An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations
Abstract
:1. Introduction
2. Materials and Methods
3. Overview of ROS
- Superoxide anion (O2•−): a free radical formed by the one-electron reduction of oxygen [29].
- Hydrogen peroxide (H2O2): a non-radical ROS that can diffuse through membranes and act as a signaling molecule [30].
- Hydroxyl radical (•OH): an extremely reactive free radical generated from H2O2 via the Fenton reaction [31].
- Singlet oxygen (1O2): a highly reactive non-radical form of oxygen produced by energy transfer to molecular oxygen [32].
- Peroxynitrite (ONOO−): formed by the reaction of nitric oxide (NO) with superoxide; it is classified as a reactive nitrogen species but often grouped with ROS [33].
- Host defense: ROS generated by phagocytes (via NOX enzymes) are crucial for destroying pathogens. This process, known as the respiratory burst, produces O2•−, which is converted into bactericidal species such as hypochlorous acid (HOCl) [37].
- Redox homeostasis: they regulate the expression of antioxidant genes through redox-sensitive transcription factors like nuclear factor erythroid 2-related factor 2 [38].
- Cellular adaptation to stress: moderate ROS levels activate stress response pathways, such as heat shock proteins and autophagy, promoting cell survival [39].
3.1. Generation Reactions
- NOX: these enzymes catalyze the transfer of electrons from NADPH to molecular oxygen, forming O2•− [41].
- Xanthine oxidase: produces O2•− and H2O2 during purine metabolism [42].
- Cytochrome P450 enzymes: generate O2•− as a byproduct during detoxification reactions [43].
- Electron leakage from the mitochondrial electron transport chain during oxidative phosphorylation can reduce oxygen to O2•− [44].
3.2. Conversion Reactions
- Superoxide dismutase (SOD) converts O2•− into H2O2: 2O2•− + 2H+ → H2O2 + O2 [47].
- Fenton reaction: H2O2 reacts with transition metals (e.g., Fe2+), producing •OH: H2O2 + Fe2+ → •OH + OH− + Fe3+ [48].
- Haber-Weiss reaction: the reaction between O2•− and H2O2 to produce •OH, which occurs in the presence of metal ions, particularly iron (Fe2+ or Fe3+): O2•− + H2O2 → •OH + OH− + O2 [49].
3.3. Interactions with Biological Molecules
- Lipid peroxidation: lipid radicals and malondialdehyde (MDA) are generated, disrupting membrane integrity [51].
- Protein oxidation: oxidation of amino acids, such as cysteine and methionine, can modify enzyme activity and signaling pathways [52].
- DNA damage: ROS can induce strand breaks and base modifications, such as the conversion of guanine to 8-oxoguanine, contributing to mutagenesis [53].
4. Parental Meiotic Errors and Offspring Susceptibility to Oxidative Stress in SCAs
Karyotypes | Key Findings on Oxidative Stress | References | |
---|---|---|---|
Single X Chromosome | 45,X (Turner syndrome, TS) | Reduced antioxidant capacity, increased oxidative stress markers (e.g., lipid peroxidation, reduced glutathione levels)—see Table 2 | [63,64] |
Mosaic TS (e.g., 45,X/46,XX) | Oxidative stress may vary depending on the degree of mosaicism; similar trends to 45,X are observed | ||
Mosaic TS with Y material (e.g., 45,X/46,XY) | Similar to 45,X, but limited data on specific oxidative stress markers in this subgroup | ||
47,XYY | Limited evidence: oxidative stress not well characterized in this aneuploidy | [65], “Limited data” | |
Multiple X Chromosomes | 47,XXY (Klinefelter syndrome) | Increased levels of oxidative stress biomarkers; associated with metabolic syndrome, which exacerbates oxidative stress—see Table 2 | [65,66,67] |
47,XXX | Limited studies: oxidative imbalance likely less pronounced than in other sex chromosome aneuploidies | [68], “Limited data” | |
Tetrasomies and pentasomies with supernumerary X (and/or Y) chromosomes | Insufficient data; presumed oxidative stress due to multiple X (and/or Y) chromosomes and severe aneuploidy effects | [69], “Limited data” |
Turner Syndrome | Klinefelter Syndrome | |
---|---|---|
Genetic Alteration | Lack of X chromosome material (45,X or different karyotypes) increases susceptibility to oxidative stress. | Extra X chromosomes (most common karyotype: 47,XXY) lead to increased ROS production and reduced antioxidant capacity. |
Oxidative Stress Response | Altered stress pathways, with increased oxidative burden due to estrogen deficiency. | Elevated ROS and impaired antioxidant defense, especially in spermatozoa. |
Molecular Mechanisms | XIAP regulates mitochondrial antioxidants (SOD-2), reducing oxidative stress. | Increased NADPH production enhances ROS generation via sperm NOX. |
Antioxidant Defenses | Estrogen upregulates SOD, catalase, and scavenges free radicals; estrogen replacement may help restore defenses. | Testosterone modulates antioxidant enzymes (SOD, GPx), with testosterone replacement improving oxidative stress. |
Cardiovascular Implications | Oxidative stress leads to endothelial dysfunction, hypertension, and aortic issues. | ROS in endothelial cells cause dysfunction, contributing to cardiovascular risk. |
Metabolic Issues | Oxidative stress impairs insulin signaling and promotes metabolic syndrome. | Excess adipose ROS exacerbates metabolic dysfunction and systemic inflammation. |
Neurodevelopmental Challenges | Oxidative stress in the brain may contribute to cognitive and developmental deficits. | Mitochondrial dysfunction and ROS accumulation affect cognitive development. |
5. SCAs and Oxidative Stress in Pediatric Populations
5.1. Turner Syndrome
5.2. Klinefelter Syndrome
5.3. 47,XXX, 47,XYY, and HGAs
5.4. Sex Chromosome-Linked and Autosomal Gene Contributors to Oxidative Stress in SCAs
- -
- SCAs lead to gene dosage imbalances due to monosomy (e.g., 45,X) or the presence of supernumerary chromosomes (e.g., 47,XXY; 47,XYY).
- -
- Genes that escape X-inactivation or are overexpressed on the Y chromosome (such as MAO-A, SLC25A5, and XIAP) are dysregulated, disrupting mitochondrial function and increasing ROS production.
- -
- These changes are compounded by a reduced antioxidant enzymatic defense (e.g., decreased expression of SOD, GPX4).
- -
- The resulting redox imbalance contributes to cellular and systemic dysfunction, particularly in cardiovascular, metabolic, and neurodevelopmental systems.
