{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T05:15:37Z","timestamp":1791954937213,"version":"4.3.4"},"reference-count":69,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Mitochondrial dysfunction represents a hallmark of both brain aging and age-related neurodegenerative disorders including Alzheimer disease (AD). AD-related mitochondrial dysfunction is characterized by an impaired electron transport chain (ETC), subsequent decreased adenosine triphoshpate (ATP) levels, and elevated generation of reactive oxygen species (ROS). The bioactive citrus flavanone hesperetin (Hst) is known to modulate inflammatory response, to function as an antioxidant, and to provide neuroprotective properties. The efficacy in improving mitochondrial dysfunction of Hst nanocrystals (HstN) with increased bioavailability has not yet been investigated. Human SH-SY5Y cells harboring neuronal amyloid precursor protein (APP695) acted as a model for the initial phase of AD. MOCK-transfected cells served as controls. The energetic metabolite ATP was determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was assessed by high-resolution respirometry using a Clarke electrode. Expression levels of mitochondrial respiratory chain complex genes were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The levels of amyloid \u03b2-protein (A\u03b21-40) were measured using homogeneous time-resolved fluorescence (HTRF). ROS levels, peroxidase activity, and cytochrome c activity were determined using a fluorescence assay. Compared to pure Hst dissolved in ethanol (HstP), SH-SY5Y-APP695 cells incubated with HstN resulted in significantly reduced mitochondrial dysfunction: ATP levels and respiratory chain complex activity significantly increased. Gene expression levels of RCC I, IV, and V were significantly upregulated. In comparison, the effects of HstN on SY5Y-MOCK control cells were relatively small. Pure Hst dissolved in ethanol (HstP) had almost no effect on both cell lines. Neither HstN nor HstP led to significant changes in A\u03b21-40 levels. HstN and HstP were both shown to lower peroxidase activity significantly. Furthermore, HstN significantly reduced cytochrome c activity, whereas HstP had a significant effect on reducing ROS in SH-SY5Y-APP695 cells. Thus, it seems that the mechanisms involved may not be linked to altered A\u03b2 production. Nanoflavonoids such as HstN have the potential to prevent mitochondria against dysfunction. Compared to its pure form, HstN showed a greater effect in combatting mitochondrial dysfunction. Further studies should evaluate whether HstN protects against age-related mitochondrial dysfunction and thus may contribute to late-onset AD.<\/jats:p>","DOI":"10.3390\/antiox10071003","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T11:28:41Z","timestamp":1624447721000},"page":"1003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Hesperetin Nanocrystals Improve Mitochondrial Function in a Cell Model of Early Alzheimer Disease"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7740-0753","authenticated-orcid":false,"given":"Lukas","family":"Babylon","sequence":"first","affiliation":[{"name":"Biomedical Research Center Seltersberg (BFS), Laboratory for Nutrition in Prevention and Therapy, Institute of Nutritional Sciences, Justus Liebig University, Schubertstr. 81, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha","family":"Grewal","sequence":"additional","affiliation":[{"name":"Biomedical Research Center Seltersberg (BFS), Laboratory for Nutrition in Prevention and Therapy, Institute of Nutritional Sciences, Justus Liebig University, Schubertstr. 81, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal-L.","family":"Stahr","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Biopharmaceutics, Philipps Universit\u00e4t, Robert-Koch-Str. 4, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8291-4900","authenticated-orcid":false,"given":"Ralph W.","family":"Eckert","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Biopharmaceutics, Philipps Universit\u00e4t, Robert-Koch-Str. 4, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8888-2340","authenticated-orcid":false,"given":"Cornelia M.","family":"Keck","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Biopharmaceutics, Philipps Universit\u00e4t, Robert-Koch-Str. 4, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunter P.","family":"Eckert","sequence":"additional","affiliation":[{"name":"Biomedical Research Center Seltersberg (BFS), Laboratory for Nutrition in Prevention and Therapy, Institute of Nutritional Sciences, Justus Liebig University, Schubertstr. 81, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ref_1","unstructured":"Alzheimer\u2019s Disease International (2019). World Alzheimer Report 2019: Attitudes to Dementia, Alzheimer\u2019s Disease International."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/00002093-200210000-00001","article-title":"Relative Frequencies of Alzheimer Disease, Lewy Body, Vascular and Frontotemporal Dementia, and Hippocampal Sclerosis in the State of Florida Brain Bank","volume":"16","author":"Barker","year":"2002","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrneurol.2009.219","article-title":"Can Alzheimer disease be prevented by amyloid-\u03b2 immunotherapy?","volume":"6","author":"Lemere","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.jalz.2013.11.003","article-title":"The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer\u2019s disease","volume":"10","author":"Drachman","year":"2014","journal-title":"Alzheimer Dement."