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This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from C9orf72 patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from C9orf72 ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to C9orf72 pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring C9orf72 expansion repeats.<\/jats:p>","DOI":"10.3390\/antiox11101897","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T21:14:28Z","timestamp":1664140468000},"page":"1897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3967-1832","authenticated-orcid":false,"given":"Jos\u00e9","family":"Jim\u00e9nez-Villegas","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), 28029 Madrid, Spain"},{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (CSIC\/UAM), 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz), 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7468-5917","authenticated-orcid":false,"given":"Janine","family":"Kirby","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1582-8316","authenticated-orcid":false,"given":"Ana","family":"Mata","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\/UAM), 28049 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Cadenas","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\/UAM), 28049 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Turner","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Malaspina","sequence":"additional","affiliation":[{"name":"Neuroscience and Trauma Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London E1 2AT, UK"},{"name":"Queen Square Motor Neuron Disease Centre, Neuromuscular Department, Institute of Neurology, University College London, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8925-2567","authenticated-orcid":false,"given":"Pamela J.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4039-7140","authenticated-orcid":false,"given":"Antonio","family":"Cuadrado","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), 28029 Madrid, Spain"},{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (CSIC\/UAM), 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz), 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid, 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Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1001\/archneur.55.4.526","article-title":"An Analysis of Extended Survival in Patients with Amyotrophic Lateral Sclerosis Treated with Riluzole","volume":"55","author":"Riviere","year":"1998","journal-title":"Arch. Neurol."},{"key":"ref_4","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":"Amyotroph. Lateral Scler. Off. Publ. World Fed. Neurol. Res. Group Mot. Neuron Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fnagi.2017.00068","article-title":"ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?","volume":"9","author":"Petrov","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.ajhg.2013.04.017","article-title":"Hypermethylation of the CpG Island near the G4C2 Repeat in ALS with a C9orf72 Expansion","volume":"92","author":"Xi","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s00401-016-1581-x","article-title":"Full Ablation of C9orf72 in Mice Causes Immune System-Related Pathology and Neoplastic Events but No Motor Neuron Defects","volume":"132","author":"Koppers","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1126\/science.1232927","article-title":"The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD\/ALS","volume":"339","author":"Mori","year":"2013","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s00401-013-1189-3","article-title":"Bidirectional Transcripts of the Expanded C9orf72 Hexanucleotide Repeat Are Translated into Aggregating Dipeptide Repeat Proteins","volume":"126","author":"Mori","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fnmol.2017.00035","article-title":"The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD","volume":"10","author":"Freibaum","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mizielinska, S., Gr\u00f6nke, S., Niccoli, T., Ridler, C.E., Clayton, E.L., Devoy, A., Moens, T., Norona, F.E., Woollacott, I.O.C., and Pietrzyk, J. (2014). C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science., 3451192\u20133451194.","DOI":"10.1126\/science.1256800"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1074\/mcp.RA119.001888","article-title":"Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity","volume":"19","author":"Radwan","year":"2020","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.freeradbiomed.2009.11.018","article-title":"Oxidative Stress in ALS: Key Role in Motor Neuron Injury and Therapeutic Target","volume":"48","author":"Barber","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Obrador, E., Salvador-Palmer, R., L\u00f3pez-Blanch, R., Jihad-Jebbar, A., Vall\u00e9s, S.L., and Estrela, J.M. (2021). The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126352"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.1128\/MCB.00180-12","article-title":"Structural