5.5. Comparative Insights: Oxidative Stress in Other Pediatric Genetic Syndromes
6. Supplementing Dietary Antioxidants as a Therapeutic Strategy
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Tartaglia, N.R.; Howell, S.; Sutherland, A.; Wilson, R.; Wilson, L. A Review of Trisomy X (47,XXX). Orphanet J. Rare Dis. 2010, 5, 8. [Google Scholar] [CrossRef] [PubMed]
- Bonomi, M.; Rochira, V.; Pasquali, D.; Balercia, G.; Jannini, E.A.; Ferlin, A.; On behalf of the Klinefelter ItaliaN Group (KING). Klinefelter Syndrome (KS): Genetics, Clinical Phenotype and Hypogonadism. J. Endocrinol. Investig. 2017, 40, 123–134. [Google Scholar] [CrossRef]
- Profeta, G.; Micangeli, G.; Tarani, F.; Paparella, R.; Ferraguti, G.; Spaziani, M.; Isidori, A.M.; Menghi, M.; Ceccanti, M.; Fiore, M.; et al. Sexual Developmental Disorders in Pediatrics. Clin. Ter. 2022, 173, 475–488. [Google Scholar] [CrossRef]
- Gravholt, C.H.; Andersen, N.H.; Conway, G.S.; Dekkers, O.M.; Geffner, M.E.; Klein, K.O.; Lin, A.E.; Mauras, N.; Quigley, C.A.; Rubin, K.; et al. Clinical Practice Guidelines for the Care of Girls and Women with Turner Syndrome: Proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur. J. Endocrinol. 2017, 177, G1–G70. [Google Scholar] [CrossRef]
- Visootsak, J.; Graham, J.M. Klinefelter Syndrome and Other Sex Chromosomal Aneuploidies. Orphanet J. Rare Dis. 2006, 1, 42. [Google Scholar] [CrossRef] [PubMed]
- Gravholt, C.H.; Jensen, A.S.; Høst, C.; Bojesen, A. Body Composition, Metabolic Syndrome and Type 2 Diabetes in Klinefelter Syndrome. Acta Paediatr. 2011, 100, 871–877. [Google Scholar] [CrossRef] [PubMed]
- Sybert, V.P.; McCauley, E. Turner’s Syndrome. N. Engl. J. Med. 2004, 351, 1227–1238. [Google Scholar] [CrossRef]
- Ricciardi, G.; Cammisa, L.; Bove, R.; Picchiotti, G.; Spaziani, M.; Isidori, A.M.; Aceti, F.; Giacchetti, N.; Romani, M.; Sogos, C. Clinical, Cognitive and Neurodevelopmental Profile in Tetrasomies and Pentasomies: A Systematic Review. Children 2022, 9, 1719. [Google Scholar] [CrossRef]
- Song, J.-P.; Jiang, Y.-F.; Gao, T.-X.-Z.; Yao, Y.-Y.; Liu, L.-J.; Xu, R.-H.; Yi, M.-Q.; Yu, C.-J.; Wang, W.-P.; Li, H. Performance of Non-Invasive Prenatal Screening for Sex Chromosome Aneuploidies and Parental Decision-Making. Chin. Med. J. Engl. 2020, 133, 1617–1619. [Google Scholar] [CrossRef]
- Micangeli, G.; Paparella, R.; Tarani, F.; Menghi, M.; Ferraguti, G.; Carlomagno, F.; Spaziani, M.; Pucarelli, I.; Greco, A.; Fiore, M.; et al. Clinical Management and Therapy of Precocious Puberty in the Sapienza University Pediatrics Hospital of Rome, Italy. Children 2023, 10, 1672. [Google Scholar] [CrossRef]
- Micangeli, G.; Profeta, G.; Colloridi, F.; Pirro, F.; Tarani, F.; Ferraguti, G.; Spaziani, M.; Isidori, A.M.; Menghi, M.; Fiore, M.; et al. The Role of the Pediatrician in the Management of the Child and Adolescent with Gender Dysphoria. Ital. J. Pediatr. 2023, 49, 71. [Google Scholar] [CrossRef] [PubMed]
- Micangeli, G.; Menghi, M.; Profeta, G.; Tarani, F.; Mariani, A.; Petrella, C.; Barbato, C.; Ferraguti, G.; Ceccanti, M.; Tarani, L.; et al. The Impact of Oxidative Stress on Pediatrics Syndromes. Antioxidants 2022, 11, 1983. [Google Scholar] [CrossRef]
- Terracina, S.; Tarani, L.; Ceccanti, M.; Vitali, M.; Francati, S.; Lucarelli, M.; Venditti, S.; Verdone, L.; Ferraguti, G.; Fiore, M. The Impact of Oxidative Stress on the Epigenetics of Fetal Alcohol Spectrum Disorders. Antioxidants 2024, 13, 410. [Google Scholar] [CrossRef] [PubMed]
- Tremellen, K. Oxidative Stress and Male Infertility—A Clinical Perspective. Hum. Reprod. Update 2008, 14, 243–258. [Google Scholar] [CrossRef] [PubMed]
- Oroian, B.A.; Ciobica, A.; Timofte, D.; Stefanescu, C.; Serban, I.L. New Metabolic, Digestive, and Oxidative Stress-Related Manifestations Associated with Posttraumatic Stress Disorder. Oxid. Med. Cell. Longev. 2021, 2021, 5599265. [Google Scholar] [CrossRef]
- Shkurat, M.A.; Mashkina, E.V.; Milyutina, N.P.; Shkurat, T.P. The Role of Polymorphism of Redox-Sensitive Genes in the Mechanisms of Oxidative Stress in Obesity and Metabolic Diseases. Ecol. Genet. 2023, 21, 261–287. [Google Scholar] [CrossRef]
- Ferraguti, G.; Terracina, S.; Micangeli, G.; Lucarelli, M.; Tarani, L.; Ceccanti, M.; Spaziani, M.; D’Orazi, V.; Petrella, C.; Fiore, M. NGF and BDNF in Pediatrics Syndromes. Neurosci. Biobehav. Rev. 2023, 145, 105015. [Google Scholar] [CrossRef]
- Lott, I.T.; Head, E. Alzheimer Disease and Down Syndrome: Factors in Pathogenesis. Neurobiol. Aging 2005, 26, 383–389. [Google Scholar] [CrossRef] [PubMed]
- Pagano, G.; Castello, G. Oxidative Stress and Mitochondrial Dysfunction in Down Syndrome. In Neurodegenerative Diseases; Ahmad, S.I., Ed.; Advances in Experimental Medicine and Biology; Springer: New York, NY, USA, 2012; Volume 724, pp. 291–299. ISBN 978-1-4614-0652-5. [Google Scholar]
- Pomatto, L.C.D.; Carney, C.; Shen, B.; Wong, S.; Halaszynski, K.; Salomon, M.P.; Davies, K.J.A.; Tower, J. The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress. Curr. Biol. 2017, 27, 1–15. [Google Scholar] [CrossRef]
- Huang, Y.; Ha, S.; Li, Z.; Li, J.; Xiao, W. CHK1-CENP B/MAD2 Is Associated with Mild Oxidative Damage-Induced Sex Chromosome Aneuploidy of Male Mouse Embryos during in Vitro Fertilization. Free Radic. Biol. Med. 2019, 137, 181–193. [Google Scholar] [CrossRef]
- Jevalikar, G.S.; Zacharin, M.; White, M.; Yau, S.W.; Li, W.; Ijspeert, C.; Russo, V.C.; Werther, G.A.; Sabin, M.A. Turner Syndrome Patients with Bicuspid Aortic Valves and Renal Malformations Exhibit Abnormal Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP). J. Pediatr. Endocrinol. Metab. 2015, 28, 1203–1208. [Google Scholar] [CrossRef]
- Clémençon, B.; Babot, M.; Trézéguet, V. The Mitochondrial ADP/ATP Carrier (SLC25 Family): Pathological Implications of Its Dysfunction. Mol. Aspects Med. 2013, 34, 485–493. [Google Scholar] [CrossRef]
- Wu, J.B.; Chen, K.; Li, Y.; Lau, Y.-F.C.; Shih, J.C. Regulation of Monoamine Oxidase A by the SRY Gene on the Y Chromosome. FASEB J. 2009, 23, 4029–4038. [Google Scholar] [CrossRef] [PubMed]
- Kumar, M.; Pathak, D.; Venkatesh, S.; Kriplani, A.; Ammini, A.C.; Dada, R. Chromosomal Abnormalities & Oxidative Stress in Women with Premature Ovarian Failure (POF). Indian J. Med. Res. 2012, 135, 92–97. [Google Scholar] [CrossRef]
