{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:03:25Z","timestamp":1776312205258,"version":"3.50.1"},"reference-count":51,"publisher":"Pharmaceutical Society of Japan","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biological & Pharmaceutical Bulletin","Biol. Pharm. Bull."],"published-print":{"date-parts":[[2021,1,1]]},"DOI":"10.1248\/bpb.b20-00574","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T22:07:03Z","timestamp":1604614023000},"page":"51-56","source":"Crossref","is-referenced-by-count":9,"title":["<i>N<\/i>,<i>N<\/i>\u2032-1,10-Bis(Naringin) Triethylenetetraamine, Synthesis and as a Cu(II) Chelator for Alzheimer\u2019s Disease Therapy"],"prefix":"10.1248","volume":"44","author":[{"given":"Li-Xia","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory of Natural Medicine Research of Chongqing Education Commission, Chongqing Technology and Business University"},{"name":"College of Environment and Resources, Chongqing Technology and Business University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicine Research of Chongqing Education Commission, Chongqing Technology and Business University"},{"name":"College of Environment and Resources, Chongqing Technology and Business University"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"163","reference":[{"key":"1","unstructured":"1) Mucke L. Neuroscience: Alzheimer\u2019s disease. Nature<\/i>, 461<\/b>, 895\u2013897 (2009)."},{"key":"2","unstructured":"2) Roberson ED, Mucke L. 100 years and counting: prospects for defeating Alzheimer\u2019s disease. Science<\/i>, 314<\/b>, 781\u2013784 (2006)."},{"key":"3","doi-asserted-by":"crossref","unstructured":"3) Unzeta M, Esteban G, Bolea I, Fogel WA, Ramsay RR, Youdim MBH, Tipton KF, Marco-Contelles J. Multi-target directed donepezil-like ligands for Alzheimer\u2019s disease. Front. Neurosci.<\/i>, 10<\/b>, 205 (2016).","DOI":"10.3389\/fnins.2016.00205"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4) Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer\u2019s disease. Mol. Brain<\/i>, 4<\/b>, 3 (2011).","DOI":"10.1186\/1756-6606-4-3"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5) Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyrenther K. Amyloid plaque core protein in Alzheimer disease and down syndrome. Proc. Natl. Acad. Sci. U.S.A.<\/i>, 82<\/b>, 4245\u20134249 (1985).","DOI":"10.1073\/pnas.82.12.4245"},{"key":"6","unstructured":"6) Barage SH, Sonawane KD. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer\u2019s disease. Neuropeptides<\/i>, 52<\/b>, 1\u201318 (2015)."},{"key":"7","doi-asserted-by":"crossref","unstructured":"7) Savelieff MG, Lee S, Liu Y, Lim MH. Untangling amyloid-\u03b2, tau, and metals in Alzheimer\u2019s disease. ACS Chem. Biol.<\/i>, 8<\/b>, 856\u2013865 (2013).","DOI":"10.1021\/cb400080f"},{"key":"8","unstructured":"8) Lee SJC, Nam E, Lee HJ, Savelieff MG, Lim MH. Towards an understanding of amyloid-\u03b2 oligomers: characterization, toxicity mechanisms, and inhibitors. Chem. Soc. Rev.<\/i>, 46<\/b>, 310\u2013323 (2017)."},{"key":"9","unstructured":"9) Nagel-Steger L, Owen MC, Strodel B. An account of amyloid oligomers: facts and figures obtained from experiments and simulations. ChemBioChem<\/i>, 17<\/b>, 657\u2013676 (2016)."},{"key":"10","doi-asserted-by":"crossref","unstructured":"10) F\u00e4ndrich M. Oligomeric intermediates in amyloid formation: structure determination and mechanisms of toxicity. J. Mol. Biol.<\/i>, 421<\/b>, 427\u2013440 (2012).","DOI":"10.1016\/j.jmb.2012.01.006"},{"key":"11","unstructured":"11) Kirkitadze MD, Bitan G, Teplow D. Paradigm shifts in Alzheimer\u2019s disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res.<\/i>, 69<\/b>, 567\u2013577 (2002)."},{"key":"12","doi-asserted-by":"crossref","unstructured":"12) Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron, zinc in Alzheimer\u2019s disease senile plaques. J. Neurol. Sci.