{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T13:55:59Z","timestamp":1794405359649,"version":"4.9.0"},"reference-count":143,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T00:00:00Z","timestamp":1555891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DU\/DST PURSE and R&amp;D","award":["CD\/2016\/1761, RC\/2015\/9677-882"],"award-info":[{"award-number":["CD\/2016\/1761, RC\/2015\/9677-882"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Oxidative stress is proposed as a regulatory element in ageing and various neurological disorders. The excess of oxidants causes a reduction of antioxidants, which in turn produce an oxidation\u2013reduction imbalance in organisms. Paucity of the antioxidant system generates oxidative-stress, characterized by elevated levels of reactive species (oxygen, hydroxyl free radical, and so on). Mitochondria play a key role in ATP supply to cells via oxidative phosphorylation, as well as synthesis of essential biological molecules. Various redox reactions catalyzed by enzymes take place in the oxidative phosphorylation process. An inefficient oxidative phosphorylation may generate reactive oxygen species (ROS), leading to mitochondrial dysfunction. Mitochondrial redox metabolism, phospholipid metabolism, and proteolytic pathways are found to be the major and potential source of free radicals. A lower concentration of ROS is essential for normal cellular signaling, whereas the higher concentration and long-time exposure of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, ultimately resulting in necrosis and apoptotic cell death. Normal and proper functioning of the central nervous system (CNS) is entirely dependent on the chemical integrity of brain. It is well established that the brain consumes a large amount of oxygen and is highly rich in lipid content, becoming prone to oxidative stress. A high consumption of oxygen leads to excessive production of ROS. Apart from this, the neuronal membranes are found to be rich in polyunsaturated fatty acids, which are highly susceptible to ROS. Various neurodegenerative diseases such as Parkinson\u2019s disease (PD), Alzheimer\u2019s disease (AD), Huntington\u2019s disease (HD), and amyotrophic lateral sclerosis (ALS), among others, can be the result of biochemical alteration (due to oxidative stress) in bimolecular components. There is a need to understand the processes and role of oxidative stress in neurodegenerative diseases. This review is an effort towards improving our understanding of the pivotal role played by OS in neurodegenerative disorders.<\/jats:p>","DOI":"10.3390\/molecules24081583","type":"journal-article","created":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T11:02:53Z","timestamp":1555930973000},"page":"1583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2128,"title":["Oxidative Stress: A Key Modulator in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4980-0669","authenticated-orcid":false,"given":"Anju","family":"Singh","sequence":"first","affiliation":[{"name":"Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi 110007, India"},{"name":"Department of Chemistry, Ramjas College, University of Delhi, Delhi 110007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ritushree","family":"Kukreti","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, Delhi 110007, India"},{"name":"Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi 110007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4530-8706","authenticated-orcid":false,"given":"Luciano","family":"Saso","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cVittorio Erspamer\u201d, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-8364","authenticated-orcid":false,"given":"Shrikant","family":"Kukreti","sequence":"additional","affiliation":[{"name":"Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi 110007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,22]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases","volume":"2016","author":"Orlacchio","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-2952(99)00289-0","article-title":"Redox sensing by prokaryotic transcription factors","volume":"59","author":"Zheng","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15091","DOI":"10.1016\/S0021-9258(18)98591-1","article-title":"Perhydroxyl radical (HOO) initiated lipid peroxidation: The role of fatty acid hydroperoxides","volume":"266","author":"Aikens","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_4","unstructured":"Halliwell, B., and Gutteridge, J.M. (1999). Free Radicals in Biology and Medicine, Oxford University Press. [3rd ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free radicals in the physiological control of cell function","volume":"82","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1089\/ars.2010.3547","article-title":"Chronic inflammatory disordersandtheirredox control from molecular mechanisms totherapeutic opportunities","volume":"15","author":"MacCarrone","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1104\/pp.106.077073","article-title":"Reactive Species and Antioxidants. Redox Biology Is a Fundamental Theme of Aerobic Life","volume":"141","author":"Halliwell","year":"2006","journal-title":"Plant Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1042\/BST0351147","article-title":"Biochemistry of oxidative stress","volume":"35","author":"Halliwell","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_9","unstructured":"Harvey, L., Arnold, B., Lawrence, Z., Paul, M., and David, B. (1999). Molecular Cell Biology, Publisher W.H. Freeman & Co. Ltd.. [4th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/74994","article-title":"Mitochondrial control of cell death","volume":"6","author":"Guido","year":"2000","journal-title":"Nat. Med."