- Sies, H.; Jones, D.P. Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents. Nat. Rev. Mol. Cell Biol. 2020, 21, 363–383. [Google Scholar] [CrossRef] [PubMed]
- Murphy, M.P. How Mitochondria Produce Reactive Oxygen Species. Biochem. J. 2009, 417, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Demirci-Çekiç, S.; Özkan, G.; Avan, A.N.; Uzunboy, S.; Çapanoğlu, E.; Apak, R. Biomarkers of Oxidative Stress and Antioxidant Defense. J. Pharm. Biomed. Anal. 2022, 209, 114477. [Google Scholar] [CrossRef]
- Andrés, C.M.C.; Pérez De La Lastra, J.M.; Andrés Juan, C.; Plou, F.J.; Pérez-Lebeña, E. Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity. Int. J. Mol. Sci. 2023, 24, 1841. [Google Scholar] [CrossRef]
- Sies, H. Hydrogen Peroxide as a Central Redox Signaling Molecule in Physiological Oxidative Stress: Oxidative Eustress. Redox Biol. 2017, 11, 613–619. [Google Scholar] [CrossRef]
- Leser, M.; Chapman, J.R.; Khine, M.; Pegan, J.; Law, M.; Makkaoui, M.E.; Ueberheide, B.M.; Brenowitz, M. Chemical Generation of Hydroxyl Radical for Oxidative ‘Footprinting’. Protein Pept. Lett. 2019, 26, 61–69. [Google Scholar] [CrossRef]
- Di Mascio, P.; Martinez, G.R.; Miyamoto, S.; Ronsein, G.E.; Medeiros, M.H.G.; Cadet, J. Singlet Molecular Oxygen Reactions with Nucleic Acids, Lipids, and Proteins. Chem. Rev. 2019, 119, 2043–2086. [Google Scholar] [CrossRef] [PubMed]
- Ferrer-Sueta, G.; Campolo, N.; Trujillo, M.; Bartesaghi, S.; Carballal, S.; Romero, N.; Alvarez, B.; Radi, R. Biochemistry of Peroxynitrite and Protein Tyrosine Nitration. Chem. Rev. 2018, 118, 1338–1408. [Google Scholar] [CrossRef] [PubMed]
- Voziyan, P.A.; Yazlovitskaya, E.M. Reactive Oxygen Species. J. Bioequivalence Bioavailab. 2014, 6. [Google Scholar] [CrossRef]
- Winterbourn, C.C. Reconciling the Chemistry and Biology of Reactive Oxygen Species. Nat. Chem. Biol. 2008, 4, 278–286. [Google Scholar] [CrossRef]
- Forman, H.J.; Maiorino, M.; Ursini, F. Signaling Functions of Reactive Oxygen Species. Biochemistry 2010, 49, 835–842. [Google Scholar] [CrossRef]
- Winterbourn, C.C.; Kettle, A.J. Redox Reactions and Microbial Killing in the Neutrophil Phagosome. Antioxid. Redox Signal. 2013, 18, 642–660. [Google Scholar] [CrossRef]
- Kasai, S.; Shimizu, S.; Tatara, Y.; Mimura, J.; Itoh, K. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Biomolecules 2020, 10, 320. [Google Scholar] [CrossRef]
- Dimauro, I.; Mercatelli, N.; Caporossi, D. Exercise-Induced ROS in Heat Shock Proteins Response. Free Radic. Biol. Med. 2016, 98, 46–55. [Google Scholar] [CrossRef]
- Wickens, A.P. Ageing and the Free Radical Theory. Respir. Physiol. 2001, 128, 379–391. [Google Scholar] [CrossRef]
- Pecchillo Cimmino, T.; Ammendola, R.; Cattaneo, F.; Esposito, G. NOX Dependent ROS Generation and Cell Metabolism. Int. J. Mol. Sci. 2023, 24, 2086. [Google Scholar] [CrossRef]
- Galbusera, C.; Orth, P.; Fedida, D.; Spector, T. Superoxide Radical Production by Allopurinol and Xanthine Oxidase. Biochem. Pharmacol. 2006, 71, 1747–1752. [Google Scholar] [CrossRef] [PubMed]
- Hrycay, E.G.; Bandiera, S.M. Involvement of Cytochrome P450 in Reactive Oxygen Species Formation and Cancer. Adv. Pharmacol. 2015, 74, 35–84. [Google Scholar]
- He, Z.; Li, Q.; Xu, Y.; Zhang, D.; Pan, X. Production of Extracellular Superoxide Radical in Microorganisms and Its Environmental Implications: A Review. Environ. Pollut. 2023, 338, 122563. [Google Scholar] [CrossRef]
- Attri, P.; Kim, Y.H.; Park, D.H.; Park, J.H.; Hong, Y.J.; Uhm, H.S.; Kim, K.-N.; Fridman, A.; Choi, E.H. Generation Mechanism of Hydroxyl Radical Species and Its Lifetime Prediction during the Plasma-Initiated Ultraviolet (UV) Photolysis. Sci. Rep. 2015, 5, 9332. [Google Scholar] [CrossRef]
- Riley, P.A. Free Radicals in Biology: Oxidative Stress and the Effects of Ionizing Radiation. Int. J. Radiat. Biol. 1994, 65, 27–33. [Google Scholar] [CrossRef]
- Miao, L.; St. Clair, D.K. Regulation of Superoxide Dismutase Genes: Implications in Disease. Free Radic. Biol. Med. 2009, 47, 344–356. [Google Scholar] [CrossRef] [PubMed]
- Muranov, K.O. Fenton Reaction in Vivo and in Vitro. Possibilities and Limitations. Biochem. Mosc. 2024, 89, S112–S126. [Google Scholar] [CrossRef] [PubMed]
- Kehrer, J.P. The Haber–Weiss Reaction and Mechanisms of Toxicity. Toxicology 2000, 149, 43–50. [Google Scholar] [CrossRef]
- Juan, C.A.; Pérez De La Lastra, J.M.; Plou, F.J.; Pérez-Lebeña, E. The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. Int. J. Mol. Sci. 2021, 22, 4642. [Google Scholar] [CrossRef]
- Gaschler, M.M.; Stockwell, B.R. Lipid Peroxidation in Cell Death. Biochem. Biophys. Res. Commun. 2017, 482, 419–425. [Google Scholar] [CrossRef]
- Stadtman, E.R.; Berlett, B.S. Reactive Oxygen-Mediated Protein Oxidation in Aging and Disease. Drug Metab. Rev. 1998, 30, 225–243. [Google Scholar] [CrossRef]
- Fleming, A.M.; Burrows, C.J. Chemistry of ROS-Mediated Oxidation to the Guanine Base in DNA and Its Biological Consequences. Int. J. Radiat. Biol. 2022, 98, 452–460. [Google Scholar] [CrossRef]
- MacDonald, M.; Hassold, T.; Harvey, J.; Wang, L.H.; Morton, N.E.; Jacobs, P. The Origin of 47,XXY and 47,XXX Aneuploidy: Heterogeneous Mechanisms and Role of Aberrant Recombination. Hum. Mol. Genet. 1994, 3, 1365–1371. [Google Scholar] [CrossRef]
- Skuse, D.; Printzlau, F.; Wolstencroft, J. Sex Chromosome Aneuploidies. In Handbook of Clinical Neurology; Elsevier: Amsterdam, The Netherlands, 2018; Volume 147, pp. 355–376. ISBN 978-0-444-63233-3. [Google Scholar]
- Hassold, T.J.; Hunt, P.A. Missed Connections: Recombination and Human Aneuploidy. Prenat. Diagn. 2021, 41, 584–590. [Google Scholar] [CrossRef] [PubMed]
- Gravholt, C.H.; Viuff, M.H.; Brun, S.; Stochholm, K.; Andersen, N.H. Turner Syndrome: Mechanisms and Management. Nat. Rev. Endocrinol. 2019, 15, 601–614. [Google Scholar] [CrossRef] [PubMed]
- Lorda-Sanchez, I.; Binkert, F.; Hinkel, K.G.; Moser, H.; Rosenkranz, W.; Maechler, M.; Schinzel, A. Uniparental Origin of Sex Chromosome Polysomies. Hum. Hered. 1992, 42, 193–197. [Google Scholar] [CrossRef]
