{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T19:47:41Z","timestamp":1783194461243,"version":"3.54.6"},"reference-count":58,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Science Research Program of the National Research Foundation of Korea (NRF)","award":["NRF-2021R1A2C1011132"],"award-info":[{"award-number":["NRF-2021R1A2C1011132"]}]},{"name":"Basic Science Research Program of the National Research Foundation of Korea (NRF)","award":["GCU-202008420011"],"award-info":[{"award-number":["GCU-202008420011"]}]},{"DOI":"10.13039\/501100002631","name":"Gachon University Research Fund of 2020","doi-asserted-by":"publisher","award":["NRF-2021R1A2C1011132"],"award-info":[{"award-number":["NRF-2021R1A2C1011132"]}],"id":[{"id":"10.13039\/501100002631","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002631","name":"Gachon University Research Fund of 2020","doi-asserted-by":"publisher","award":["GCU-202008420011"],"award-info":[{"award-number":["GCU-202008420011"]}],"id":[{"id":"10.13039\/501100002631","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Age-related macular degeneration is a slow-progressing disease in which lipofuscin accumulates in the retina, causing inflammation and apoptosis of retinal pigment epithelial (RPE) cells. This study aimed to identify N-methyl-D-aspartate (NMDA) signaling as a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. Materials and Methods: A2E degradation assays were performed in ARPE-19 cells using fluorescently labeled A2E. The autophagic activity in ARPE-19 cells was measured upon blue light (BL) exposure, after A2E treatment. Autophagy flux was determined by measuring LC3-II formation using immunoblotting and confocal microscopy. To determine whether autophagy via the NMDA receptor is involved in A2E clearance, ATG5-deficient cells were used. Results: Ro 25-6981, an NR2B-selective NMDA receptor antagonist, effectively cleared A2E. Ro 25-6981 reduced A2E accumulation in the lysosomes of ARPE-19 cells at sub-cytotoxic concentrations, while increasing the formation of LC3-II and decreasing p62 protein levels in a concentration-dependent manner. The autophagic flux monitored by RFP-GFP-LC3 and bafilomycin A1 assays was significantly increased by Ro 25-6981. A2E clearance by Ro 25-6981 was abolished in ATG5-depleted ARPE-19 cells, suggesting that A2E degradation by Ro 25-6981 was mediated by autophagy. Furthermore, treatment with other NMDA receptor antagonists, CP-101,606 and AZD6765, showed similar effects on autophagy activation and A2E degradation in ARPE-19 cells. In contrast, glutamate, an NMDA receptor agonist, exhibited a contrasting effect, suggesting that both the activation of autophagy and the degradation of A2E by Ro 25-6981 in ARPE-19 cells occur through inhibition of the NMDA receptor pathway. Conclusions: This study demonstrates that NMDA receptor antagonists degrade lipofuscin via autophagy in human RPE cells and suggests that NMDA receptor antagonists could be promising new therapeutics for retinal degenerative diseases.<\/jats:p>","DOI":"10.3390\/medicina58081129","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T23:51:01Z","timestamp":1661125861000},"page":"1129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells"],"prefix":"10.3390","volume":"58","author":[{"given":"Jae Rim","family":"Lee","sequence":"first","affiliation":[{"name":"College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2258-8354","authenticated-orcid":false,"given":"Kwang Won","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.ophtha.2006.10.040","article-title":"Fifteen-year cumulative incidence of age-related macular degeneration: The Beaver Dam Eye Study","volume":"114","author":"Klein","year":"2007","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.2174\/157015908784533851","article-title":"Neurodegenerative diseases of the retina and potential for protection and recovery","volume":"6","author":"Schmidt","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1001\/archopht.1984.01040031330019","article-title":"Age-related macular degeneration and blindness due to neovascular maculopathy","volume":"102","author":"Ferris","year":"1984","journal-title":"Arch. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1038\/eye.2009.13","article-title":"New paradigms in the treatment of wet AMD: The impact of anti-VEGF therapy","volume":"23","author":"Menon","year":"2009","journal-title":"Eye"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"470","DOI":"10.5301\/ejo.5000886","article-title":"Comparing ranibizumab monotherapy and combination with single photodynamic therapy in wet AMD: Retreatment and morphologic results","volume":"27","author":"Hatz","year":"2017","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111041","DOI":"10.1016\/j.biopha.2020.111041","article-title":"Protective effects of PARP1-inhibitory compound in dry age-related macular degeneration","volume":"133","author":"Ho","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"86","DOI":"10.17116\/oftalma202013604186","article-title":"Practical application of ophthalmic nutraceuticals in patients with dry form of age-related macular degeneration","volume":"136","author":"Eskina","year":"2020","journal-title":"Vestn. Oftalmol."},{"key":"ref_8","first-page":"24","article-title":"Nutraceuticals for dry age-related macular degeneration: A case report based on novel pathogenic and morphological insights","volume":"158","author":"Pinelli","year":"2020","journal-title":"Arch. Ital. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9783429","DOI":"10.1155\/2019\/9783429","article-title":"Health Benefits of Polyphenols and Carotenoids in Age-Related Eye Diseases","volume":"2019","author":"Bungau","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_10","first-page":"297","article-title":"Treatments for dry age-related macular degeneration: Therapeutic avenues, clinical trials and future directions","volume":"106","author":"Georgiou","year":"2021","journal-title":"Br. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1167\/iovs.16-21272","article-title":"Timing of Antioxidant Gene Therapy: Implications for Treating Dry AMD","volume":"58","author":"Biswal","year":"2017","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1007\/s00417-021-05147-7","article-title":"Drusen ooze: Predictor for progression of dry age-related macular degeneration","volume":"259","author":"Jhingan","year":"2021","journal-title":"Graefes. Arch. Clin. Exp. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/0-387-32442-9_10","article-title":"A2E, a fluorophore of RPE lipofuscin, can destabilize membrane","volume":"572","author":"Sparrow","year":"2006","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/361724a0","article-title":"Retinal age pigments generated by self-assembling lysosomotropic detergents","volume":"361","author":"Eldred","year":"1993","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"18207","DOI":"10.1074\/jbc.M300457200","article-title":"A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation","volume":"278","author":"Sparrow","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110555","DOI":"10.1016\/j.fct.2019.06.002","article-title":"Photoactivation of N-retinylidene-N-retinylethanolamine compromises autophagy in retinal pigmented epithelial cells","volume":"131","author":"Jeong","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s40123-020-00325-y","article-title":"The Patient Experience: Symptoms and Impact of Dry Age-Related Macular Degeneration","volume":"10","author":"Schultz","year":"2021","journal-title":"Ophthalmol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/path.4266","article-title":"Mechanisms of age-related macular degeneration and therapeutic opportunities","volume":"232","author":"LeCouter","year":"2014","journal-title":"J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.scr.2018.01.014","article-title":"A2E-associated cell death and inflammation in retinal pigmented epithelial cells from human induced pluripotent stem cells","volume":"27","author":"Parmar","year":"2018","journal-title":"Stem. Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"22040","DOI":"10.18632\/aging.203558","article-title":"A2E-induced inflammation and angiogenesis in RPE cells in vitro are modulated by PPAR-alpha, -beta\/delta, -gamma, and RXR antagonists and by norbixin","volume":"13","author":"Fontaine","year":"2021","journal-title":"Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jff.2017.10.009","article-title":"Protective mechanisms of polyphenol-enriched fraction of Vaccinium uliginosum L. Against blue light-induced cell death of human retinal pigmented epithelial cells","volume":"39","author":"Jin","year":"2017","journal-title":"J. Funct. Foods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"291","DOI":"10.4062\/biomolther.2021.155","article-title":"Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells","volume":"30","author":"Jin","year":"2022","journal-title":"Biomol. Ther"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jpba.2015.10.010","article-title":"A novel fluorescence-based assay for measuring A2E removal from human retinal pigment epithelial cells to screen for age-related macular degeneration inhibitors","volume":"117","author":"Jin","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_24","first-page":"2988","article-title":"A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture","volume":"40","author":"Sparrow","year":"1999","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Feng, J., Chen, Y., Lu, B., Sun, X., Zhu, H., and Sun, X. (2019). Autophagy activated via GRP78 to alleviate endoplasmic reticulum stress for cell survival in blue light-mediated damage of A2E-laden RPEs. BMC Ophthalmol., 19.","DOI":"10.1186\/s12886-019-1261-4"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.cmet.2011.04.004","article-title":"Autophagy in the cellular energetic balance","volume":"13","author":"Singh","year":"2011","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"24131","DOI":"10.1074\/jbc.M702824200","article-title":"p62\/SQSTM1 binds directly to Atg8\/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy","volume":"282","author":"Pankiv","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yoshii, S.R., and Mizushima, N. (2017). Monitoring and Measuring Autophagy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091865"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","article-title":"Methods in mammalian autophagy research","volume":"140","author":"Mizushima","year":"2010","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1972","DOI":"10.1038\/cddis.2015.330","article-title":"Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: Implications for age-related macular degeneration","volume":"6","author":"Zhang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1016\/j.cell.2019.05.026","article-title":"Autophagy-Independent Functions of the Autophagy Machinery","volume":"177","author":"Galluzzi","year":"2019","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.3389\/fimmu.2018.02334","article-title":"Exploring the Role of Autophagy-Related Gene 5 (ATG5) Yields Important Insights Into Autophagy in Autoimmune\/Autoinflammatory Diseases","volume":"9","author":"Ye","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4672","DOI":"10.1111\/febs.13540","article-title":"p62\/SQSTM1 functions as a signaling hub and an autophagy adaptor","volume":"282","author":"Katsuragi","year":"2015","journal-title":"FEBS J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.molcel.2013.08.003","article-title":"Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy","volume":"51","author":"Ichimura","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1001\/archopht.122.4.564","article-title":"Prevalence of age-related macular degeneration in the United States","volume":"122","author":"Friedman","year":"2004","journal-title":"Arch. Ophthalmol."