},{"key":"ref_11","first-page":"658","article-title":"Reactive oxygen species: Oxidative damage and pathogenesis","volume":"77","author":"Uday","year":"1990","journal-title":"Curr. Sci."},{"key":"ref_12","first-page":"9","article-title":"Role of oxidative DNA damage in cancer initiation and promotion","volume":"7","author":"Poulson","year":"1998","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/S0899-9007(02)00916-4","article-title":"Free radicals, antioxidants, and nutrition","volume":"18","author":"Sheng","year":"2002","journal-title":"Nutrition"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/j.nut.2009.11.009","article-title":"More than thesumofitsparts? Nutritionin Alzheimer\u2019s disease","volume":"26","author":"Gola","year":"2010","journal-title":"Nutrition"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1080\/1028415X.1998.11747230","article-title":"Dietary antioxidant deficiency facilitates cortical spreading depression induced by photoactivated riboflavin","volume":"1","author":"Guedes","year":"1998","journal-title":"Nutr. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"729","DOI":"10.2165\/00023210-200317100-00004","article-title":"Neuroprotective strategies in Parkinson\u2019s disease: An update on progress","volume":"17","author":"Mandel","year":"2003","journal-title":"CNS Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1002\/jnr.22011","article-title":"Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado Joseph disease","volume":"87","author":"Yu","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1046\/j.1471-4159.1997.69031196.x","article-title":"Oxidative DNA damage in the parkinsonian brain: An apparent selective increase in 8-hydroxyguanine levels in substantia nigra","volume":"69","author":"Alam","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1046\/j.1471-4159.1998.71052034.x","article-title":"Increased nuclear DNA oxidation in the brain in Alzheimer\u2019s disease","volume":"71","author":"Gabbita","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/nchembio0909-602","article-title":"Working towards an exegesis for lipids in biology","volume":"5","author":"Brown","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj2190001","article-title":"Oxygen toxicity, oxygen radicals, transition metals and disease","volume":"219","author":"Halliwell","year":"1984","journal-title":"Biochem. J."},{"key":"ref_22","first-page":"242","article-title":"Mitochondrial Dysfunction during Brain Aging: Role of Oxidative Stress and Modulation by Antioxidant Supplementation","volume":"2","author":"Chakrabarti","year":"2011","journal-title":"Aging Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Federico, A., Cardaioli, E., da Pozzo, P., Formichi, P., Gallus, G.N., and Radi, E. (2012). Mitochondria, oxidative stress and neurodegeneration. J. Neurol. Sci.","DOI":"10.1016\/j.jns.2012.05.030"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1152\/physrev.1998.78.2.547","article-title":"The free radical theory of aging matures","volume":"78","author":"Beckman","year":"1998","journal-title":"Physiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jchromb.2005.04.023","article-title":"Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview","volume":"827","author":"Mariani","year":"2005","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1194\/jlr.M010520","article-title":"Cardiolipin: Characterization of distinct oxidized molecular species","volume":"52","author":"Junhwan","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.neuint.2007.01.007","article-title":"Depolarization and cardiolipin depletion in aged rat brain mitochondria: Relationship with oxidative stress and electron transport chain activity","volume":"50","author":"Sen","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1111\/j.1471-4159.1992.tb10990.x","article-title":"Reactive Oxygen Species and the Central Nervous System","volume":"59","author":"Halliwell","year":"1992","journal-title":"J. Neurochem."