- Nagaoka, S.I.; Hassold, T.J.; Hunt, P.A. Human Aneuploidy: Mechanisms and New Insights into an Age-Old Problem. Nat. Rev. Genet. 2012, 13, 493–504. [Google Scholar] [CrossRef]
- Liu, S.; Akula, N.; Reardon, P.K.; Russ, J.; Torres, E.; Clasen, L.S.; Blumenthal, J.; Lalonde, F.; McMahon, F.J.; Szele, F.; et al. Aneuploidy Effects on Human Gene Expression across Three Cell Types. Proc. Natl. Acad. Sci. USA 2023, 120, e2218478120. [Google Scholar] [CrossRef] [PubMed]
- Wilson, M.A.; Makova, K.D. Evolution and Survival on Eutherian Sex Chromosomes. PLoS Genet. 2009, 5, e1000568. [Google Scholar] [CrossRef]
- Lanfranco, F.; Kamischke, A.; Zitzmann, M.; Nieschlag, E. Klinefelter’s Syndrome. Lancet 2004, 364, 273–283. [Google Scholar] [CrossRef]
- Biradar, V.S.; Rajpathak, S.N.; Joshi, S.R.; Deobagkar, D.D. Functional and Regulatory Aspects of Oxidative Stress Response in X Monosomy. Vitro Cell. Dev. Biol.-Anim. 2021, 57, 661–675. [Google Scholar] [CrossRef] [PubMed]
- Soto, M.E.; Soria-Castro, E.; Guarner Lans, V.; Muruato Ontiveros, E.; Iván Hernández Mejía, B.; Jorge Martínez Hernandez, H.; Barragán García, R.; Herrera, V.; Pérez-Torres, I. Analysis of Oxidative Stress Enzymes and Structural and Functional Proteins on Human Aortic Tissue from Different Aortopathies. Oxid. Med. Cell. Longev. 2014, 2014, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Aitken, R.; Krausz, C. Oxidative Stress, DNA Damage and the Y Chromosome. Reproduction 2001, 122, 497–506. [Google Scholar] [CrossRef]
- Aitken, R.J.; Baker, M.A. The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis? Front. Endocrinol. 2020, 11, 581838. [Google Scholar] [CrossRef] [PubMed]
- Tarani, L.; Ceci, F.M.; Carito, V.; Ferraguti, G.; Petrella, C.; Greco, A.; Ralli, M.; Minni, A.; Spaziani, M.; Isidori, A.M.; et al. Neuroimmune Dysregulation in Prepubertal and Adolescent Individuals Affected by Klinefelter Syndrome. Endocr. Metab. Immune Disord. Drug Targets 2023, 23, 105–114. [Google Scholar] [CrossRef]
- Otter, M.; Schrander-Stumpel, C.T.R.M.; Curfs, L.M.G. Triple X Syndrome: A Review of the Literature. Eur. J. Hum. Genet. EJHG 2010, 18, 265–271. [Google Scholar] [CrossRef]
- Tartaglia, N.; Ayari, N.; Howell, S.; D’Epagnier, C.; Zeitler, P. 48,XXYY, 48,XXXY and 49,XXXXY Syndromes: Not Just Variants of Klinefelter Syndrome: 48,XXYY, 48,XXXY and 49,XXXXY Syndromes. Acta Paediatr. 2011, 100, 851–860. [Google Scholar] [CrossRef] [PubMed]
- Lavoie, J.-C.; Tremblay, A. Sex-Specificity of Oxidative Stress in Newborns Leading to a Personalized Antioxidant Nutritive Strategy. Antioxidants 2018, 7, 49. [Google Scholar] [CrossRef]
- Steiner, M.; Saenger, P. Turner Syndrome. Adv. Pediatr. 2022, 69, 177–202. [Google Scholar] [CrossRef]
- Zhu, C.; Xu, F.; Fukuda, A.; Wang, X.; Fukuda, H.; Korhonen, L.; Hagberg, H.; Lannering, B.; Nilsson, M.; Eriksson, P.S.; et al. X Chromosome-Linked Inhibitor of Apoptosis Protein Reduces Oxidative Stress after Cerebral Irradiation or Hypoxia-Ischemia through up-Regulation of Mitochondrial Antioxidants. Eur. J. Neurosci. 2007, 26, 3402–3410. [Google Scholar] [CrossRef]
- Mohamad, N.-V.; Ima-Nirwana, S.; Chin, K.-Y. Are Oxidative Stress and Inflammation Mediators of Bone Loss Due to Estrogen Deficiency? A Review of Current Evidence. Endocr. Metab. Immune Disord. Drug Targets 2020, 20, 1478–1487. [Google Scholar] [CrossRef]
- Elliot, S.J.; Catanuto, P.; Pereira-Simon, S.; Xia, X.; Pastar, I.; Thaller, S.; Head, C.R.; Stojadinovic, O.; Tomic-Canic, M.; Glassberg, M.K. Catalase, a Therapeutic Target in the Reversal of Estrogen-Mediated Aging. Mol. Ther. J. Am. Soc. Gene Ther. 2022, 30, 947–962. [Google Scholar] [CrossRef] [PubMed]
- Borrás, C.; Ferrando, M.; Inglés, M.; Gambini, J.; Lopez-Grueso, R.; Edo, R.; Mas-Bargues, C.; Pellicer, A.; Viña, J. Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause. Oxid. Med. Cell. Longev. 2021, 2021, 8101615. [Google Scholar] [CrossRef]
- White, R.E.; Gerrity, R.; Barman, S.A.; Han, G. Estrogen and Oxidative Stress: A Novel Mechanism That May Increase the Risk for Cardiovascular Disease in Women. Steroids 2010, 75, 788–793. [Google Scholar] [CrossRef] [PubMed]
- Borrás, C.; Gambini, J.; Gómez-Cabrera, M.C.; Sastre, J.; Pallardó, F.V.; Mann, G.E.; Viña, J.; Borrás, C.; Gambini, J.; Gómez-Cabrera, M.C.; et al. Genistein, a Soy Isoflavone, Up-regulates Expression of Antioxidant Genes: Involvement of Estrogen Receptors, ERK1/2, and NFκB. FASEB J. 2006, 20, 2136–2138. [Google Scholar] [CrossRef] [PubMed]
- Felty, Q.; Xiong, W.-C.; Sun, D.; Sarkar, S.; Singh, K.P.; Parkash, J.; Roy, D. Estrogen-Induced Mitochondrial Reactive Oxygen Species as Signal-Transducing Messengers. Biochemistry 2005, 44, 6900–6909. [Google Scholar] [CrossRef]
- Chen, J.; Yager, J.D. Estrogen’s Effects on Mitochondrial Gene Expression: Mechanisms and Potential Contributions to Estrogen Carcinogenesis. Ann. N. Y. Acad. Sci. 2004, 1028, 258–272. [Google Scholar] [CrossRef]
- Hertiš Petek, T.; Petek, T.; Močnik, M.; Marčun Varda, N. Systemic Inflammation, Oxidative Stress and Cardiovascular Health in Children and Adolescents: A Systematic Review. Antioxidants 2022, 11, 894. [Google Scholar] [CrossRef]
- Mavinkurve, M.; O’Gorman, C.S. Cardiometabolic and Vascular Risks in Young and Adolescent Girls with Turner Syndrome. BBA Clin. 2015, 3, 304–309. [Google Scholar] [CrossRef]
- Vilas-Boas, E.A.; Almeida, D.C.; Roma, L.P.; Ortis, F.; Carpinelli, A.R. Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress. Cells 2021, 10, 3328. [Google Scholar] [CrossRef]
- Fernández-Sánchez, A.; Madrigal-Santillán, E.; Bautista, M.; Esquivel-Soto, J.; Morales-González, Á.; Esquivel-Chirino, C.; Durante-Montiel, I.; Sánchez-Rivera, G.; Valadez-Vega, C.; Morales-González, J.A. Inflammation, Oxidative Stress, and Obesity. Int. J. Mol. Sci. 2011, 12, 3117–3132. [Google Scholar] [CrossRef]
- Teleanu, D.M.; Niculescu, A.-G.; Lungu, I.I.; Radu, C.I.; Vladâcenco, O.; Roza, E.; Costăchescu, B.; Grumezescu, A.M.; Teleanu, R.I. An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases. Int. J. Mol. Sci. 2022, 23, 5938. [Google Scholar] [CrossRef] [PubMed]
