{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:01:00Z","timestamp":1786464060105,"version":"build-2736575974"},"reference-count":73,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Glaucoma is the leading cause of irreversible blindness worldwide and a paradigmatic age-related neurodegenerative disease in which retinal ganglion cells (RGCs) are selectively lost through mechanisms that extend beyond intraocular pressure. Age-dependent NAD+ depletion in RGCs, compounded by the progressive impairment of NAD+ biosynthesis and by the hyperactivation of NAD+-consuming enzymes under oxidative stress, defines a metabolic vulnerability that current pressure-lowering therapy does not address. Pyrroloquinoline quinone (PQQ) is a tricyclic ortho-quinone present in plant-derived foods that acts on the NAD+ pool through a mechanism distinct from that of conventional precursors. Rather than expanding the pool by net synthesis, PQQ binds lactate dehydrogenase and oxidizes NADH to NAD+ through catalytic redox cycling, raising NAD+ availability without altering the total dinucleotide content and independently of the two biosynthetic enzymes selectively impaired in glaucomatous RGCs. The resulting increase in NAD+ availability activates sirtuin-dependent programs that drive mitochondrial biogenesis. PQQ additionally engages an NRF2-dependent antioxidant response, addressing molecular deficits directly implicated in glaucomatous RGC degeneration. In retinal cell models, PQQ preserves ATP content and viability under mitochondrial stress. In vivo, it protects RGC density in optic nerve degeneration models and elevates NAD+ along the visual pathway. A randomized clinical trial demonstrated functional improvement in glaucoma patients receiving a PQQ-containing combination. The redox biochemistry of PQQ places it at a mechanistic intersection with the NAD+ deficit that characterizes glaucomatous neurodegeneration. Its complementarity with conventional NAD+ precursors and neuroprotective compounds acting on distinct molecular targets supports the design of combination regimens addressing multiple dimensions of RGC vulnerability. Critical questions regarding bioavailability, molecular target characterization, and clinical validation in dedicated trials remain open.<\/jats:p>","DOI":"10.3390\/ph19081268","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:46:16Z","timestamp":1786455976000},"page":"1268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pyrroloquinoline Quinone and NAD+ Metabolism in Glaucoma: A Molecular Rationale for Combined Neuroprotection"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-607X","authenticated-orcid":false,"given":"Alessandro","family":"Medoro","sequence":"first","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, Universit\u00e0 degli Studi del Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-7199","authenticated-orcid":false,"given":"Sergio","family":"Davinelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, Universit\u00e0 degli Studi del Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1829-9288","authenticated-orcid":false,"given":"Cosimo Giuseppe","family":"Mazzotta","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Ophthalmology Unit, Faculty of Medicine and Surgery, University Kore of Enna, 94100 Enna, Italy"},{"name":"Siena Cross-Linking Center, 53035 Monteriggioni, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1625-6305","authenticated-orcid":false,"given":"Luca","family":"Agnifili","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Ageing Science, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-5586","authenticated-orcid":false,"given":"Giovanni","family":"Scapagnini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. 