},{"key":"ref_29","first-page":"1","article-title":"Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson\u2019s Disease","volume":"2","author":"Navarro","year":"2010","journal-title":"Front. Aging Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/BF02815160","article-title":"Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain","volume":"31","author":"Mecocci","year":"1997","journal-title":"Mol. Chem. Neuropathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0197-4580(03)00037-X","article-title":"Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson\u2019s disease","volume":"25","author":"Simon","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/ng1292-324","article-title":"Mitochondrial DNA deletions in human brain: Regional variability and increase with advanced age","volume":"2","author":"Horton","year":"1992","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1089\/rej.2009.0849","article-title":"Age-dependent down-regulation of mitochondrial 8-oxoguanine DNA glycosylase in SAM-P\/8 mouse brain and its effect on brain aging","volume":"12","author":"Tian","year":"2009","journal-title":"Rejuvenation Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.neurobiolaging.2005.06.002","article-title":"Mitochondrial and nuclear DNArepair capacity of various brain regions in mouse is altered in an age-dependent manner","volume":"27","author":"Imam","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.abb.2008.01.028","article-title":"Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?","volume":"476","author":"Halliwell","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1179\/1351000211Y.0000000015","article-title":"Exploration of pro-oxidant and antioxidant activities of the flavonoid myricetin","volume":"16","author":"Chobot","year":"2011","journal-title":"Redox Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejphar.2006.06.025","article-title":"Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: A review of their intracellular targets","volume":"545","author":"Ramasamy","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.bbadis.2006.03.002","article-title":"Anti-amyloidogenic effects of antioxidants: Implications for the prevention and therapeutics of Alzheimer\u2019s disease","volume":"1762","author":"Ono","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0168-8278(01)00236-7","article-title":"Protective effect to flow dose of ascorbic acid on hepatobiliary function in hepatic ischemia\/repersfusioninrats","volume":"36","author":"Seo","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/761264","article-title":"Oxidative Stress, Prooxidants, and Antioxidants: The Interplay","volume":"2014","author":"Rahal","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_41","first-page":"1","article-title":"Environmental Pollutants as risk factors for neurodegenerative disorder: Alzheimer and Parkinson diseases","volume":"9","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rai, M., Ingle, A., and Medici, S. (2018). Biochemical and molecular targets of heavy metals and their actions. Biomedical Applications of Metals, Springer.","DOI":"10.1007\/978-3-319-74814-6"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fchem.2017.00070","article-title":"Synergistic effects of heavy metals and pesticides in living systems","volume":"5","author":"Singh","year":"2017","journal-title":"Front. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuro.2005.05.004","article-title":"Mercury exposure: Evaluation and intervention the inappropriate use of chelating agents in the diagnosis and treatment of putative mercury poisoning","volume":"26","author":"Risher","year":"2005","journal-title":"Neurotoxicology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/tox.10116","article-title":"Environmental exposure to mercury and its toxicopathologic implications for public health","volume":"18","author":"Tchounwou","year":"2003","journal-title":"Environ. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1021\/acs.chemrestox.8b00193","article-title":"Biochemical and molecular bases of lead-induced toxicity in mammalian systems and possible mitigations","volume":"31","author":"Singh","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cca.2007.04.024","article-title":"Low level lead exposure andoxidative stress: Current opinions","volume":"383","author":"Ahamed","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.envint.2014.04.019","article-title":"Arsenic and selenium toxicity and their interactive effects in humans","volume":"69","author":"Sun","year":"2014","journal-title":"Environ. Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"640754","DOI":"10.1155\/2014\/640754","article-title":"Biomedical implications of heavy metals induced imbalances in redox systems","volume":"2014","author":"Sharma","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_50","first-page":"1","article-title":"Effects of Mercury, Lead, Arsenic and Zinc to Human Renal Oxidative Stress and Functions: A Review","volume":"4","year":"2018","journal-title":"J. Heavy Met. Toxic. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Neitemeier, S., Jelinek, A., Laino, V., Hoffmann, L., Eisenbach, I., Eying, R., Ganjam, G.K., Dolga, A.M., Oppermann, S., and Culmsee, C. (2017). BID links ferroptosis to mitochondrial cell death pathways. Redox Biol., 558\u2013570.","DOI":"10.1016\/j.redox.2017.03.007"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.tcb.2015.10.014","article-title":"Ferroptosis: Death by lipid peroxidation","volume":"26","author":"Yang","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41598-017-18935-1","article-title":"Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells","volume":"8","author":"Wu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_54","unstructured":"Magtanong, L., and Dixon, S.J. (2019). Ferroptosis and Brain Injury. Dev. Neurosci., 1\u201314."