<\/i>, 158<\/b>, 47\u201352 (1998).","DOI":"10.1016\/S0022-510X(98)00092-6"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13) Miller LM, Wang Q, Telivala TP, Smith RJ, Lanzirotti A, Miklossy J. Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with \u03b2-amyloid deposits in Alzheimer\u2019s disease. J. Struct. Biol.<\/i>, 155<\/b>, 30\u201337 (2006).","DOI":"10.1016\/j.jsb.2005.09.004"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14) Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer\u2019s disease is a source of redox-generated free radicals. Proc. Natl. Acad. Sci. U.S.A.<\/i>, 94<\/b>, 9866\u20139868 (1997).","DOI":"10.1073\/pnas.94.18.9866"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15) Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science<\/i>, 265<\/b>, 1464\u20131467 (1994).","DOI":"10.1126\/science.8073293"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16) Duce JA, Bush AI, Adlard PA. Role of amyloid-\u03b2-metal interactions in Alzheimer\u2019s disease. Future Neurol.<\/i>, 6<\/b>, 641\u2013659 (2011).","DOI":"10.2217\/fnl.11.43"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17) Bush AI. Metals and neuroscience. Curr. Opin. Chem. Biol.<\/i>, 4<\/b>, 184\u2013191 (2000).","DOI":"10.1016\/S1367-5931(99)00073-3"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18) Bush AI. The metallobiology of Alzheimer\u2019s disease. Trends Neurosci.<\/i>, 26<\/b>, 207\u2013214 (2003).","DOI":"10.1016\/S0166-2236(03)00067-5"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19) Bush AI. Drug development based on the metals hypothesis of Alzheimer\u2019s disease. J. Alzheimer\u2019s Dis.<\/i>, 15<\/b>, 223\u2013240 (2008).","DOI":"10.3233\/JAD-2008-15208"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20) Bush AI, Tanzi RE. Therapeutics for Alzheimmer\u2019s disease based on the metal hypothesis. Neurotherapeutics<\/i>, 5<\/b>, 421\u2013432 (2008).","DOI":"10.1016\/j.nurt.2008.05.001"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21) Bagheri S, Squitti R, Haertl\u00e9 T, Siotto M, Saboury AA. Role of copper in the onset of Alzheimer\u2019s disease compared to other metals. Front. Aging Neurosci.<\/i>, 9<\/b>, 446 (2018).","DOI":"10.3389\/fnagi.2017.00446"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22) Kepp KP. Bioinorganic chemistry of Alzheimer\u2019s disease. Chem. Rev.<\/i>, 112<\/b>, 5193\u20135239 (2012).","DOI":"10.1021\/cr300009x"},{"key":"23","unstructured":"23) Jakob-Roetne R, Jacobsen H. Alzheimer\u2019s disease: from pathology to therapeutic approaches. Angew. Chem. Int. Ed. Engl<\/i>., 48<\/b>, 3030\u20133059 (2009)."},{"key":"24","doi-asserted-by":"crossref","unstructured":"24) Telpoukhovskaia MA, Orvig C. Werner coordination chemistry and neurodegeneration. Chem. Soc. Rev.<\/i>, 42<\/b>, 1836\u20131846 (2013).","DOI":"10.1039\/C2CS35236B"},{"key":"25","unstructured":"25) Geng J, Li M, Wu L, Ren J, Qu X. Liberation of copper from amyloid plaques: Making a risk factor useful for Alzheimer\u2019s disease treatment. J. Med. Chem.<\/i>, 55<\/b>, 9146\u20139155 (2012)."},{"key":"26","doi-asserted-by":"crossref","unstructured":"26) Wang B, Wang Z, Chen H, Lu C-J, Li X. Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with (benzo[d<\/i>][1,2]selenazol-3-(2H<\/i>)-one) as effective inhibitor of metal-induced A\u03b2 aggregation and antioxidant. Bioorg. Med. Chem.<\/i>, 24<\/b>, 4741\u20134749 (2016).","DOI":"10.1016\/j.bmc.2016.08.017"},{"key":"27","unstructured":"27) Wang X-H, Wang X-Y, Guo Z-J. Metal-involved theranostics: An emerging strategy for fighting Alzheimer\u2019s disease. Coord. Chem. Rev.<\/i>, 362<\/b>, 72\u201384 (2018)."},{"key":"28","doi-asserted-by":"crossref","unstructured":"28) Sharma AK, Pavlova ST, Kim J, Finkelstein D, Hawco NJ, Rath NP, Kim J, Mirica L. Bifunctional compounds for controlling metal-mediated aggregation of the A\u03b242<\/sub> peptide. J. Am. Chem. Soc.