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Eye Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1001\/archopht.120.10.1268","article-title":"Reduction of Intraocular Pressure and Glaucoma Progression: Results from the Early Manifest Glaucoma Trial","volume":"120","author":"Heijl","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"546","DOI":"10.14336\/AD.2023.0630-1","article-title":"Aging, Cellular Senescence, and Glaucoma","volume":"15","author":"Zhang","year":"2024","journal-title":"Aging Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of Aging: An Expanding Universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.preteyeres.2010.11.002","article-title":"Mitochondrial Optic Neuropathies\u2014Disease Mechanisms and Therapeutic Strategies","volume":"30","author":"Griffiths","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B3 Modulates Mitochondrial Vulnerability and Prevents Glaucoma in Aged Mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1038\/s41591-024-03068-6","article-title":"Peripheral Blood Mononuclear Cell Respiratory Function Is Associated with Progressive Glaucomatous Vision Loss","volume":"30","author":"Petriti","year":"2024","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1167\/iovs.19-27099","article-title":"Nicotinamide Deficiency in Primary Open-Angle Glaucoma","volume":"60","author":"Guehlouz","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1017\/S0952523805225130","article-title":"Inherited Glaucoma in DBA\/2J Mice: Pertinent Disease Features for Studying the Neurodegeneration","volume":"22","author":"Libby","year":"2005","journal-title":"Vis. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101988","DOI":"10.1016\/j.redox.2021.101988","article-title":"Nicotinamide Provides Neuroprotection in Glaucoma by Protecting against Mitochondrial and Metabolic Dysfunction","volume":"43","author":"Tribble","year":"2021","journal-title":"Redox Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/ceo.13818","article-title":"Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B3) Supplementation: A Crossover Randomized Clinical Trial","volume":"48","author":"Hui","year":"2020","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1001\/jamaophthalmol.2021.4576","article-title":"Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial","volume":"140","author":"John","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mohamad Ishak, N.S., Kikuchi, M., and Ikemoto, K. (2024). Dietary Pyrroloquinoline Quinone Hinders Aging Progression in Male Mice and D-Galactose-Induced Cells. Front. Aging, 5.","DOI":"10.3389\/fragi.2024.1351860"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26723","DOI":"10.1038\/srep26723","article-title":"Identification of Lactate Dehydrogenase as a Mammalian Pyrroloquinoline Quinone (PQQ)-Binding Protein","volume":"6","author":"Akagawa","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1074\/jbc.M109.030130","article-title":"Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through CAMP Response Element-Binding Protein Phosphorylation and Increased PGC-1\u03b1 Expression","volume":"285","author":"Chowanadisai","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1021\/acs.biochem.7b01185","article-title":"Pyrroloquinoline Quinone, a Redox-Active o-Quinone, Stimulates Mitochondrial Biogenesis by Activating the SIRT1\/PGC-1\u03b1 Signaling Pathway","volume":"56","author":"Saihara","year":"2017","journal-title":"Biochemistry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.aac4854","article-title":"NAD+ in Aging, Metabolism, and Neurodegeneration","volume":"350","author":"Verdin","year":"2015","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41580-020-00313-x","article-title":"NAD+ Metabolism and Its Roles in Cellular Processes during Ageing","volume":"22","author":"Covarrubias","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.cmet.2018.03.018","article-title":"Quantitative Analysis of NAD Synthesis-Breakdown Fluxes","volume":"27","author":"Liu","year":"2018","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Fiedorowicz, M., Choragiewicz, T., Turski, W.A., Kocki, T., Nowakowska, D., Wertejuk, K., Kami\u0144ska, A., Avitabile, T., We\u0142niak-Kaminska, M., and Grieb, P. (2021). Tryptophan Pathway Abnormalities in a Murine Model of Hereditary Glaucoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031039"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.tibs.2020.05.010","article-title":"Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells","volume":"45","author":"Cambronne","year":"2020","journal-title":"Trends Biochem. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50754","DOI":"10.1074\/jbc.M408388200","article-title":"The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells","volume":"279","author":"Revollo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gilley, J., and Coleman, M.P. (2010). Endogenous NMNAT2 Is an Essential Survival Factor for Maintenance of Healthy Axons. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000300"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41586-020-2741-7","article-title":"SLC25A51 Is a Mammalian Mitochondrial NAD+ Transporter","volume":"588","author":"Luongo","year":"2020","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nature08778","article-title":"SIRT3 Regulates Mitochondrial Fatty-Acid Oxidation by Reversible Enzyme Deacetylation","volume":"464","author":"Hirschey","year":"2010","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14447","DOI":"10.1073\/pnas.0803790105","article-title":"A Role for the Mitochondrial Deacetylase Sirt3 in Regulating Energy Homeostasis","volume":"105","author":"Ahn","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.cmet.2010.11.015","article-title":"Calorie Restriction Reduces Oxidative Stress by SIRT3-Mediated SOD2 Activation","volume":"12","author":"Qiu","year":"2010","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1021\/bi901627u","article-title":"Regulation of Succinate Dehydrogenase Activity by SIRT3 in Mammalian Mitochondria","volume":"49","author":"Cimen","year":"2010","journal-title":"Biochemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature03354","article-title":"Nutrient Control of Glucose Homeostasis through a Complex of PGC-1alpha and SIRT1","volume":"434","author":"Rodgers","year":"2005","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18308","DOI":"10.1073\/pnas.0606526103","article-title":"Poly(ADP-Ribose) (PAR) Polymer Is a Death Signal","volume":"103","author":"Andrabi","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1111\/bph.12416","article-title":"Parthanatos: Mitochondrial-Linked Mechanisms and Therapeutic Opportunities","volume":"171","author":"Fatokun","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hogan, K.A., Chini, C.C.S., and Chini, E.N. (2019). The Multi-Faceted Ecto-Enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01187"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.cmet.2016.05.006","article-title":"CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism","volume":"23","author":"Chini","year":"2016","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tcb.2014.04.002","article-title":"NAD+ and Sirtuins in Aging and Disease","volume":"24","author":"Imai","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1356956","DOI":"10.1080\/19420889.2017.1356956","article-title":"Nicotinamide Treatment Robustly Protects from Inherited Mouse Glaucoma","volume":"11","author":"Williams","year":"2018","journal-title":"Commun. Integr. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Milde, S., Gilley, J., and Coleman, M.P. (2013). Subcellular Localization Determines the Stability and Axon Protective Capacity of Axon Survival Factor NMNAT2. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001539"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.ymthe.2022.01.035","article-title":"NMNAT2 Is Downregulated in Glaucomatous RGCs, and RGC-Specific Gene Therapy Rescues Neurodegeneration and Visual Function","volume":"30","author":"Fang","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.molmed.2017.08.001","article-title":"NAD+ in Aging: Molecular Mechanisms and Translational Implications","volume":"23","author":"Fang","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.coph.2012.09.008","article-title":"Oxidative Stress and Mitochondrial Dysfunction in Glaucoma","volume":"13","author":"Chrysostomou","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_41","first-page":"209","article-title":"Glucose Dehydrogenase of Bacterium Anitratum: An Enzyme with a Novel Prosthetic Group","volume":"89","author":"Hauge","year":"1964","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S1389-1723(00)80002-X","article-title":"The PQQ Story","volume":"88","author":"Duine","year":"1999","journal-title":"J. Biosci. Bioeng."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kato, C., Kawai, E., Shimizu, N., Mikekado, T., Kimura, F., Miyazawa, T., and Nakagawa, K. (2018). Determination of Pyrroloquinoline Quinone by Enzymatic and LC-MS\/MS Methods to Clarify Its Levels in Foods. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0209700"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100889","DOI":"10.1016\/j.crfs.2024.100889","article-title":"Pyrroloquinoline Quinone (PQQ): Its Impact on Human Health and Potential Benefits: PQQ: Human Health Impacts and Benefits","volume":"9","author":"Yan","year":"2024","journal-title":"Curr. Res. Food Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1042\/bj3070331","article-title":"Levels of Pyrroloquinoline Quinone in Various Foods","volume":"307","author":"Kumazawa","year":"1995","journal-title":"Biochem. J."},{"key":"ref_46","first-page":"268","article-title":"Potential Physiological Importance of Pyrroloquinoline Quinone","volume":"14","author":"Rucker","year":"2009","journal-title":"Altern. Med. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/09168451.2015.1062715","article-title":"Recent Progress in Studies on the Health Benefits of Pyrroloquinoline Quinone","volume":"80","author":"Akagawa","year":"2016","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Petricca, S., Matrone, A., Capece, D., Flati, I., Flati, V., Ricevuto, E., Celenza, G., Franceschini, N., Mastrangelo, M., and Pellegrini, C. (2025). Pyrroloquinoline Quinone (PQQ) Attenuates Hydrogen Peroxide-Induced Injury Through the Enhancement of Mitochondrial Function in Human Trabecular Meshwork Cells. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146938"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.bioelechem.2008.07.005","article-title":"Isolation and Purification of PQQ-Dependent Lactate Dehydrogenase from Gluconobacter and Use for Direct Electron Transfer at Carbon and Gold Electrodes","volume":"74","author":"Treu","year":"2008","journal-title":"Bioelectrochemistry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.nutres.2015.06.014","article-title":"Pyrroloquinoline Quinone Increases the Expression and Activity of Sirt1 and -3 Genes in HepG2 Cells","volume":"35","author":"Zhang","year":"2015","journal-title":"Nutr. Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Medoro, A., Davinelli, S., Jafar, T.H., Trung, T.T., Costagliola, C., Rossi, G.C.M., and Scapagnini, G. (2026). Pyrroloquinoline Quinone Targets the Allosteric Activation Site of Nicotinamide Phosphoribosyltransferase (NAMPT): Structural Basis and Consequences for NAD+ Metabolism in Aging. Appl. Sci., 16.","DOI":"10.3390\/app16136695"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/jn\/136.2.390","article-title":"Pyrroloquinoline Quinone Modulates Mitochondrial Quantity and Function in Mice","volume":"136","author":"Stites","year":"2006","journal-title":"J. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s40478-023-01642-6","article-title":"Pyrroloquinoline Quinone Drives ATP Synthesis in Vitro and in Vivo and Provides Retinal Ganglion Cell Neuroprotection","volume":"11","author":"Canovai","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Rossi, G.C.M., Rinaldi, M., Matarazzo, F., Strianese, D., Campagna, G., La Ragione, M., Esposito Veneruso, P., Scapagnini, G., and Costagliola, C. (2025). Randomized, Crossover, Multicenter, Single-Blind Study Comparing Citicoline 500 Mg\/Homotaurine 50 Mg\/Vitamin B3 54 Mg\/Pyrroloquinoline Quinone 5 Mg and Citicoline 800 Mg on Pattern Electroretinogram (PERG) and Quality of Life in Patients with Primary Open-Angle Glaucoma with Well-Controlled Intraocular Pressure. J. Clin. Med., 14.","DOI":"10.3390\/jcm14113774"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Li, X., Sun, Y., Zhou, Z., Li, J., Liu, S., Chen, L., Shi, Y., Wang, M., Zhu, Z., and Wang, G. (2024). Deep Learning-Driven Exploration of Pyrroloquinoline Quinone Neuroprotective Activity in Alzheimer\u2019s Disease. Adv. Sci., 11.","DOI":"10.1002\/advs.202308970"},{"key":"ref_56","first-page":"13845","article-title":"PQQ Ameliorates D-Galactose Induced Cognitive Impairments by Reducing Glutamate Neurotoxicity via the GSK-3\u03b2\/Akt Signaling Pathway in Mouse","volume":"8","author":"Zhou","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic Targeting of the NRF2 and KEAP1 Partnership in Chronic Diseases","volume":"18","author":"Cuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_58","first-page":"1809","article-title":"Computational Assessment of Carotenoids as Keap1-Nrf2 Protein\u2013Protein Interaction Inhibitors: Implications for Antioxidant Strategies","volume":"89","author":"Medoro","year":"2024","journal-title":"Biochemistry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"118020","DOI":"10.1016\/j.biopha.2025.118020","article-title":"Exploring