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnins.2019.00115","article-title":"The Potential Role of Ferroptosis in Neonatal Brain Injury","volume":"13","author":"Wu","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Raychaudhuri, S. (2010). A minimal model of signaling network elucidates cell-to-cell stochastic variability in apoptosis. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011930"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1080\/15216540500091890","article-title":"Reactive oxygen species as mediators of cellular senescence","volume":"57","author":"Colavitti","year":"2005","journal-title":"IUBMB Life"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/978-1-62703-556-9_11","article-title":"Methods of cellular senescence induction using oxidative stress","volume":"1048","author":"Wang","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s10522-014-9532-1","article-title":"Are there roles for brain cell senescence in aging and neurodegenerative disorders?","volume":"15","author":"Tan","year":"2014","journal-title":"Biogerontology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fenvs.2014.00053","article-title":"Reactive Oxygen Species (ROS) and responses of antioxidants as ROS-scavengers during environmental stress in plants","volume":"2","author":"Das","year":"2014","journal-title":"Front. Environ. Sci."},{"key":"ref_62","first-page":"1","article-title":"Oxidative Stress: Harms and Benefits for Human Health","volume":"2017","author":"Pizzino","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Liu, J., Wang, J., Lee, S., and Wen, R. (2018). Copper-caused oxidative stress triggers the activation of antioxidant enzymes via ZmMPK3 in maize leaves. PLoS ONE.","DOI":"10.1371\/journal.pone.0203612"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00441-004-0976-5","article-title":"Redox imbalance","volume":"318","author":"Berg","year":"2004","journal-title":"Cell Tissue Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pediatrneurol.2003.10.001","article-title":"Selective vulnerability in the developing central nervous system","volume":"30","author":"McQuillen","year":"2004","journal-title":"Pediatr. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/jnr.20280","article-title":"Peroxide detoxification by brain cells","volume":"79","author":"Dringen","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/jnr.10439","article-title":"New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain","volume":"70","author":"Rougemont","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0301-0082(99)00060-X","article-title":"Metabolism and functions of glutathione in brain","volume":"62","author":"Dringen","year":"2000","journal-title":"Prog. Neurobiol."},{"key":"ref_69","first-page":"250","article-title":"Effects of right-unilateral 6-hydroxydopamine infusion-induced memory impairment and oxidative stress: Relevance for Parkinson\u2019s disease","volume":"3","author":"Hritcu","year":"2008","journal-title":"Cent. Eur. J. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3233\/JAD-2006-9S334","article-title":"Oxidative stress and iron imbalance in Alzheimer disease: How rust became the fuss!","volume":"9","author":"Smith","year":"2006","journal-title":"J. Alzheimers Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1007\/s11064-008-9593-0","article-title":"Protein levels and activity of some antioxidant enzymes in hippocampus of subjects with amnestic mild cognitive impairment","volume":"33","author":"Sultana","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0165-0173(97)00045-3","article-title":"Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death","volume":"25","author":"Bains","year":"1997","journal-title":"Brain Res. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3233\/JAD-2001-3111","article-title":"Alzheimer\u2019s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein","volume":"3","author":"Selkoe","year":"2001","journal-title":"J. Alzheimers Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nature02621","article-title":"Pathways towards and away from Alzheimer\u2019s disease","volume":"430","author":"Mattson","year":"2004","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.tips.2008.09.001","article-title":"Oxidative stress hypothesis in Alzheimer\u2019s disease: A reappraisal","volume":"29","author":"Pratico","year":"2008","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zhao, Y., and Zhao, B. (2013). Oxidative stress and the pathogenesis of Alzheimer\u2019s disease. Oxid. Med. Cell. Longev., 316523.","DOI":"10.1155\/2013\/316523"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.bbadis.2013.10.015","article-title":"Oxidative stress and mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"1842","author":"Wang","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.freeradbiomed.2012.09.036","article-title":"Antioxidant