- Vázquez-González, D.; Carreón-Trujillo, S.; Alvarez-Arellano, L.; Abarca-Merlin, D.M.; Domínguez-López, P.; Salazar-García, M.; Corona, J.C. A Potential Role for Neuroinflammation in ADHD. In Neuroinflammation, Gut-Brain Axis and Immunity in Neuropsychiatric Disorders; Kim, Y.-K., Ed.; Advances in Experimental Medicine and Biology; Springer Nature: Singapore, 2023; Volume 1411, pp. 327–356. ISBN 978-981-19737-5-8. [Google Scholar]
- Usui, N.; Kobayashi, H.; Shimada, S. Neuroinflammation and Oxidative Stress in the Pathogenesis of Autism Spectrum Disorder. Int. J. Mol. Sci. 2023, 24, 5487. [Google Scholar] [CrossRef] [PubMed]
- Ildarabadi, A.; Mir Mohammad Ali, S.N.; Rahmani, F.; Mosavari, N.; Pourbakhtyaran, E.; Rezaei, N. Inflammation and Oxidative Stress in Epileptic Children: From Molecular Mechanisms to Clinical Application of Ketogenic Diet. Rev. Neurosci. 2024, 35, 473–488. [Google Scholar] [CrossRef]
- Gravholt, C.H.; Chang, S.; Wallentin, M.; Fedder, J.; Moore, P.; Skakkebæk, A. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr. Rev. 2018, 39, 389–423. [Google Scholar] [CrossRef] [PubMed]
- Pozza, C.; Sesti, F.; Tenuta, M.; Spaziani, M.; Tarantino, C.; Carlomagno, F.; Minnetti, M.; Pofi, R.; Paparella, R.; Lenzi, A.; et al. Testicular Dysfunction in 47,XXY Boys: When It All Begins. A Semilongitudinal Study. J. Clin. Endocrinol. Metab. 2023, 108, 2486–2499. [Google Scholar] [CrossRef]
- Zitzmann, M.; Aksglaede, L.; Corona, G.; Isidori, A.M.; Juul, A.; T’Sjoen, G.; Kliesch, S.; D’Hauwers, K.; Toppari, J.; Słowikowska-Hilczer, J.; et al. European Academy of Andrology Guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology. Andrology 2021, 9, 145–167. [Google Scholar] [CrossRef]
- Carlomagno, F.; Minnetti, M.; Angelini, F.; Pofi, R.; Sbardella, E.; Spaziani, M.; Aureli, A.; Anzuini, A.; Paparella, R.; Tarani, L.; et al. Altered Thyroid Feedback Loop in Klinefelter Syndrome: From Infancy Through the Transition to Adulthood. J. Clin. Endocrinol. Metab. 2023, 108, e1329–e1340. [Google Scholar] [CrossRef]
- Paparella, R.; Ferraguti, G.; Fiore, M.; Menghi, M.; Micangeli, G.; Tarani, F.; Ligotino, A.; Messina, M.P.; Ceccanti, M.; Minni, A.; et al. Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study. Int. J. Mol. Sci. 2024, 25, 2214. [Google Scholar] [CrossRef]
- Nassau, D.E.; Chu, K.Y.; Blachman-Braun, R.; Castellan, M.; Ramasamy, R. The Pediatric Patient and Future Fertility: Optimizing Long-Term Male Reproductive Health Outcomes. Fertil. Steril. 2020, 113, 489–499. [Google Scholar] [CrossRef]
- Tostes, R.C.; Carneiro, F.S.; Carvalho, M.H.C.; Reckelhoff, J.F. Reactive Oxygen Species: Players in the Cardiovascular Effects of Testosterone. Am. J. Physiol.-Regul. Integr. Comp. Physiol. 2016, 310, R1–R14. [Google Scholar] [CrossRef]
- Cruz-Topete, D.; Dominic, P.; Stokes, K.Y. Uncovering Sex-Specific Mechanisms of Action of Testosterone and Redox Balance. Redox Biol. 2020, 31, 101490. [Google Scholar] [CrossRef] [PubMed]
- Tam, N.N.C.; Gao, Y.; Leung, Y.-K.; Ho, S.-M. Androgenic Regulation of Oxidative Stress in the Rat Prostate. Am. J. Pathol. 2003, 163, 2513–2522. [Google Scholar] [CrossRef]
- Mancini, A.; Leone, E.; Festa, R.; Grande, G.; Silvestrini, A.; De Marinis, L.; Pontecorvi, A.; Maira, G.; Littarru, G.P.; Meucci, E. Effects of Testosterone on Antioxidant Systems in Male Secondary Hypogonadism. J. Androl. 2008, 29, 622–629. [Google Scholar] [CrossRef]
- Leisegang, K.; Roychoudhury, S.; Slama, P.; Finelli, R. The Mechanisms and Management of Age-Related Oxidative Stress in Male Hypogonadism Associated with Non-Communicable Chronic Disease. Antioxidants 2021, 10, 1834. [Google Scholar] [CrossRef] [PubMed]
- Aksglaede, L.; Molgaard, C.; Skakkebaek, N.E.; Juul, A. Normal Bone Mineral Content but Unfavourable Muscle/Fat Ratio in Klinefelter Syndrome. Arch. Dis. Child. 2008, 93, 30–34. [Google Scholar] [CrossRef] [PubMed]
- Haymana, C.; Aydogdu, A.; Demirci, I.; Dinc, M.; Demir, O.; Torun, D.; Yesildal, F.; Meric, C.; Basaran, Y.; Sonmez, A.; et al. Increased Endothelial Dysfunction and Insulin Resistance in Patients with Klinefelter Syndrome. Endocr. Metab. Immune Disord.-Drug Targets 2018, 18, 401–406. [Google Scholar] [CrossRef]
- Panvino, F.; Paparella, R.; Gambuti, L.; Cerrito, A.; Menghi, M.; Micangeli, G.; Petrella, C.; Fiore, M.; Tarani, L.; Ardizzone, I. Klinefelter Syndrome: A Genetic Disorder Leading to Neuroendocrine Modifications and Psychopathological Vulnerabilities in Children—A Literature Review and Case Report. Children 2024, 11, 509. [Google Scholar] [CrossRef]
- Fiore, M.; Tarani, L.; Radicioni, A.; Spaziani, M.; Ferraguti, G.; Putotto, C.; Gabanella, F.; Maftei, D.; Lattanzi, R.; Minni, A.; et al. Serum Prokineticin-2 in Prepubertal and Adult Klinefelter Individuals. Can. J. Physiol. Pharmacol. 2021, 100, 151–157. [Google Scholar] [CrossRef]
- Berglund, A.; Viuff, M.H.; Skakkebæk, A.; Chang, S.; Stochholm, K.; Gravholt, C.H. Changes in the Cohort Composition of Turner Syndrome and Severe Non-Diagnosis of Klinefelter, 47,XXX and 47,XYY Syndrome: A Nationwide Cohort Study. Orphanet J. Rare Dis. 2019, 14, 16. [Google Scholar] [CrossRef]
- Berglund, A.; Stochholm, K.; Gravholt, C.H. Morbidity in 47,XYY Syndrome: A Nationwide Epidemiological Study of Hospital Diagnoses and Medication Use. Genet. Med. 2020, 22, 1542–1551. [Google Scholar] [CrossRef] [PubMed]
- Rappold, G.A. The Pseudoautosomal Regions of the Human Sex Chromosomes. Hum. Genet. 1993, 92, 315–324. [Google Scholar] [CrossRef]
- Spaziani, M.; Carlomagno, F.; Tarantino, C.; Angelini, F.; Paparella, R.; Tarani, L.; Putotto, C.; Badagliacca, R.; Pozza, C.; Isidori, A.M.; et al. From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-Dosage Effect of Supernumerary X Chromosomes. J. Clin. Endocrinol. Metab. 2024, 109, dgad730. [Google Scholar] [CrossRef] [PubMed]
- Shimojima Yamamoto, K.; Yamamoto, S.; Imaizumi, T.; Kumada, S.; Yamamoto, T. Uniparental Maternal Tetrasomy X Co-Occurrence with Paternal Nondisjunction: Investigation of the Origin of 48,XXXX. Hum. Genome Var. 2024, 11, 31. [Google Scholar] [CrossRef]