<\/i>, 134<\/b>, 6625\u20136636 (2012).","DOI":"10.1021\/ja210588m"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29) Liu Y, Kochi A, Pithadia AS, Lee S, Nam Y, Beck MW, He X, Lee D, Lim MH. Tuning reactivity of diphenylpropynone derivatives with metal-associated amyloid-\u03b2 species via<\/i> structural modifications. Inorg. Chem.<\/i>, 52<\/b>, 8121\u20138130 (2013).","DOI":"10.1021\/ic400851w"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30) Choi J-S, Braymer JJ, Nanga RPR, Ramamoorthy A, Lim MH. Design of small molecules that target metal-A\u03b2 species and regulate metal-induced A\u03b2 aggregation and neurotoxicity. Proc. Natl. Acad. Sci. U.S.A.<\/i>, 107<\/b>, 21990\u201321995 (2010).","DOI":"10.1073\/pnas.1006091107"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31) Hindo SS, Mancino AM, Braymer JJ, Liu Y, Vivekanandan S, Ramamoorthy A, Lim MH. Small molecule modulators of copper-induced A\u03b2 aggregation. J. Am. Chem. Soc.<\/i>, 131<\/b>, 16663\u201316665 (2009).","DOI":"10.1021\/ja907045h"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32) Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI. The A\u03b2 peptide of Alzheimer\u2019s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry<\/i>, 38<\/b>, 7609\u20137616 (1999).","DOI":"10.1021\/bi990438f"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33) Cherny RA, Atwood CS, Xilinas ME, Gray ND, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y-S, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI. Treatment with a copper-zinc chelator markedly and rapidly inhibits \u03b2-amyloid accumulation in Alzheimer\u2019s disease transgenic mice. Neuron<\/i>, 30<\/b>, 665\u2013676 (2001).","DOI":"10.1016\/S0896-6273(01)00317-8"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34) Yurdakul S, Arici K. Synthesis and vibrational spectra of metal halide complexes of 8-hydroxyquinoline in relation to their structures. J. Mol. Struct.<\/i>, 691<\/b>, 45\u201349 (2004).","DOI":"10.1016\/j.molstruc.2003.11.014"},{"key":"35","unstructured":"35) Tripoli E, La GM, Giammanco S, Majo DD, Giammanco M. Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review. Food Chem.<\/i>, 104<\/b>, 466\u2013479 (2007)."},{"key":"36","doi-asserted-by":"crossref","unstructured":"36) Qi Z, Xu Y, Liang Z, Li S, Wang J, Wei Y, Dong B. Naringin ameliorates cognitive deficits via<\/i> oxidative stress, proinflammatory factors and the PPAR\u03b3 signaling pathway in a type 2 diabetic rat model. Mol. Med. Rep.<\/i>, 12<\/b>, 7093\u20137101 (2015).","DOI":"10.3892\/mmr.2015.4232"},{"key":"37","unstructured":"37) Wang H, Xu YS, Wang ML, Cheng C, Bian R, Yuan H, Wang Y, Guo T, Zhu LL, Zhou H. Protective effect of naringin against the LPS-induced apoptosis of PC12 cells: Implications for the treatment of neurodegenerative disorders. Int. J. Mol. Med.<\/i>, 39<\/b>, 819\u2013830 (2017)."},{"key":"38","doi-asserted-by":"crossref","unstructured":"38) Kulasekaran G, Ganapasam S. Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells. Mol. Cell. Biochem.<\/i>, 409<\/b>, 199\u2013211 (2015).","DOI":"10.1007\/s11010-015-2525-9"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39) Ha EK, Na MS, Lee S, Baek H, Lee SJ, Sheen YH, Jung Y-H, Lee KS, Kim MA, Jee HM, Han MY. Prevalence and clinical characteristics of local allergic rhinitis in children sensitized to house dust mites. Int. Arch. Allergy Immunol.<\/i>, 174<\/b>, 183\u2013189 (2017).","DOI":"10.1159\/000481091"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40) Wang DM, Gao K, Li XY, Shen XH, Zhang X, Ma CM, Qin C, Zhang LF. Long-term naringin consumption reverses a glucose uptake defect and improves cognitive deficits in a mouse model of Alzheimer\u2019s disease. Pharmacol. Biochem. Behav.