role of amyloid \u00ce2 protein in cell-free and biological systems: Implication for the pathogenesis of Alzheimer disease","volume":"56","author":"Sinha","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.neuint.2012.08.014","article-title":"Metal dyshomeostasis and oxidative stress in Alzheimer\u2019s disease","volume":"62","author":"Greenough","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Craddock, T.J., Tuszynski, J.A., Chopra, D., Casey, N., Goldstein, L.E., Hameroff, S.R., and Tanzi, R.E. (2012). The zinc dyshomeostasis hypothesis of Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/annotation\/57c710a6-83ba-444c-a352-b9f60125f2fa"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1196\/annals.1306.012","article-title":"Redox-active metals, oxidative stress, and Alzheimer\u2019s disease pathology","volume":"1012","author":"Huang","year":"2004","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0165-0173(02)00219-9","article-title":"Zinc takes the center stage: Its paradoxical role in Alzheimer\u2019s disease","volume":"41","author":"Cuajungco","year":"2003","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3892\/br.2016.630","article-title":"Role of oxidative stress in Alzheimer\u2019s disease (Review)","volume":"4","author":"Huang","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1016\/j.neurobiolaging.2007.12.005","article-title":"Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice","volume":"30","author":"Hauptmann","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1096\/fj.05-3735fje","article-title":"Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer\u2019s disease","volume":"19","author":"Caspersen","year":"2005","journal-title":"FASEB J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"S265","DOI":"10.3233\/JAD-2010-100339","article-title":"The Alzheimer\u2019s disease mitochondrial cascade hypothesis","volume":"20","author":"Swerdlow","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"780179","DOI":"10.1155\/2014\/780179","article-title":"Mitochondrial dysfunction: Different routes to Alzheimer\u2019s disease therapy","volume":"2014","author":"Picone","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0006-8993(02)03280-8","article-title":"Aberrant expression of NOS isoforms in Alzheimer\u2019s disease is structurally related to nitrotyrosine formation","volume":"953","author":"Arendt","year":"2002","journal-title":"Brain Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0006-8993(01)02758-5","article-title":"Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer\u2019s disease, in APP23 transgenic mice and after experimental brain lesion in rat: Evidence for an induction by amyloid pathology","volume":"913","author":"Holzer","year":"2001","journal-title":"Brain Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"662","DOI":"10.2174\/157015911798376244","article-title":"Neuronal and vascular oxidative stress in Alzheimer\u2019s disease","volume":"9","author":"Massaad","year":"2011","journal-title":"Curr. Neuropharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1139\/Y09-048","article-title":"Cerebral blood flow regulation by nitric oxide in neurological disorders","volume":"87","author":"Toda","year":"2009","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/978-1-60327-029-8_8","article-title":"Nanoparticle and iron chelators as a potential novel Alzheimer therapy","volume":"610","author":"Liu","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association work groups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.bbadis.2011.10.006","article-title":"Antioxidant clinical trials in mild cognitive impairment and Alzheimer\u2019s disease","volume":"1822","author":"Mecocci","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_95","first-page":"461","article-title":"The Role of Oxidative Stress in Parkinson\u2019s Disease","volume":"3","author":"Dias","year":"2013","journal-title":"J. Park. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/mds.23732","article-title":"Etiology and pathogenesis of Parkinson\u2019s disease","volume":"26","author":"Schapira","year":"2011","journal-title":"Mov. Disord."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nm.2165","article-title":"Missing pieces in the Parkinson\u2019s disease puzzle","volume":"16","author":"Obeso","year":"2010","journal-title":"Nat. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jns.2011.04.005","article-title":"Converging environmental and genetic pathways in the pathogenesis of Parkinson\u2019s disease","volume":"306","author":"Burbulla","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nchembio782","article-title":"Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synucleinfibrilization","volume":"2","author":"Bosco","year":"2006","journal-title":"Nat. Chem. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/jnr.21191","article-title":"Oxidative damage in nucleic acids and Parkinson\u2019s disease","volume":"85","author":"Nakabeppu","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.biopha.2008.01.017","article-title":"Glutathione and Parkinson\u2019s disease: Is this the elephant in the room?","volume":"62","author":"Zeevalk","year":"2008","journal-title":"Biomed. Pharmacother."