- Andriani, G.A.; Vijg, J.; Montagna, C. Mechanisms and Consequences of Aneuploidy and Chromosome Instability in the Aging Brain. Mech. Ageing Dev. 2017, 161, 19–36. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.-Y.; Liu, L.-N.; Zhao, Z.-B. The Role of ROS Toxicity in Spontaneous Aneuploidy in Cultured Cells. Tissue Cell 2013, 45, 47–53. [Google Scholar] [CrossRef]
- Banan, A.; Fields, J.Z.; Decker, H.; Zhang, Y.; Keshavarzian, A. Nitric Oxide and Its Metabolites Mediate Ethanol-Induced Microtubule Disruption and Intestinal Barrier Dysfunction. J. Pharmacol. Exp. Ther. 2000, 294, 997–1008. [Google Scholar] [CrossRef]
- Baraibar, M.A.; Friguet, B. Changes of the Proteasomal System During the Aging Process. In Progress in Molecular Biology and Translational Science; Elsevier: Amsterdam, The Netherlands, 2012; Volume 109, pp. 249–275. ISBN 978-0-12-397863-9. [Google Scholar]
- Roh, M.; Van Der Meer, R.; Abdulkadir, S.A. Tumorigenic Polyploid Cells Contain Elevated ROS and ARE Selectively Targeted by Antioxidant Treatment. J. Cell. Physiol. 2012, 227, 801–812. [Google Scholar] [CrossRef]
- Palmieri, F. The Mitochondrial Transporter Family SLC25: Identification, Properties and Physiopathology. Mol. Aspects Med. 2013, 34, 465–484. [Google Scholar] [CrossRef]
- Edmondson, D.E.; Binda, C. Monoamine Oxidases. In Membrane Protein Complexes: Structure and Function; Harris, J.R., Boekema, E.J., Eds.; Subcellular Biochemistry; Springer: Singapore, 2018; Volume 87, pp. 117–139. ISBN 978-981-10-7756-2. [Google Scholar]
- Ingold, I.; Berndt, C.; Schmitt, S.; Doll, S.; Poschmann, G.; Buday, K.; Roveri, A.; Peng, X.; Porto Freitas, F.; Seibt, T.; et al. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell 2018, 172, 409–422.e21. [Google Scholar] [CrossRef]
- Chen, G.; Li, Z.; Iemura, K.; Tanaka, K. Oxidative Stress Induces Chromosomal Instability through Replication Stress in Fibroblasts from Aged Mice. J. Cell Sci. 2023, 136, jcs260688. [Google Scholar] [CrossRef] [PubMed]
- Kozel, B.A.; Danback, J.R.; Waxler, J.L.; Knutsen, R.H.; de las Fuentes, L.; Reusz, G.S.; Kis, E.; Bhatt, A.B.; Pober, B.R. Williams Syndrome Predisposes to Vascular Stiffness Modified by Antihypertensive Use and Copy Number Changes in NCF1. Hypertens. Dallas Tex 1979 2014, 63, 74–79. [Google Scholar] [CrossRef]
- Kozel, B.A.; Knutsen, R.H.; Ye, L.; Ciliberto, C.H.; Broekelmann, T.J.; Mecham, R.P. Genetic Modifiers of Cardiovascular Phenotype Caused by Elastin Haploinsufficiency Act by Extrinsic Noncomplementation. J. Biol. Chem. 2011, 286, 44926–44936. [Google Scholar] [CrossRef] [PubMed]
- Pober, B.R. Williams-Beuren Syndrome. N. Engl. J. Med. 2010, 362, 239–252. [Google Scholar] [CrossRef]
- Vassalle, C.; Sabatino, L.; Pingitore, A.; Chatzianagnostou, K.; Mastorci, F.; Ceravolo, R. Antioxidants in the Diet and Cognitive Function: Which Role for the Mediterranean Life-Style? J. Prev. Alzheimers Dis. 2016, 4, 58–64. [Google Scholar] [CrossRef] [PubMed]
- Padayatty, S.J.; Katz, A.; Wang, Y.; Eck, P.; Kwon, O.; Lee, J.-H.; Chen, S.; Corpe, C.; Dutta, A.; Dutta, S.K.; et al. Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention. J. Am. Coll. Nutr. 2003, 22, 18–35. [Google Scholar] [CrossRef]
- Aguirre, R.; May, J.M. Inflammation in the Vascular Bed: Importance of Vitamin C. Pharmacol. Ther. 2008, 119, 96–103. [Google Scholar] [CrossRef]
- Dulac, Y.; Pienkowski, C.; Abadir, S.; Tauber, M.; Acar, P. Cardiovascular Abnormalities in Turner’s Syndrome: What Prevention? Arch. Cardiovasc. Dis. 2008, 101, 485–490. [Google Scholar] [CrossRef]
- Spaziani, M.; Radicioni, A.F. Metabolic and Cardiovascular Risk Factors in Klinefelter Syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 2020, 184, 334–343. [Google Scholar] [CrossRef]
- Calcaterra, V.; Brambilla, P.; Maffè, G.C.; Klersy, C.; Albertini, R.; Introzzi, F.; Bozzola, E.; Bozzola, M.; Larizza, D. Metabolic Syndrome in Turner Syndrome and Relation Between Body Composition and Clinical, Genetic, and Ultrasonographic Characteristics. Metab. Syndr. Relat. Disord. 2014, 12, 159–164. [Google Scholar] [CrossRef]
- Mameli, C.; Fiore, G.; Sangiorgio, A.; Agostinelli, M.; Zichichi, G.; Zuccotti, G.; Verduci, E. Metabolic and Nutritional Aspects in Paediatric Patients with Klinefelter Syndrome: A Narrative Review. Nutrients 2022, 14, 2107. [Google Scholar] [CrossRef]
- Paparella, R.; Panvino, F.; Leonardi, L.; Pucarelli, I.; Menghi, M.; Micangeli, G.; Tarani, F.; Niceta, M.; Rasio, D.; Pancheva, R.; et al. Water-Soluble Vitamins: Hypo- and Hypervitaminosis in Pediatric Population. Pharmaceutics 2025, 17, 118. [Google Scholar] [CrossRef]
- Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids; National Academy Press: Washington, DC, USA, 2000. [Google Scholar]
- Carr, A.C.; Maggini, S. Vitamin C and Immune Function. Nutrients 2017, 9, 1211. [Google Scholar] [CrossRef]
- Jiang, Q. Natural Forms of Vitamin E: Metabolism, Antioxidant, and Anti-Inflammatory Activities and Their Role in Disease Prevention and Therapy. Free Radic. Biol. Med. 2014, 72, 76–90. [Google Scholar] [CrossRef]
- Hannah-Shmouni, F.; Schoepp, M.; Abd-Elmoniem, K.Z.; Matta, J.; Ghanem, A.; Hanover, J.A.; Gharib, A.M. Coronary Atherosclerosis in Females with Turner Syndrome. Can. J. Diabetes 2017, 41, S30. [Google Scholar] [CrossRef]
- Strain, J.J.; Mulholland, C.W. Vitamin C and Vitamin E—Synergistic Interactions in Vivo? In Free Radicals and Aging; Emerit, I., Chance, B., Eds.; Birkhäuser: Basel, Switzerland, 1992; pp. 419–422. ISBN 978-3-0348-7462-5. [Google Scholar]
- Eskenazi, B.; Kidd, S.A.; Marks, A.R.; Sloter, E.; Block, G.; Wyrobek, A.J. Antioxidant Intake Is Associated with Semen Quality in Healthy Men. Hum. Reprod. 2005, 20, 1006–1012. [Google Scholar] [CrossRef]
- Couto, N.; Wood, J.; Barber, J. The Role of Glutathione Reductase and Related Enzymes on Cellular Redox Homoeostasis Network. Free Radic. Biol. Med. 2016, 95, 27–42. [Google Scholar] [CrossRef]
- Enns, G.M.; Moore, T.; Le, A.; Atkuri, K.; Shah, M.K.; Cusmano-Ozog, K.; Niemi, A.-K.; Cowan, T.M. Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status. PLoS ONE 2014, 9, e100001. [Google Scholar] [CrossRef]
- Izigov, N.; Farzam, N.; Savion, N. S-Allylmercapto-N-Acetylcysteine up-Regulates Cellular Glutathione and Protects Vascular Endothelial Cells from Oxidative Stress. Free Radic. Biol. Med. 2011, 50, 1131–1139. [Google Scholar] [CrossRef]