},{"key":"ref_36","first-page":"340","article-title":"Age-related macular degeneration (AMD)\u2014A frequent cause of vision loss in the aged","volume":"38","author":"Wolf","year":"2000","journal-title":"Krankenpfl J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1093\/hmg\/ddn018","article-title":"Gene-environment interaction in progression of AMD: The CFH gene, smoking and exposure to chronic infection","volume":"17","author":"Baird","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3842","DOI":"10.1073\/pnas.052025899","article-title":"The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium","volume":"99","author":"Finnemann","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","first-page":"1691","article-title":"Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration","volume":"30","author":"Dorey","year":"1989","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1016\/S0042-6989(03)00475-9","article-title":"A2E, a byproduct of the visual cycle","volume":"43","author":"Sparrow","year":"2003","journal-title":"Vision Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4393","DOI":"10.1167\/iovs.05-0820","article-title":"Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: A potential therapy for treatment of lipofuscin-based retinal diseases","volume":"46","author":"Radu","year":"2005","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1016\/S0960-894X(01)00314-6","article-title":"Fluorescent pigments of the retinal pigment epithelium and age-related macular degeneration","volume":"11","author":"Parish","year":"2001","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1006\/exer.2001.1192","article-title":"Phosphatidylglycerol potently protects human retinal pigment epithelial cells against apoptosis induced by A2E, a compound suspected to cause age-related macula degeneration","volume":"75","author":"Shaban","year":"2002","journal-title":"Exp. Eye Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1039\/c0pp00133c","article-title":"Blue light induced A2E oxidation in rat eyes--experimental animal model of dry AMD","volume":"9","author":"Wielgus","year":"2010","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_45","first-page":"1356","article-title":"Blue light-induced apoptosis of A2E-containing RPE: Involvement of caspase-3 and protection by Bcl-2","volume":"42","author":"Sparrow","year":"2001","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Shin, C.Y., Lee, M.H., Kim, H.M., Chung, H.C., Kim, D.U., Lee, J.H., and Jeong, K.W. (2022). Protective Effect of Ribes nigrum Extract against Blue Light-Induced Retinal Degeneration In Vitro and In Vivo. Antioxidants, 11.","DOI":"10.3390\/antiox11050832"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Pham, T.N.M., Shin, C.Y., Park, S.H., Lee, T.H., Ryu, H.Y., Kim, S.B., Auh, K., and Jeong, K.W. (2021). Solanum melongena L. Extract Protects Retinal Pigment Epithelial Cells from Blue Light-Induced Phototoxicity in In Vitro and In Vivo Models. Nutrients, 13.","DOI":"10.3390\/nu13020359"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.fob.2014.11.003","article-title":"Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E","volume":"4","author":"Saadat","year":"2014","journal-title":"FEBS Open Bio."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.brainresbull.2012.10.004","article-title":"Neuroprotective effect of estrogen: Role of nonsynaptic NR2B-containing NMDA receptors","volume":"93","author":"Liu","year":"2013","journal-title":"Brain Res. Bull."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1089\/neu.2008.0783","article-title":"A novel protein complex in membrane rafts linking the NR2B glutamate receptor and autophagy is disrupted following traumatic brain injury","volume":"26","author":"Bigford","year":"2009","journal-title":"J. Neurotrauma"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/alz.12398","article-title":"Pathogenesis of sporadic Alzheimer\u2019s disease by deficiency of NMDA receptor subunit GluN3A","volume":"18","author":"Zhong","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Corsi, L., Mescola, A., and Alessandrini, A. (2019). Glutamate Receptors and Glioblastoma Multiforme: An Old \u201cRoute\u201d for New Perspectives. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071796"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.bbrc.2019.08.025","article-title":"Neuroprotective effects of memantine via enhancement of autophagy","volume":"518","author":"Hirano","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3340\/jkns.2016.0101.006","article-title":"Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells","volume":"60","author":"Yoon","year":"2017","journal-title":"J. Korean Neurosurg. Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/2050-490X-2-8","article-title":"Promising targets of cell death signaling of NR2B receptor subunit in stroke pathogenesis","volume":"2","author":"Shu","year":"2014","journal-title":"Regen. Med. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7143","DOI":"10.1074\/jbc.M109.063933","article-title":"Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17","volume":"285","author":"Selvi","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wen, L.Y., Wan, L., Lai, J.N., Chen, C.S., Chen, J.J., Wu, M.Y., Hu, K.C., Chiu, L.T., Tien, P.T., and Lin, H.J. (2021). Increased risk of Alzheimer\u2019s disease among patients with age-related macular degeneration: A nationwide population-based study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0250440"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3233\/JAD-200111","article-title":"Co-Prevalence of Alzheimer\u2019s Disease and Age-Related Macular Degeneration Established by Histopathologic Diagnosis","volume":"76","author":"Schwaber","year":"2020","journal-title":"J. Alzheimers. Dis."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/8\/1129\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:12:44Z","timestamp":1760141564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/8\/1129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,20]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["medicina58081129"],"URL":"https:\/\/doi.org\/10.3390\/medicina58081129","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,20]]}}}