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/nn.4018","article-title":"Three dimensions of the amyloid hypothesis: Time, space and \u2018wingmen\u2019","volume":"18","author":"Musiek","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/jnc.14079","article-title":"Re-imagining Alzheimer\u2019s disease\u2014The diminishing importance of amyloid and a glimpse of what lies ahead","volume":"143","author":"Tse","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s12035-010-8141-5","article-title":"Mitochondrial dysfunction: Common final Pathway in brain aging and Alzheimer\u2019s disease\u2014Therapeutic aspects","volume":"41","author":"Eckert","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_8","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. Alzheimer Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jnr.10389","article-title":"Role of mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"70","author":"Castellani","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1471-4159.2009.05867.x","article-title":"The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer\u2019s disease","volume":"109","author":"Wang","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.neurobiolaging.2009.07.002","article-title":"Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI","volume":"32","author":"Landau","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/0169-328X(94)90147-3","article-title":"Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease","volume":"24","author":"Chandrasekaran","year":"1994","journal-title":"Mol. Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1212\/WNL.44.6.1090","article-title":"Electron transport chain defects in Alzheimer\u2019s disease brain","volume":"44","author":"Parker","year":"1994","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20057","DOI":"10.1073\/pnas.0905529106","article-title":"Amyloid- and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer\u2019s disease mice","volume":"106","author":"Rhein","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9090","DOI":"10.1523\/JNEUROSCI.1357-09.2009","article-title":"Impaired balance of mitochondrial fission and fusion in Alzheimer\u2019s disease","volume":"29","author":"Wang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.freeradbiomed.2020.01.021","article-title":"Increased mitochondrial content and function by resveratrol and select flavonoids protects against benzo[a]pyrene-induced bioenergetic dysfunction and ROS generation in a cell model of neoplastic transformation","volume":"152","author":"Omidian","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/(SICI)1097-0010(20000515)80:7<1073::AID-JSFA568>3.0.CO;2-B","article-title":"Flavanones, chalcones and dihydrochalcones\u2014nature, occurrence and dietary burden","volume":"80","author":"Clifford","year":"2000","journal-title":"J. Sci. Food Agric."},{"key":"ref_19","unstructured":"Watson, R.R., Preedy, V.R., and Zibadi, S. (2014). Cardiovascular Effects of Hesperidin. Polyphenols in Human Health and Disease, Elsevier Acad. Press."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1248\/yakushi1881.48.10_938","article-title":"Polyhydroxychalcones, polyhydroxyhydrochalcones and polyhydroxyflavanones. III. Synthesis of hesperetin","volume":"48","author":"Shinoda","year":"1928","journal-title":"J. Pharm. Soc. Jpn."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s10735-013-9514-7","article-title":"Hesperetin protects against cardiac remodelling induced by pressure overload in mice","volume":"44","author":"Deng","year":"2013","journal-title":"J. Mol. Histol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0009-8981(02)00344-3","article-title":"Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats","volume":"327","author":"Kim","year":"2003","journal-title":"Clin. Chim. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/ejcn.2010.6","article-title":"Relative bioavailability of the flavonoids quercetin, hesperetin and naringenin given simultaneously through diet","volume":"64","author":"Krogholm","year":"2010","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/ptr.6264","article-title":"Hesperidin, a major flavonoid in orange juice, might not affect lipid profile and blood pressure: A systematic review and meta-analysis of randomized controlled clinical trials","volume":"33","author":"Mohammadi","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s13346-020-00888-0","article-title":"Investigating hesperetin nanocrystals with tailor-made sizes for the prevention and treatment of Alzheimer\u2019s disease","volume":"11","author":"Stahr","year":"2021","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/(SICI)1522-2683(20000301)21:4<706::AID-ELPS706>3.0.CO;2-5","article-title":"Measurement of bilirubin partition coefficients in bile salt micelle\/aqueous buffer solutions by micellar electrokinetic chromatography","volume":"21","author":"Maeder","year":"2000","journal-title":"Electrophoresis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1046\/j.1471-4159.2003.01652.x","article-title":"Interaction between flavonoids and the blood-brain barrier: In Vitro studies","volume":"85","author":"Youdim","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/ptr.5256","article-title":"Antioxidant and Anti-Inflammatory Properties of the Citrus Flavonoids Hesperidin and Hesperetin: An Updated Review of their Molecular Mechanisms and Experimental Models","volume":"29","author":"Parhiz","year":"2015","journal-title":"Phytother. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1021\/jf072826r","article-title":"Neuroprotective Effects of the Citrus Flavanones against H2O2-Induced Cytotoxicity in PC12 Cells","volume":"56","author":"Hwang","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.ijpharm.2015.11.047","article-title":"Simple low-cost miniaturization approach for pharmaceutical nanocrystals production","volume":"501","author":"Romero","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.biopha.2017.11.047","article-title":"Neuroprotective effect of hesperetin and nano-hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer\u2019s disease","volume":"97","author":"Kheradmand","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jconrel.2010.05.023","article-title":"The characteristics, cellular uptake and intracellular trafficking of nanoparticles made of hydrophobically-modified chitosan","volume":"146","author":"Chiu","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.jnutbio.2013.10.002","article-title":"Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals","volume":"25","author":"Wang","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3233\/JAD-140381","article-title":"A Cell Model for the Initial Phase of Sporadic Alzheimer\u2019s Disease","volume":"42","author":"Stockburger","year":"2014","journal-title":"J. Alzheimer Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113248","DOI":"10.1016\/j.expneurol.2020.113248","article-title":"Purified oleocanthal and ligstroside protect against mitochondrial dysfunction in models of early Alzheimer\u2019s disease and brain ageing","volume":"328","author":"Grewal","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"719","DOI":"10.21037\/atm.2020.01.117","article-title":"The recent failure of the PROMESA clinical trial for multiple system atrophy raises the question\u2014are polyphenols a viable therapeutic option against proteinopathies?","volume":"8","author":"Bitan","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"927","DOI":"10.3233\/JAD-132084","article-title":"Rice Bran Extract Compensates Mitochondrial Dysfunction in a Cellular Model of Early Alzheimer\u2019s Disease","volume":"43","author":"Hagl","year":"2014","journal-title":"J. Alzheimer Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1385\/CBB:44:2:179","article-title":"Preserved Coupling of Oxidative Phosphorylation but Decreased Mitochondrial Respiratory Capacity in IL-1\u03b2-Treated Human Peritoneal Mesothelial Cells","volume":"44","author":"Stadlmann","year":"2006","journal-title":"CBB"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1107\/S1744309109008343","article-title":"Structure of pig heart citrate synthase at 1.78 \u00c5 resolution","volume":"65","author":"Larson","year":"2009","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1113\/jphysiol.2012.230185","article-title":"Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects","volume":"590","author":"Larsen","year":"2012","journal-title":"J. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9408","DOI":"10.1038\/s41598-018-27614-8","article-title":"High throughput screening of mitochondrial bioenergetics in human differentiated myotubes identifies novel enhancers of muscle performance in aged mice","volume":"8","author":"Biesemann","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s12035-012-8271-z","article-title":"Mitochondrial Dysfunction\u2014A Pharmacological Target in Alzheimer\u2019s Disease","volume":"46","author":"Eckert","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How mitochondria produce reactive oxygen species","volume":"417","author":"Murphy","year":"2008","journal-title":"Biochem. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S0955-2863(02)00208-5","article-title":"Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships","volume":"13","author":"Heim","year":"2002","journal-title":"J. Nutr. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1080\/10715760410001713844","article-title":"Hesperetin: A Potent Antioxidant Against Peroxynitrite","volume":"38","author":"Kim","year":"2004","journal-title":"Free. Radic. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1021\/acsnano.5b08045","article-title":"Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer\u2019s Disease","volume":"10","author":"Kwon","year":"2016","journal-title":"ACS Nano"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1021\/nl052396o","article-title":"Determining the Size and Shape Dependence of Gold Nanoparticle Uptake into Mammalian Cells","volume":"6","author":"Chithrani","year":"2006","journal-title":"Nano Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/bj20031253","article-title":"Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis","volume":"377","author":"Rejman","year":"2004","journal-title":"Biochem. J."