<\/i>, 102<\/b>, 13\u201320 (2012).","DOI":"10.1016\/j.pbb.2012.03.013"},{"key":"41","unstructured":"41) Guo LX, Sun B. Studies of synthesis and bio-activity of naringin bis-Schiff base. Chem. Res. Appl. <\/i>(China), 31<\/b>, 1454\u20131460 (2019)."},{"key":"42","doi-asserted-by":"crossref","unstructured":"42) Gaggelli E, Kozlowski D, Valensin D, Valensin G. Copper homeostasis and neurodegenerative disorders (Alzheimer\u2019s, Prion, and Parkinson\u2019s diseases and amyotrophic lateral sclerosis). Chem. Rev.<\/i>, 106<\/b>, 1995\u20132044 (2006).","DOI":"10.1021\/cr040410w"},{"key":"43","unstructured":"43) Hureau C, Faller P. A\u03b2-mediated ROS production by Cu ions: structural insights, mechanisms and relevance to Alzheimer\u2019s disease. Biochimie<\/i>, 91<\/b>, 1212\u20131217 (2009)."},{"key":"44","doi-asserted-by":"crossref","unstructured":"44) Markesbery WR. Oxidative stress hypothesis in Alzheimer\u2019s disease. Free Radic. Biol. Med.<\/i>, 23<\/b>, 134\u2013147 (1997).","DOI":"10.1016\/S0891-5849(96)00629-6"},{"key":"45","unstructured":"45) Wojsiat J, Zoltowska KM, Laskowska-Kaszub K, Wojda U. Oxidant\/Antioxidant Imbalance in Alzheimer\u2019s Disease: Therapeutic and Diagnostic Prospects. Oxid. Med. Cell. Longev.<\/i>, 2018<\/b>, 6435861 (2018)."},{"key":"46","doi-asserted-by":"crossref","unstructured":"46) Schuessel K, Leutner S, Cairus NJ, Muller WE, Eckert A. Impact of gender on upregulation of antioxidant defense mechanisms in Alzheimer\u2019s disease brain. J. Neural Transm. <\/i>(Vienna), 111<\/b>, 1167\u20131182 (2004).","DOI":"10.1007\/s00702-004-0156-5"},{"key":"47","doi-asserted-by":"crossref","unstructured":"47) Esposito L, Raber J, Kekonius L, Yan F, Yu GQ, Bien-Ly N, Puoliv\u00e4li J, Scearce-Levie K, Masliah E, Mucke L. Reduction in mitochondrial superoxide dismutase modulates Alzheimer\u2019s disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J. Neurosci.<\/i>, 26<\/b>, 5167\u20135179 (2006).","DOI":"10.1523\/JNEUROSCI.0482-06.2006"},{"key":"48","doi-asserted-by":"crossref","unstructured":"48) Schuessel K, Schafer S, Bayer TA, Czech C, Pradier L, Muller-Spahn F, Muller WE, Eckert A. Impaired Cu\/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice. Neurobiol. Dis.<\/i>, 18<\/b>, 89\u201399 (2005).","DOI":"10.1016\/j.nbd.2004.09.003"},{"key":"49","doi-asserted-by":"crossref","unstructured":"49) Murakami K, Murata N, Noda Y, Tahara S, Kaneko T, Kinoshita N, Hatsuta H, Murayama S, Barnham KJ, Irie K, Shirasawa T, Shimizu T. SOD1 (Copper\/Zinc superoxide dismutase) deficiency drives amyloid \u03b2 protein oligomerizaation and memory loss in mouse model of Alzheimer\u2019s disease. J. Biol. Chem.<\/i>, 286<\/b>, 44557\u201344568 (2011).","DOI":"10.1074\/jbc.M111.279208"},{"key":"50","unstructured":"50) Massaad CA, Breitling BJ, Klann E, Pautler RG. Overexpression of SOD-2 reduces A\u03b2nlevels and improves the axonal transport deficits in the Tg2576 Alzheimer model mice. Proc. Intl. Soc. Magn. Reson. Med. Sci. Meet. Exhib.<\/i>, 16<\/b>, 528\u2013528 (2008)."},{"key":"51","doi-asserted-by":"crossref","unstructured":"51) Massaad CA, Washington TM, Pautler RG, Klann E. Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzhheimer\u2019s disease. Proc. Natl. Acad. Sci. U.S.A.<\/i>, 106<\/b>, 13576\u201313581 (2009).","DOI":"10.1073\/pnas.0902714106"}],"container-title":["Biological and Pharmaceutical Bulletin"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/bpb\/44\/1\/44_b20-00574\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T22:09:00Z","timestamp":1669500540000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/bpb\/44\/1\/44_b20-00574\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,1]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1248\/bpb.b20-00574","relation":{},"ISSN":["0918-6158","1347-5215"],"issn-type":[{"value":"0918-6158","type":"print"},{"value":"1347-5215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,1]]}}}