Thyroid dysfunction in Down's syndrome. Arch Dis Child
Erdamar H, Demirci H, Yaman H, Erbil MK, Yakar T, Sancak B, et al
. The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clin Chem Lab Med
Dumitriu L, Bartoc R, Ursu H, Purice M, Ionescu V. Significance of high levels of serum malonyl dialdehyde (MDA) and ceruloplasmin (CP) in hyper- and hypothyroidism. Endocrinologie
Costantini F, Pierdomenico SD, De Cesare D, De Remigis P, Bucciarelli T, Bittolo-Bon G, et al
. Effect of thyroid function on LDL oxidation. Arterioscler Thromb Vas Biol
Yilmaz S, Ozan S, Benzer F, Canatan H. Oxidative damage and antioxidant enzyme activities in experimental hypothyroidism. Cell Biochem Funct
Sarandöl E, Taº S, Dirican M, Serdar Z. Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: effect of vitamin E supplementation. Cell Biochem Funct
Santos GM, Afonso V, Barra B, Togashi M, Webb P, Neves FA, et al
. Negative regulation of superoxide dismutase-1 promoter by thyroid hormone. Mol Pharmacol
Kanavin ØJ, Aaseth J, Birketvedt GS. Thyroid hypofunction in Down's syndrome. Is it related to oxidative stress? Biol Trace Elem Res
Campos C, Guzmán R, López-Fernández E, Casado A. Evaluation of urinary biomarkers of oxidative/nitrosative stress in children with Down syndrome. Life Sci
Campos C, Guzmán R, López-Fernández E, Casado A. Evaluation of urinary biomarkers of oxidative/nitrosative stress in adolescents and adults with Down syndrome. Biochim Biophys Acta
Guzman R, Campos C, López-Fernández E, Casado A. Biomarkers of age effect on renal function in Down syndrome. Biomarkers
Lafayette RA, Costa ME, King AJ. Increased serum creatinine in the absence of renal failure in profound hypothyroidism. Am J Med
Montenegro J, González O, Saracho R, Aguirre R, González O, Martínez I. Changes in renal function in primary hypothyroidism. Am J Kidney Dis
Kumar J, Gordillo R, Kaskel FJ, Druschel CM, Woroniecki RP. Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism. J Pediatr
Coburn SP, Seidenberg M, Mertz ET. Clearance of uric acid, urea, and creatinine in Down's syndrome. J Appl Physiol
Nishida Y, Akaoka I, Kobayashi M, Maruki K, Oshima Y. Renal impairment in urate excretion in patients with Down´s syndrome. J Rheumatol
Nève J, Sinet PM, Molle L, Nicole A. Selenium, zinc and copper in Down's syndrome (trisomy 21): blood levels and relations with glutathione peroxidase and superoxide dismutase. Clin Chim Acta
Shaposhnikov AM, Khal'chitskiĭ SE, Shvarts EI. Disorders of phenylalanine and tyrosine metabolism in Down's syndrome. Voprosy medit-sinskoĭ khimii Soviet Union Ministerstvo zdravookhraneni (Vopr Med Khim)
Dowjat WK, Adayev T, Kuchna I, Nowicki K, Palminiello S, Hwang YW, et al
. Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome. Neurosci Lett
Shaw CK, Thapalial A, Nanda S, Shaw P. Thyroid dysfunction in Down syndrome. KUMJ
van Trotsenburg AS, Vulsma T, van Rozenburg-Marres SL, van Baar AL, Ridder JC, Heymans HS, et al
. The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial. J Clin Endocrinol Metabol
Prasher V, Haque MS. Misdiagnosis of thyroid disorders in Down syndrome: time to re-examine the myth? Am J Ment Retard
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| ||Sepideh Safayee,Narges Karbalaei,Ali Noorafshan,Elham Nadimi |
| ||European Journal of Pharmacology. 2016; 791: 147 |
|[Pubmed] | [DOI]|
||Down syndrome: from the age of characterization to the era of curative approach
| ||Bani Bandana Ganguly,Nitin N. Kadam |
| ||The Nucleus. 2016; |
|[Pubmed] | [DOI]|
||Synthetic combinations of missense polymorphic genetic changes underlying Down syndrome susceptibility
| ||Rebecca A. Jackson,Mai Linh Nguyen,Angela N. Barrett,Yuan Yee Tan,Mahesh A. Choolani,Ee Sin Chen |
| ||Cellular and Molecular Life Sciences. 2016; |
|[Pubmed] | [DOI]|
||NNTmutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects
| ||Florence Roucher-Boulez,Delphine Mallet-Motak,Dinane Samara-Boustani,Houweyda Jilani,Asmahane Ladjouze,Pierre-Franšois Souchon,Dominique Simon,Sylvie Nivot,Claudine Heinrichs,Maryline Ronze,Xavier Bertagna,Laure Groisne,Bruno Leheup,Catherine Naud-Saudreau,Gilles Blondin,Christine Lefevre,Laetitia Lemarchand,Yves Morel |
| ||European Journal of Endocrinology. 2016; 175(1): 73 |
|[Pubmed] | [DOI]|