the Links between Polyphenols, Nrf2, and Diabetes: A Review","volume":"186","author":"Ebrahimi","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e14202","DOI":"10.1111\/acel.14202","article-title":"Nrf2 Activation by Pyrroloquinoline Quinone Inhibits Natural Aging-Related Intervertebral Disk Degeneration in Mice","volume":"23","author":"Xue","year":"2024","journal-title":"Aging Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e13912","DOI":"10.1111\/acel.13912","article-title":"Pyrroloquinoline Quinone Alleviates Natural Aging-Related Osteoporosis via a Novel MCM3-Keap1-Nrf2 Axis-Mediated Stress Response and Fbn1 Upregulation","volume":"22","author":"Li","year":"2023","journal-title":"Aging Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7629","DOI":"10.1074\/jbc.M110.208173","article-title":"Acetylation-Deacetylation of the Transcription Factor Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) Regulates Its Transcriptional Activity and Nucleocytoplasmic Localization","volume":"286","author":"Kawai","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.3892\/ijmm.2016.2503","article-title":"SIRT1 Exerts Protective Effects against Paraquat-Induced Injury in Mouse Type II Alveolar Epithelial Cells by Deacetylating NRF2 in Vitro","volume":"37","author":"Ding","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1016\/j.jnutbio.2013.07.008","article-title":"Dietary Pyrroloquinoline Quinone (PQQ) Alters Indicators of Inflammation and Mitochondrial-Related Metabolism in Human Subjects","volume":"24","author":"Harris","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_65","first-page":"e05058","article-title":"Safety of Pyrroloquinoline Quinone Disodium Salt as a Novel Food Pursuant to Regulation (EC) No 258\/97","volume":"15","author":"Turck","year":"2017","journal-title":"EFSA J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1136\/bjo-2025-328096","article-title":"Effects of Nicotinamide Supplementation in Normal-Tension Glaucoma: A Crossover Placebo-Controlled Randomised Clinical Trial","volume":"110","author":"Ha","year":"2026","journal-title":"Br. J. Ophthalmol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13103","DOI":"10.1038\/ncomms13103","article-title":"NRK1 Controls Nicotinamide Mononucleotide and Nicotinamide Riboside Metabolism in Mammalian Cells","volume":"7","author":"Ratajczak","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2825703","DOI":"10.1155\/2017\/2825703","article-title":"Cytoprotective Effects of Citicoline and Homotaurine against Glutamate and High Glucose Neurotoxicity in Primary Cultured Retinal Cells","volume":"2017","author":"Davinelli","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s13311-021-01033-6","article-title":"Citicoline Modulates Glaucomatous Neurodegeneration through Intraocular Pressure-Independent Control","volume":"18","author":"Murphy","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Gandolfi, S., Marchini, G., Caporossi, A., Scuderi, G., Tomasso, L., and Brunoro, A. (2020). Cytidine 5\u2032-Diphosphocholine (Citicoline): Evidence for a Neuroprotective Role in Glaucoma. Nutrients, 12.","DOI":"10.3390\/nu12030793"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000350496","article-title":"Citicoline Oral Solution in Glaucoma: Is There a Role in Slowing Disease Progression?","volume":"229","author":"Ottobelli","year":"2013","journal-title":"Ophthalmologica"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Meera, P., Uusi-Oukari, M., Lipshutz, G.S., and Wallner, M. (2023). GABAA Receptors as Plausible Molecular Targets and Mediators for Taurine and Homotaurine Actions. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1271203"},{"key":"ref_73","first-page":"718","article-title":"Intravitreal Injection of Forskolin, Homotaurine, and L-Carnosine Affords Neuroprotection to Retinal Ganglion Cells Following Retinal Ischemic Injury","volume":"21","author":"Russo","year":"2015","journal-title":"Mol. Vis."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1268\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:49:35Z","timestamp":1786456175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":73,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ph19081268"],"URL":"https:\/\/doi.org\/10.3390\/ph19081268","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}