{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T02:53:41Z","timestamp":1789095221166,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tri-Service General Hospital Research Foundation","award":["TSGH-E-114265"],"award-info":[{"award-number":["TSGH-E-114265"]}]},{"name":"National Defense Medical Center Foundation","award":["MND-MAB-D-114118"],"award-info":[{"award-number":["MND-MAB-D-114118"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glaucoma continues to be a primary contributor to permanent vision loss worldwide, frequently advancing even when intraocular pressure management is clinically adequate. Accumulating research emphasizes the metabolic susceptibility of retinal ganglion cells (RGCs), specifically concerning the progressive depletion of nicotinamide adenine dinucleotide (NAD+), a pivotal coenzyme fundamental to mitochondrial energy production and cellular survival mechanisms. As a key biosynthetic precursor in NAD+ synthesis pathways, nicotinamide (NAM), a form of vitamin B3, has exhibited significant neuroprotective properties across various preclinical experimental models and preliminary clinical investigations, demonstrating enhanced preservation of RGC morphology and physiological function. This comprehensive review systematically examines the current body of evidence supporting NAM\u2019s therapeutic utility in glaucomatous neuroprotection, focusing particularly on underlying metabolic pathways, obstacles in clinical translation, and prospective therapeutic applications. Through systematic integration of data from cellular and molecular research, animal experimental studies, and population-based epidemiological investigations, we establish a conceptual framework for repurposing NAM as an innovative complementary therapeutic strategy in comprehensive glaucoma care, addressing key considerations for future clinical development including optimal dosing strategies, delivery mechanisms, and patient selection criteria for maximizing therapeutic outcomes in this challenging neurodegenerative condition.<\/jats:p>","DOI":"10.3390\/ijms262110789","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:51:43Z","timestamp":1762451503000},"page":"10789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Update on Nicotinamide and Its Application in the Management of Glaucoma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8263-9607","authenticated-orcid":false,"given":"Ta-Hung","family":"Chiu","sequence":"first","affiliation":[{"name":"Department of General Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Heng","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8134-3619","authenticated-orcid":false,"given":"Chiao-Hsin","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Medical Education, National Taiwan University Hospital, Taipei 100225, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1473-2531","authenticated-orcid":false,"given":"Wei-Ting","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Wen","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B(3) modulates mitochondrial vulnerability and prevents glaucoma in aged mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_3","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_4","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_5","doi-asserted-by":"crossref","first-page":"141","DOI":"10.5005\/jp-journals-10078-1390","article-title":"Niacinamide and Neuroprotection: The Glaucoma Holy Grail","volume":"16","author":"Bhartiya","year":"2022","journal-title":"J. Curr. Glaucoma Pract."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Babighian, S., Gattazzo, I., Zanella, M.S., Galan, A., D\u2019Esposito, F., Musa, M., Gagliano, C., Lapenna, L., and Zeppieri, M. (2024). Nicotinamide: Bright Potential in Glaucoma Management. Biomedicines, 12.","DOI":"10.3390\/biomedicines12081655"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100881","DOI":"10.1016\/j.preteyeres.2020.100881","article-title":"Retinal energy metabolism in health and glaucoma","volume":"81","author":"Casson","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1167\/iovs.02-0333","article-title":"Varicosities of intraretinal ganglion cell axons in human and nonhuman primates","volume":"44","author":"Wang","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18426","DOI":"10.1074\/jbc.M301295200","article-title":"Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress","volume":"278","author":"Du","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-020-00311-7","article-title":"NAD(+) metabolism: Pathophysiologic mechanisms and therapeutic potential","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Petriti, B., Williams, P.A., Lascaratos, G., Chau, K.Y., and Garway-Heath, D.F. (2021). Neuroprotection in Glaucoma: NAD(+)\/NADH Redox State as a Potential Biomarker and Therapeutic Target. Cells, 10.","DOI":"10.3390\/cells10061402"},{"key":"ref_12","unstructured":"Garway-Heath, D., Petriti, B., Rabiolo, A., Chau, K., Williams, P., Giovanni, M., and Lascaratos, G. (2023). Mitochondrial respiratory function is strongly associated with progressive glaucomatous vision loss. Res. Sq."