- Grinberg, L.; Fibach, E.; Amer, J.; Atlas, D. N-Acetylcysteine Amide, a Novel Cell-Permeating Thiol, Restores Cellular Glutathione and Protects Human Red Blood Cells from Oxidative Stress. Free Radic. Biol. Med. 2005, 38, 136–145. [Google Scholar] [CrossRef]
- Arancibia-Riveros, C.; Domínguez-López, I.; Laveriano-Santos, E.P.; Parilli-Moser, I.; Tresserra-Rimbau, A.; Ruiz-León, A.M.; Sacanella, E.; Casas, R.; Estruch, R.; Bodega, P.; et al. Unlocking the Power of Polyphenols: A Promising Biomarker of Improved Metabolic Health and Anti-Inflammatory Diet in Adolescents. Clin. Nutr. 2024, 43, 1865–1871. [Google Scholar] [CrossRef]
- Tresserra-Rimbau, A. Dietary Polyphenols and Human Health. Nutrients 2020, 12, 2893. [Google Scholar] [CrossRef]
- Carito, V.; Ceccanti, M.; Cestari, V.; Natella, F.; Bello, C.; Coccurello, R.; Mancinelli, R.; Fiore, M. Olive Polyphenol Effects in a Mouse Model of Chronic Ethanol Addiction. Nutrition 2017, 33, 65–69. [Google Scholar] [CrossRef]
- Fiore, M.; Messina, M.P.; Petrella, C.; D’Angelo, A.; Greco, A.; Ralli, M.; Ferraguti, G.; Tarani, L.; Vitali, M.; Ceccanti, M. Antioxidant Properties of Plant Polyphenols in the Counteraction of Alcohol-Abuse Induced Damage: Impact on the Mediterranean Diet. J. Funct. Foods 2020, 71, 104012. [Google Scholar] [CrossRef]
- Petrella, C.; Di Certo, M.G.; Gabanella, F.; Barbato, C.; Ceci, F.M.; Greco, A.; Ralli, M.; Polimeni, A.; Angeloni, A.; Severini1, C.; et al. Mediterranean Diet, Brain and Muscle: Olive Polyphenols and Resveratrol Protection in Neurodegenerative and Neuromuscular Disorders. Curr. Med. Chem. 2021, 28, 7595–7613. [Google Scholar] [CrossRef]
- Ghosh, D.; Scheepens, A. Vascular Action of Polyphenols. Mol. Nutr. Food Res. 2009, 53, 322–331. [Google Scholar] [CrossRef]
- Lau, F.C.; Shukitt-Hale, B.; Joseph, J.A. Nutritional Intervention in Brain Aging: Reducing the Effects of Inflammation and Oxidative Stress. Subcell. Biochem. 2007, 42, 299–318. [Google Scholar]
- De Santis, S.; Clodoveo, M.L.; Cariello, M.; D’Amato, G.; Franchini, C.; Faienza, M.F.; Corbo, F. Polyphenols and Obesity Prevention: Critical Insights on Molecular Regulation, Bioavailability and Dose in Preclinical and Clinical Settings. Crit. Rev. Food Sci. Nutr. 2021, 61, 1804–1826. [Google Scholar] [CrossRef]
- Wisnuwardani, R.W.; De Henauw, S.; Androutsos, O.; Forsner, M.; Gottrand, F.; Huybrechts, I.; Knaze, V.; Kersting, M.; Le Donne, C.; Marcos, A.; et al. Estimated Dietary Intake of Polyphenols in European Adolescents: The HELENA Study. Eur. J. Nutr. 2019, 58, 2345–2363. [Google Scholar] [CrossRef]
- Krinsky, N.I.; Johnson, E.J. Carotenoid Actions and Their Relation to Health and Disease. Mol. Aspects Med. 2005, 26, 459–516. [Google Scholar] [CrossRef]
- Fiedor, J.; Burda, K. Potential Role of Carotenoids as Antioxidants in Human Health and Disease. Nutrients 2014, 6, 466–488. [Google Scholar] [CrossRef]
- Kaulmann, A.; Bohn, T. Carotenoids, Inflammation, and Oxidative Stress--Implications of Cellular Signaling Pathways and Relation to Chronic Disease Prevention. Nutr. Res. 2014, 34, 907–929. [Google Scholar] [CrossRef]
- Landrum, J.T.; Bone, R.A. Lutein, Zeaxanthin, and the Macular Pigment. Arch. Biochem. Biophys. 2001, 385, 28–40. [Google Scholar] [CrossRef]
- Stahl, W.; Sies, H. Bioactivity and Protective Effects of Natural Carotenoids. Biochim. Biophys. Acta 2005, 1740, 101–107. [Google Scholar] [CrossRef]
- Tan, D.-X.; Manchester, L.; Esteban-Zubero, E.; Zhou, Z.; Reiter, R. Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism. Molecules 2015, 20, 18886–18906. [Google Scholar] [CrossRef]
- Chen, Y.-C.; Tain, Y.-L.; Sheen, J.-M.; Huang, L.-T. Melatonin Utility in Neonates and Children. J. Formos. Med. Assoc. 2012, 111, 57–66. [Google Scholar] [CrossRef]
- Lee, S.K.M.; Smith, L.; Tan, E.C.K.; Cairns, R.; Grunstein, R.; Cheung, J.M.Y. Melatonin Use in Children and Adolescents: A Scoping Review of Caregiver Perspectives. Sleep Med. Rev. 2023, 70, 101808. [Google Scholar] [CrossRef]
- Chitimus, D.M.; Popescu, M.R.; Voiculescu, S.E.; Panaitescu, A.M.; Pavel, B.; Zagrean, L.; Zagrean, A.-M. Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules 2020, 10, 1211. [Google Scholar] [CrossRef]
- Garofoli, F.; Franco, V.; Accorsi, P.; Albertini, R.; Angelini, M.; Asteggiano, C.; Aversa, S.; Ballante, E.; Borgatti, R.; Cabini, R.F.; et al. Fate of Melatonin Orally Administered in Preterm Newborns: Antioxidant Performance and Basis for Neuroprotection. J. Pineal Res. 2024, 76, e12932. [Google Scholar] [CrossRef]
- Luboshitzky, R.; Wagner, O.; Lavi, S.; Herer, P.; Lavie, P. Decreased Nocturnal Melatonin Secretion in Patients with Klinefelter’s Syndrome. Clin. Endocrinol. Oxf. 1996, 45, 749–754. [Google Scholar] [CrossRef]
- Caglayan, S.; Ozata, M.; Ozisik, G.; Turan, M.; Bolu, E.; Oktenli, C.; Arslan, N.; Erbil, K.; Gul, D.; Ozdemir, I.C. Plasma Melatonin Concentration before and during Testosterone Replacement in Klinefelter’s Syndrome: Relation to Hepatic Indolamine Metabolism and Sympathoadrenal Activity. J. Clin. Endocrinol. Metab. 2001, 86, 738–743. [Google Scholar] [CrossRef] [PubMed]
- Rouen, A.; Elbaz, M.; Duquesne, E.; Caetano, G.; Léger, D. Multifactorial Sleep Disturbance in Klinefelter Syndrome: A Case Report. Transl. Androl. Urol. 2023, 12, 1204–1210. [Google Scholar] [CrossRef]
- Attanasio, A.; Borrelli, P.; Munding, G.; Gupta, D. Melatonin Day-Night Rhythms in Subjects with Turner Syndrome. Pediatr. Res. 1984, 18, 1227. [Google Scholar] [CrossRef]
- Schober, E.; Waldhauser, F.; Frisch, H.; Schuster, E.; Bieglmayer, C. Melatonin secretion in turner’s syndrome: Lack of effect of oestrogen administration. Clin. Endocrinol. Oxf. 1989, 31, 475–479. [Google Scholar] [CrossRef]
- Paparella, R.; Panvino, F.; Gambuti, L.; Cerrito, A.; Pallante, A.; Micangeli, G.; Menghi, M.; Pisani, F.; Bruni, O.; Ardizzone, I.; et al. Evaluation of Sleep Disorders in Children and Adolescents Affected by Klinefelter Syndrome. Eur. J. Pediatr. 2025, 184, 129. [Google Scholar] [CrossRef] [PubMed]