and Functional Characterization of Nrf2 Degradation by the Glycogen Synthase Kinase 3\/\u03b2-TrCP Axis","volume":"32","author":"Rada","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31556","DOI":"10.1074\/jbc.M403061200","article-title":"Redox-Regulated Turnover of Nrf2 Is Determined by at Least Two Separate Protein Domains, the Redox-Sensitive Neh2 Degron and the Redox-Insensitive Neh6 Degron","volume":"279","author":"McMahon","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 Represses Nuclear Activation of Antioxidant Responsive Elements by Nrf2 through Binding to the Amino-Terminal Neh2 Domain","volume":"13","author":"Itoh","year":"1999","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11908","DOI":"10.1073\/pnas.172398899","article-title":"Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants","volume":"99","author":"Holtzclaw","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1128\/MCB.26.1.221-229.2006","article-title":"Oxidative and Electrophilic Stresses Activate Nrf2 through Inhibition of Ubiquitination Activity of Keap1","volume":"26","author":"Kobayashi","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1042\/BJ20090471","article-title":"Cul3-Mediated Nrf2 Ubiquitination and Antioxidant Response Element (ARE) Activation Are Dependent on the Partial Molar Volume at Position 151 of Keap1","volume":"422","author":"Eggler","year":"2009","journal-title":"Biochem. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1124\/pr.117.014753","article-title":"Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach","volume":"70","author":"Cuadrado","year":"2018","journal-title":"Pharmacol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1136\/jnnp-2020-325014","article-title":"Value of Systematic Genetic Screening of Patients with Amyotrophic Lateral Sclerosis","volume":"92","author":"Shepheard","year":"2021","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/hmg\/ddx022","article-title":"C9ORF72 Hexanucleotide Repeat Exerts Toxicity in a Stable, Inducible Motor Neuronal Cell Model, Which Is Rescued by Partial Depletion of Pten","volume":"26","author":"Stopford","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"472932","DOI":"10.1155\/2012\/472932","article-title":"Antioxidant Therapies for Alzheimer\u2019s Disease","volume":"2012","author":"Feng","year":"2012","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/jnc.14687","article-title":"Nuclear Factor-Kappa \u03b2 as a Therapeutic Target for Alzheimer\u2019s Disease","volume":"150","author":"Jha","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.1254917","article-title":"Poly-Dipeptides Encoded by the C9orf72 Repeats Bind Nucleoli, Impede RNA Biogenesis, and Kill Cells","volume":"345","author":"Kwon","year":"2014","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12740","DOI":"10.1038\/s41598-018-31096-z","article-title":"Characterization of Membrane Penetration and Cytotoxicity of C9orf72-Encoding Arginine-Rich Dipeptides","volume":"8","author":"Kanekura","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1093\/hmg\/ddw052","article-title":"Poly-Dipeptides Encoded by the C9ORF72 Repeats Block Global Protein Translation","volume":"25","author":"Kanekura","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gill, A.L., Wang, M.Z., Levine, B., Premasiri, A., and Vieira, F.G. (2019). Primary Neurons and Differentiated NSC-34 Cells Are More Susceptible to Arginine-Rich ALS Dipeptide Repeat Protein-Associated Toxicity than Non-Differentiated NSC-34 and CHO Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246238"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1074\/jbc.M209195200","article-title":"Degradation of Transcription Factor Nrf2 via the Ubiquitin-Proteasome Pathway and Stabilization by Cadmium","volume":"278","author":"Stewart","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/brain\/awr355","article-title":"Distinct Clinical and Pathological Characteristics of Frontotemporal Dementia Associated with C9ORF72 Mutations","volume":"135","author":"Snowden","year":"2012","journal-title":"Brain J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15259","DOI":"10.1073\/pnas.1305687110","article-title":"Regulatory Flexibility in the Nrf2-Mediated Stress Response Is Conferred by Conformational Cycling of the Keap1-Nrf2 Protein Complex","volume":"110","author":"Baird","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14636","DOI":"10.1096\/fj.201901930R","article-title":"Post-Transcriptional Regulation of Nrf2-MRNA by the MRNA-Binding Proteins HuR and AUF1","volume":"33","author":"Poganik","year":"2019","journal-title":"FASEB J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nmeth.1314","article-title":"SUnSET, a Nonradioactive Method to Monitor Protein Synthesis","volume":"6","author":"Schmidt","year":"2009","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.cell.2016.10.002","article-title":"C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics and Function of Membrane-Less Organelles","volume":"167","author":"Lee","year":"2016","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1073\/pnas.040461197","article-title":"Copper Chaperone for Superoxide Dismutase Is Essential to Activate Mammalian Cu\/Zn Superoxide Dismutase","volume":"97","author":"Wong","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1270256","DOI":"10.1155\/2020\/1270256","article-title":"Oxidative Stress and Mitochondrial Damage in Neurodegenerative Diseases: From Molecular Mechanisms to Targeted Therapies","volume":"2020","author":"Cenini","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"dmm049092","DOI":"10.1242\/dmm.049092","article-title":"Reduction of Oxidative Stress Suppresses Poly-GR-Mediated Toxicity in Zebrafish Embryos","volume":"14","author":"Riemslagh","year":"2021","journal-title":"Dis. Model. Mech."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.neuron.2016.09.015","article-title":"Poly(GR) in C9ORF72-Related ALS\/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in IPSC-Derived Motor Neurons","volume":"92","author":"Lu","year":"2016","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/s41593-019-0397-0","article-title":"C9ORF72-ALS\/FTD-Associated Poly(GR) Binds Atp5a1 and Compromises Mitochondrial Function in Vivo","volume":"22","author":"Choi","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ebiom.2019.11.026","article-title":"Human IPSC-Derived Astrocytes from ALS Patients with Mutated C9ORF72 Show Increased Oxidative Stress and Neurotoxicity","volume":"50","author":"Birger","year":"2019","journal-title":"eBioMedicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"dmm039552","DOI":"10.1242\/dmm.039552","article-title":"C9ORF72-Related Cellular Pathology in Skeletal Myocytes Derived from ALS-Patient Induced Pluripotent Stem Cells","volume":"12","author":"Lynch","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1097\/NEN.0b013e31818b4906","article-title":"Nuclear Erythroid 2-Related Factor 2-Antioxidative Response Element Signaling Pathway in Motor Cortex and Spinal Cord in Amyotrophic Lateral Sclerosis","volume":"67","author":"Sarlette","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1080\/15548627.2019.1644076","article-title":"ALS-FTLD-Linked Mutations of SQSTM1\/P62 Disrupt Selective Autophagy and NFE2L2\/NRF2 Anti-Oxidative Stress Pathway","volume":"16","author":"Deng","year":"2020","journal-title":"Autophagy"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.3892\/mmr.2014.2087","article-title":"Effect of the Human SOD1-G93A Gene on the Nrf2\/ARE Signaling Pathway in NSC-34 Cells","volume":"9","author":"Wang","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1093\/hmg\/ddx093","article-title":"TDP-43 Mutations Causing Amyotrophic Lateral Sclerosis Are Associated with Altered Expression of RNA-Binding Protein HnRNP K and Affect the Nrf2 Antioxidant Pathway","volume":"26","author":"Moujalled","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e85817","DOI":"10.1172\/jci.insight.85817","article-title":"Heme Oxygenase-1 Regulates Mitochondrial Quality Control in the Heart","volume":"1","author":"Hull","year":"2016","journal-title":"JCI Insight"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1093\/brain\/awz302","article-title":"C9orf72 Expansion within Astrocytes Reduces Metabolic Flexibility in Amyotrophic Lateral Sclerosis","volume":"142","author":"Allen","year":"2019","journal-title":"Brain J. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1002\/acn3.51446","article-title":"Safety and Efficacy of Dimethyl Fumarate in ALS: Randomised Controlled Study","volume":"8","author":"Vucic","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1002\/mc.22609","article-title":"Brusatol Overcomes Chemoresistance through Inhibition of Protein Translation","volume":"56","author":"Harder","year":"2017","journal-title":"Mol. Carcinog."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15728","DOI":"10.1038\/s41598-019-52035-6","article-title":"C9orf72-Generated Poly-GR and Poly-PR Do Not Directly Interfere with Nucleocytoplasmic Transport","volume":"9","author":"Vanneste","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s00401-018-1946-4","article-title":"C9orf72 Arginine-Rich Dipeptide Proteins Interact with Ribosomal Proteins in Vivo to Induce a Toxic Translational Arrest That Is Rescued by EIF1A","volume":"137","author":"Moens","year":"2019","journal-title":"Acta Neuropathol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/10\/1897\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:39:03Z","timestamp":1760143143000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/10\/1897"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,25]]},"references-count":53,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["antiox11101897"],"URL":"https:\/\/doi.org\/10.3390\/antiox11101897","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,25]]}}}