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Kumar, P., Nagarajan, A., and Uchil, P.D. (2018). Analysis of Cell Viability by the Lactate Dehydrogenase Assay. Cold Spring Harb. Protoc., 2018.","DOI":"10.1101\/pdb.prot095497"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s41386-018-0090-0","article-title":"Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease","volume":"44","author":"Holper","year":"2019","journal-title":"Neuropsychopharmacology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.mito.2006.10.004","article-title":"Impaired platelet mitochondrial activity in Alzheimer\u2019s disease and mild cognitive impairment","volume":"6","author":"Valla","year":"2006","journal-title":"Mitochondrion"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/S0006-2952(03)00534-3","article-title":"Mitochondrial dysfunction, apoptotic cell death, and Alzheimer\u2019s disease","volume":"66","author":"Eckert","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fmolb.2016.00043","article-title":"Dynamics of Human Mitochondrial Complex I Assembly: Implications for Neurodegenerative Diseases","volume":"3","author":"Giachin","year":"2016","journal-title":"Front. Mol. Biosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1080\/01616412.2020.1747716","article-title":"Hesperetin nanoparticles attenuate anxiogenic-like behavior and cerebral oxidative stress through the upregulation of antioxidant enzyme expression in experimental dementia of Alzheimer\u2019s type","volume":"42","author":"Moghaddam","year":"2020","journal-title":"Neurol. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.jalz.2016.09.003","article-title":"Nuclear but not mitochondrial-encoded oxidative phosphorylation genes are altered in aging, mild cognitive impairment, and Alzheimer\u2019s disease","volume":"13","author":"Mastroeni","year":"2016","journal-title":"Alzheimer Dement."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nrg3185","article-title":"Insights into the regulation of protein abundance from proteomic and transcriptomic analyses","volume":"13","author":"Vogel","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"113286","DOI":"10.1016\/j.expneurol.2020.113286","article-title":"Olesoxime improves cerebral mitochondrial dysfunction and enhances A\u03b2 levels in preclinical models of Alzheimer\u2019s disease","volume":"329","author":"Eckert","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.abb.2010.04.023","article-title":"Hesperidin and hesperetin membrane interaction: Understanding the role of 7-O-glycoside moiety in flavonoids","volume":"499","author":"Jaramillo","year":"2010","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13234","DOI":"10.1021\/acs.langmuir.6b02219","article-title":"Experimental Modeling of Flavonoid\u2013Biomembrane Interactions","volume":"32","author":"Sanver","year":"2016","journal-title":"Langmuir"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.bbamem.2009.01.012","article-title":"The interaction of beta-amyloid protein with cellular membranes stimulates its own production","volume":"1788","author":"Peters","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1021\/bi061854k","article-title":"Cardiolipin switch in mitochondria: Shutting off the reduction of cytochrome c and turning on the peroxidase activity","volume":"46","author":"Basova","year":"2007","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1002\/mnfr.200700402","article-title":"Mitochondria-targeted disruptors and inhibitors of cytochromec\/cardiolipin peroxidase complexes: A new strategy in anti-apoptotic drug discovery","volume":"53","author":"Kagan","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nchembio727","article-title":"Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors","volume":"1","author":"Kagan","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3233\/JAD-170711","article-title":"Free Heme and Amyloid-\u03b2: A Fatal Liaison in Alzheimer\u2019s Disease","volume":"61","author":"Chiziane","year":"2018","journal-title":"J. Alzheimer Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s00775-011-0842-3","article-title":"Amyloid beta\u2013heme peroxidase promoted protein nitrotyrosination: Relevance to widespread protein nitration in Alzheimer\u2019s disease","volume":"17","author":"Yuan","year":"2011","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1073\/pnas.0600134103","article-title":"Amyloid-beta peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer\u2019s disease","volume":"103","author":"Atamna","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"54","DOI":"10.2174\/138920310790274626","article-title":"Conformations and Biological Activities of Amyloid Beta Peptide 25\u201335","volume":"11","author":"Millucci","year":"2010","journal-title":"Curr. Protein Pept. Sci."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/7\/1003\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:21:48Z","timestamp":1760163708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/7\/1003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":69,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["antiox10071003"],"URL":"https:\/\/doi.org\/10.3390\/antiox10071003","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]}}}