- Karbasi, S.; Mohamadian, M.; Naseri, M.; Khorasanchi, Z.; Zarban, A.; Bahrami, A.; Ferns, G.A. A Mediterranean Diet Is Associated with Improved Total Antioxidant Content of Human Breast Milk and Infant Urine. Nutr. J. 2023, 22, 11. [Google Scholar] [CrossRef] [PubMed]
- Gantenbein, K.V.; Kanaka-Gantenbein, C. Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing. Nutrients 2021, 13, 1951. [Google Scholar] [CrossRef]
- Li, P.; Cheng, F.; Xiu, L. Height Outcome of the Recombinant Human Growth Hormone Treatment in Turner Syndrome: A Meta-Analysis. Endocr. Connect. 2018, 7, 573–583. [Google Scholar] [CrossRef]
- Ross, J.L.; Kushner, H.; Kowal, K.; Bardsley, M.; Davis, S.; Reiss, A.L.; Tartaglia, N.; Roeltgen, D. Androgen Treatment Effects on Motor Function, Cognition, and Behavior in Boys with Klinefelter Syndrome. J. Pediatr. 2017, 185, 193–199.e4. [Google Scholar] [CrossRef]
- Chaudhary, P.; Janmeda, P.; Docea, A.O.; Yeskaliyeva, B.; Abdull Razis, A.F.; Modu, B.; Calina, D.; Sharifi-Rad, J. Oxidative Stress, Free Radicals and Antioxidants: Potential Crosstalk in the Pathophysiology of Human Diseases. Front. Chem. 2023, 11, 1158198. [Google Scholar] [CrossRef]
- Poljsak, B. Strategies for Reducing or Preventing the Generation of Oxidative Stress. Oxid. Med. Cell. Longev. 2011, 2011, 194586. [Google Scholar] [CrossRef] [PubMed]
Gene (Chromosomal Location) | Function | Biochemical Reaction | Damage Caused | Related Conditions |
---|---|---|---|---|
XIAP (Xq25) | Inhibits apoptosis; promotes SOD-2 | Prevents caspase cascade, promotes mitochondrial integrity | Mitochondrial dysfunction, oxidative neuronal injury | Neurodevelopmental delay, cardiovascular issues (TS) |
SLC25A5 (Xq24) | Mitochondrial ADP/ATP exchange | Regulates mitochondrial respiration and ROS generation | ROS accumulation, metabolic inefficiency | Metabolic syndrome, energy dysregulation |
EGR1 (Xq13.1) | Transcription factor, oxidative stress response | Regulates apoptotic and redox-responsive genes | Abnormal proliferation and stress signaling | Growth abnormalities, altered cell cycle (TS) |
KLF4 (Xq24) | Anti-inflammatory and antioxidant TF | Regulates endothelial and immune antioxidant genes | Vascular inflammation, endothelial dysfunction | Atherosclerosis, vascular aging |
SOX11 (Xp22.3) | Osteogenic and neurodevelopmental TF | Modulates BMP signaling, regulates differentiation | Skeletal malformations, neurocognitive dysfunction | Turner-related skeletal dysplasia |
MAO-A (Xp11.3; SRY-regulated) | Degrades monoamines, regulated by SRY (Yp11.2) | Produces H2O2 during catecholamine metabolism | Oxidative stress in neurons, H2O2 accumulation | ADHD, autism spectrum disorders |
GPX4 (19p13.11) | Detoxifies lipid peroxides | Reduces phospholipid hydroperoxides (prevents ferroptosis) | Ferroptotic cell death, especially in testis and neurons | Infertility (KS), cognitive decline |
NOX4 (11q14.3) | NADPH oxidase, generates ROS | Produces H2O2 from oxygen and NADPH | DNA/protein oxidative damage, tissue fibrosis | Thyroid disorders, diabetes, fibrosis |
GADD45B (19p13.3) | Stress-responsive TF, MAPK modulator | Interacts with MAPKs, regulates apoptosis and DNA repair | Inflammation, susceptibility to neoplastic transformation | Inflammatory disease, colorectal cancer |
DUOXA1 (15q21.1) | DUOX maturation factor | Enables H2O2 production in thyroid hormone synthesis | ROS imbalance in thyroid; hypothyroidism | Congenital hypothyroidism |
SCA Type | Age Group | Suggested Antioxidants | Adjunct Therapy | Clinical Focus |
---|---|---|---|---|
Turner Syndrome | Prepubertal | Vitamin C, vitamin E, polyphenol-rich diet | Cardiovascular monitoring | Endothelial health, metabolic prevention |
Turner Syndrome | Adolescent | NAC, vitamin E | Estrogen replacement therapy | Oxidative stress reduction, lipid control |
Klinefelter Syndrome | Prepubertal | Polyphenol-rich diet, multivitamins | Lifestyle advice | Prevent early metabolic impairment |
Klinefelter Syndrome | Adolescent | NAC, CoQ10, vitamin E | Testosterone replacement therapy | Redox balance, neuroprotection |
47,XXX/47,XYY/HGAs | All ages | General antioxidant-rich diet, vitamin C | Multidisciplinary surveillance | Neurocognitive support, systemic defense |
Rank | Antioxidant | Main Mechanism of Action | Targeted Complications | Notes |
---|---|---|---|---|
1 | Vitamin C + Vitamin E | ROS scavenging, lipid peroxidation prevention, vascular protection | Cardiovascular, metabolic | Synergistic effect, safe and well-studied |
2 | N-acetylcysteine (NAC) | Glutathione precursor, mitochondrial support | Neurocognitive, metabolic | Evidence from cystic fibrosis and others |
3 | Melatonin | ROS scavenger, upregulates antioxidant enzymes, neuroprotection | Neurodevelopmental | Also useful for sleep disturbances |
4 | Dietary polyphenols | Anti-inflammatory improves endothelial function | Metabolic, cardiovascular | Requires dietary adherence |
5 | Carotenoids | Free radical quenching, protects DNA, lipids, proteins | Neurodevelopmental, vision, immunity | Lutein and beta-carotene most relevant |
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Paparella, R.; Panvino, F.; Tarani, F.; D’Agostino, B.; Leonardi, L.; Ferraguti, G.; Venditti, S.; Colloridi, F.; Pucarelli, I.; Tarani, L.; et al. An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations. Antioxidants 2025, 14, 531. https://doi.org/10.3390/antiox14050531
Paparella R, Panvino F, Tarani F, D’Agostino B, Leonardi L, Ferraguti G, Venditti S, Colloridi F, Pucarelli I, Tarani L, et al. An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations. Antioxidants. 2025; 14(5):531. https://doi.org/10.3390/antiox14050531
Chicago/Turabian StylePaparella, Roberto, Fabiola Panvino, Francesca Tarani, Benedetto D’Agostino, Lucia Leonardi, Giampiero Ferraguti, Sabrina Venditti, Fiorenza Colloridi, Ida Pucarelli, Luigi Tarani, and et al. 2025. "An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations" Antioxidants 14, no. 5: 531. https://doi.org/10.3390/antiox14050531
APA StylePaparella, R., Panvino, F., Tarani, F., D’Agostino, B., Leonardi, L., Ferraguti, G., Venditti, S., Colloridi, F., Pucarelli, I., Tarani, L., & Fiore, M. (2025). An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations. Antioxidants, 14(5), 531. https://doi.org/10.3390/antiox14050531