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13041-017-0340-9","article-title":"Oxidative stress and cellular pathologies in Parkinson\u2019s disease","volume":"10","author":"Lesly","year":"2017","journal-title":"Mol. Brain"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.expneurol.2011.09.035","article-title":"Stress, depression and Parkinson\u2019s disease","volume":"233","author":"Hemmerle","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0361-9230(03)00182-5","article-title":"The role of metals in neurodegenerative processes: Aluminum, manganese, and zinc","volume":"62","author":"Zatta","year":"2003","journal-title":"Brain Res. Bull."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/j.1753-4887.2012.00521.x","article-title":"Limbic system pathologies associated with deficiencies and excesses of the trace elements iron, zinc, copper, and selenium","volume":"70","author":"VieyraReyes","year":"2012","journal-title":"Nutr. Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1080\/1521654032000114320","article-title":"Nitric oxide and reactive oxygen species in Parkinson\u2019s disease","volume":"55","author":"Tieu","year":"2003","journal-title":"IUBMB Life"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0306-4522(95)00578-1","article-title":"Nitric oxide synthase and neuronal vulnerability in Parkinson\u2019s disease","volume":"72","author":"Hunot","year":"1996","journal-title":"Neuroscience"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/S0169-328X(98)00259-9","article-title":"Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson\u2019s disease","volume":"63","author":"Eve","year":"1998","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1126\/science.1096284","article-title":"Hereditary early-onset Parkinson\u2019s disease caused by mutations in PINK1","volume":"304","author":"Valente","year":"2004","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","article-title":"Mutation in the alpha-synuclein gene identified in families with Parkinson\u2019s disease","volume":"276","author":"Polymeropoulos","year":"1997","journal-title":"Science"},{"key":"ref_111","first-page":"412","article-title":"A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson\u2019s disease","volume":"365","author":"Rohe","year":"2005","journal-title":"Lancet"},{"key":"ref_112","first-page":"410","article-title":"Genetic screening for a single common LRRK2 mutation in familial Parkinson\u2019s disease","volume":"365","author":"Nichols","year":"2005","journal-title":"Lancet"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1077209","article-title":"Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism","volume":"299","author":"Bonifati","year":"2003","journal-title":"Science"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature14893","article-title":"The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy","volume":"524","author":"Lazarou","year":"2015","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2014.12.007","article-title":"The roles of PINK1, Parkin, and mitochondrial Fidelity in Parkinson\u2019s disease","volume":"85","author":"Pickrell","year":"2015","journal-title":"Neuron"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"9103","DOI":"10.1073\/pnas.0402959101","article-title":"The Parkinson\u2019s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization","volume":"101","author":"Miller","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e1350","DOI":"10.1038\/cddis.2014.307","article-title":"DJ-1 interactions with \u03b1-synuclein attenuate aggregation and cellular toxicity in models of Parkinson\u2019s disease","volume":"5","author":"Zondler","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"141ra90","DOI":"10.1126\/scitranslmed.3003985","article-title":"Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson\u2019s disease","volume":"4","author":"Cooper","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1080\/146608202760196020","article-title":"Detection of N epsilon\u2013(carboxymethyl)lysine (CML) and non\u2013CML advanced glycation end\u2013products in the anterior horn of amyotrophic lateral sclerosis spinal cord","volume":"3","author":"Kikuchi","year":"2002","journal-title":"Amyotroph. Lateral Scler Other Motor Neuron Disord."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.brainres.2014.09.041","article-title":"BiomarkerdevelopmentforC9orf72 repeat expansion in ALS","volume":"1607","author":"Mendez","year":"2015","journal-title":"Brain Res."},{"key":"ref_122","first-page":"38","article-title":"Role of oxidative stress, ER stress and ubiquitin proteasome system in neurodegeneration","volume":"1","author":"Jha","year":"2014","journal-title":"MOJ Cell Sci. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/S0140-6736(96)91680-3","article-title":"Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis\/Riluzole Study GroupII","volume":"347","author":"Lacomblez","year":"1996","journal-title":"Lancet"},{"key":"ref_124","first-page":"241","article-title":"Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (phase II study)","volume":"7","author":"Yoshino","year":"2006","journal-title":"Amyotrop. Later. Sclerosis Off. Public World Fed. Neurol. Res. Group Motor Neuron Dis."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1001\/archneur.1995.00540300031009","article-title":"Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis","volume":"52","author":"Louwerse","year":"1995","journal-title":"Arch. Neurol."},{"key":"ref_126","first-page":"2003","article-title":"Oxidative stress, mitochondrial damage and neurodegenerative diseases","volume":"8","author":"Guo","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_127","first-page":"4094","article-title":"Oxidative Stress in Neurodegenerative Diseases","volume":"53","author":"Niedzielska","year":"2016","journal-title":"Mol. Neuro Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1177\/1073858414561795","article-title":"SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes","volume":"21","author":"Saccon","year":"2015","journal-title":"Neuroscientist"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"3683","DOI":"10.1038\/s41467-018-06111-6","article-title":"Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis","volume":"9","author":"Wang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_130","first-page":"1","article-title":"Unifying Mechanism for Multiple Sclerosis and Amyotrophic Lateral Sclerosis: Reactive Oxygen Species, Oxidative Stress, and Antioxidants","volume":"2","author":"Kovacic","year":"2018","journal-title":"J. Biopharm. Ther. Chal."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/00005072-199805000-00001","article-title":"Huntington disease","volume":"57","author":"Vonsattel","year":"1998","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1017\/S0033291700047966","article-title":"The association of affective disorder with Huntington\u2019s disease in a case series and in families","volume":"13","author":"Folstein","year":"1983","journal-title":"Psychol. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1177\/1073858404266777","article-title":"Huntingtin and its role in neuronal degeneration","volume":"10","author":"Li","year":"2004","journal-title":"Neuroscientist"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1196\/annals.1427.008","article-title":"Evidence of oxidant damage in Huntington\u2019s disease: Translational strategies using antioxidants","volume":"1147","author":"Stack","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"5602","DOI":"10.1021\/jm200605a","article-title":"Important Role of Oxidative Stress Biomarkers in Huntington\u2019s disease","volume":"54","author":"Tunez","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nrg1689","article-title":"Repeat instability: Mechanisms of dynamic mutations","volume":"6","author":"Pearson","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.bbadis.2011.11.014","article-title":"Antioxidants in Huntington\u2019s Disease","volume":"1822","author":"Johri","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3233\/JHD-160205","article-title":"Oxidative Stress and Huntington\u2019s Disease: The Good, The Bad, and The Ugly","volume":"5","author":"Kumar","year":"2016","journal-title":"J. Huntingt. Dis."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"386","DOI":"10.15406\/japlr.2018.07.00256","article-title":"Role of free radicals and certain antioxidants in the management of huntington\u2019s disease: A review","volume":"7","author":"Khan","year":"2018","journal-title":"J. Anal. Pharm. Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnmol.2018.00329","article-title":"A Mitochondria-Associated Oxidative Stress Perspective on Huntington\u2019s disease","volume":"11","author":"Zheng","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/157015909787602823","article-title":"Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options","volume":"7","author":"Uttara","year":"2009","journal-title":"Curr. Neuropharmacol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5455\/oams.191015.rv.020","article-title":"Oxidative stress in neurodegenerative conditions and the protective potential of a natural antioxidant, dietary saffron","volume":"4","author":"Purushothuman","year":"2015","journal-title":"Oxid. Antioxid. Med. Sci."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"2525967","DOI":"10.1155\/2017\/2525967","article-title":"Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications","volume":"2017","author":"Liu","year":"2017","journal-title":"Oxid. Med. Cell. Longev."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/8\/1583\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:46:18Z","timestamp":1760186778000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/8\/1583"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,22]]},"references-count":143,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["molecules24081583"],"URL":"https:\/\/doi.org\/10.3390\/molecules24081583","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,22]]}}}