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40478-023-01513-0","article-title":"NAD salvage pathway machinery expression in normal and glaucomatous retina and optic nerve","volume":"11","author":"Tribble","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"36334","DOI":"10.1074\/jbc.M508660200","article-title":"Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms","volume":"280","author":"Berger","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Felici, R., Lapucci, A., Ramazzotti, M., and Chiarugi, A. (2013). Insight into molecular and functional properties of NMNAT3 reveals new hints of NAD homeostasis within human mitochondria. PLoS ONE, 8, Erratum in PLoS ONE 2013, 8.","DOI":"10.1371\/annotation\/f5e6107f-a911-4c15-a881-7cb7e4946ff6"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13503","DOI":"10.1074\/jbc.M300073200","article-title":"Structural characterization of a human cytosolic NMN\/NaMN adenylyltransferase and implication in human NAD biosynthesis","volume":"278","author":"Zhang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_17","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_18","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_19","first-page":"2398","article-title":"Up-regulation of sirtuins in the glaucomatous human retina","volume":"55","author":"Yang","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","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_21","first-page":"3630","article-title":"Cell Death Markers in Primary Open-Angle Glaucoma","volume":"50","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Williams, P.A., Harder, J.M., Cardozo, B.H., Foxworth, N.E., and John, S.W.M. (2018). Nicotinamide treatment robustly protects from inherited mouse glaucoma. Commun. Integr. Biol., 11.","DOI":"10.1080\/19420889.2017.1356956"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, X., Zhang, N., Chrenek, M.A., Girardot, P.E., Wang, J., Sellers, J.T., Geisert, E.E., Brenner, C., Nickerson, J.M., and Boatright, J.H. (2021). Systemic Treatment with Nicotinamide Riboside Is Protective in Two Mouse Models of Retinal Ganglion Cell Damage. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060893"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","unstructured":"Williams, P.A., Harder, J.M., Foxworth, N.E., Cardozo, B.H., Cochran, K.E., and John, S.W.M. (2017). Nicotinamide and WLD(S) Act Together to Prevent Neurodegeneration in Glaucoma. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00232"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6256","DOI":"10.1038\/s41467-024-50354-5","article-title":"NMNAT2 is a druggable target to drive neuronal NAD production","volume":"15","author":"Tribble","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s40478-024-01777-0","article-title":"Extracellular vesicle encapsulated nicotinamide delivered via a trans-scleral route provides retinal ganglion cell neuroprotection","volume":"12","author":"Kim","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.cmet.2011.03.004","article-title":"PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation","volume":"13","author":"Bai","year":"2011","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1016\/S0021-9258(18)99829-7","article-title":"Studies on the biosynthesis of nicotinamide adenine dinucleotide. 3. Comparative in vivo studies on nicotinic acid, nicotinamide, and quinolinic acid as precursors of nicotinamide adenine dinucleotide","volume":"241","author":"Ijichi","year":"1966","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s40478-024-01850-8","article-title":"Oral nicotinamide provides robust, dose-dependent structural and metabolic neuroprotection of retinal ganglion cells in experimental glaucoma","volume":"12","author":"Cimaglia","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Williams, P.A., Howell, G.R., Barbay, J.M., Braine, C.E., Sousa, G.L., John, S.W., and Morgan, J.E. (2013). Retinal ganglion cell dendritic atrophy in DBA\/2J glaucoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072282"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1097\/WNO.0b013e318177edf0","article-title":"Dendritic and Synaptic Protection: Is It Enough to Save the Retinal Ganglion Cell Body and Axon?","volume":"28","author":"Morquette","year":"2008","journal-title":"J. Neuro-Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Boodram, V., and Lim, H. (2024). Differential protection by nicotinamide in a mouse model of glaucoma DBA\/2J revealed by second-harmonic generation microscopy. PLoS ONE, 19.","DOI":"10.1101\/2024.03.07.583928"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1167\/iovs.13-12157","article-title":"SIRT1 promotes RGC survival and delays loss of function following optic nerve crush","volume":"54","author":"Zuo","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1111\/j.1460-9568.2008.06426.x","article-title":"The WldS gene delays axonal but not somatic degeneration in a rat glaucoma model","volume":"28","author":"Beirowski","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_36","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_37","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1001\/archopht.126.8.1030","article-title":"Canadian Glaucoma Study: 2. risk factors for the progression of open-angle glaucoma","volume":"126","author":"Chauhan","year":"2008","journal-title":"Arch. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1167\/iovs.64.14.34","article-title":"Nicotinamide Prevents Retinal Vascular Dropout in a Rat Model of Ocular Hypertension and Supports Ocular Blood Supply in Glaucoma Patients","volume":"64","author":"Gustavsson","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","unstructured":"Jung, K.I., Kim, Y.C., and Park, C.K. (2018). Dietary Niacin and Open-Angle Glaucoma: The Korean National Health and Nutrition Examination Survey. Nutrients, 10.","DOI":"10.3390\/nu10040387"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lee, J.Y., Kim, J.M., Lee, K.Y., Kim, B., Lee, M.Y., and Park, K.H. (2020). Relationships between Obesity, Nutrient Supply and Primary Open Angle Glaucoma in Koreans. Nutrients, 12.","DOI":"10.3390\/nu12030878"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1097\/IJG.0000000000002216","article-title":"Associations Between Niacin Intake and Glaucoma in the National Health and Nutrition Examination Survey","volume":"32","author":"Lee","year":"2023","journal-title":"J. Glaucoma"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Taechameekietichai, T., Chansangpetch, S., Peerawaranun, P., and Lin, S.C. (2021). Association between Daily Niacin Intake and Glaucoma: National Health and Nutrition Examination Survey. Nutrients, 13.","DOI":"10.3390\/nu13124263"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hou, J., Wen, Y., Gao, S., Jiang, Z., and Tao, L. (2024). Association of dietary intake of B vitamins with glaucoma. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-58526-5"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"701","DOI":"10.4162\/nrp.2024.18.5.701","article-title":"Comparison of food and nutrient intake according to the presence of glaucoma among Korean older adults","volume":"18","author":"Kim","year":"2024","journal-title":"Nutr. Res. Pract."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s001250051536","article-title":"Safety of high-dose nicotinamide: A review","volume":"43","author":"Knip","year":"2000","journal-title":"Diabetologia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/jop.2023.0125","article-title":"Vitamin B(3) Supplementation for Optic Neuropathies: A Comprehensive Review","volume":"40","author":"Almeida","year":"2024","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Cimaglia, G., Votruba, M., Morgan, J.E., Andre, H., and Williams, P.A. (2020). Potential Therapeutic Benefit of NAD(+) Supplementation for Glaucoma and Age-Related Macular Degeneration. Nutrients, 12.","DOI":"10.3390\/nu12092871"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hwang, E.S., and Song, S.B. (2020). Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Biomolecules, 10.","DOI":"10.3390\/biom10050687"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2692794","DOI":"10.1155\/2020\/2692794","article-title":"Implications of NAD(+) Metabolism in the Aging Retina and Retinal Degeneration","volume":"2020","author":"Jadeja","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13195-025-01693-y","article-title":"Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer\u2019s disease","volume":"17","author":"Ketron","year":"2025","journal-title":"Alzheimers Res. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Leung, C.K.S., Ren, S.T., Chan, P.P.M., Wan, K.H.N., Kam, A.K.W., Lai, G.W.K., Chiu, V.S.M., Ko, M.W.L., Yiu, C.K.F., and Yu, M.C.Y. (2022). Nicotinamide riboside as a neuroprotective therapy for glaucoma: Study protocol for a randomized, double-blind, placebo-control trial. Trials, 23, Correction in Trials 2022, 23, 134.","DOI":"10.1186\/s13063-022-06079-1"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Tezel, G. (2021). Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects. Cells, 10.","DOI":"10.3390\/cells10061372"},{"key":"ref_54","unstructured":"(2025, September 05). ClinicalTrials.gov. The Glaucoma Nicotinamide Trial, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05275738."},{"key":"ref_55","unstructured":"(2025, September 30). ClinicalTrials.gov. Nicotinamide in Glaucoma (NAMinG): A Randomised, Placebo-Controlled, Multi-Centre, Phase III Trial (NAMinG), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05405868."},{"key":"ref_56","unstructured":"(2025, September 30). ClinicalTrials.gov. Nicotinamide and Pyruvate for Open Angle Glaucoma: A Randomized Clinical Study, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05695027."},{"key":"ref_57","unstructured":"(2025, September 30). ClinicalTrials.gov. Efficacy of Nicotinamide on Retinal Ganglion Cell Functions in Glaucoma Patients, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT06078605."},{"key":"ref_58","unstructured":"(2025, September 30). ClinicalTrials.gov. Comparisons of NAD Precursors for Neuroenhancement in Glaucoma Patients, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT06991712."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10789\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:51:55Z","timestamp":1762451515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":58,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110789"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110789","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]}}}