{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:23:44Z","timestamp":1760149424111,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,13]],"date-time":"2023-08-13T00:00:00Z","timestamp":1691884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS)","doi-asserted-by":"publisher","award":["22K11347"],"award-info":[{"award-number":["22K11347"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.<\/jats:p>","DOI":"10.3390\/ijms241612752","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T10:13:57Z","timestamp":1692008037000},"page":"12752","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8773-0967","authenticated-orcid":false,"given":"Kimio","family":"Watanabe","sequence":"first","affiliation":[{"name":"Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan"},{"name":"Kidney Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6998-2909","authenticated-orcid":false,"given":"Emiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-2745","authenticated-orcid":false,"given":"Eikan","family":"Mishima","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Rheumatology and Endocrinology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"},{"name":"Institute of Metabolism and Cell Death, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinobu","family":"Moriya","sequence":"additional","affiliation":[{"name":"Clinical Engineering Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuma","family":"Sakabe","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuya","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Momoko","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Fujimaru","sequence":"additional","affiliation":[{"name":"Kidney Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yugo","family":"Ito","sequence":"additional","affiliation":[{"name":"Kidney Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumika","family":"Taki","sequence":"additional","affiliation":[{"name":"Kidney Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiko","family":"Nagahama","sequence":"additional","affiliation":[{"name":"Kidney Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junichiro James","family":"Kazama","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Kidney Center, St Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.kisu.2020.12.002","article-title":"Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease","volume":"11","author":"Haase","year":"2021","journal-title":"Kidney Int. Suppl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1001\/jamainternmed.2022.0605","article-title":"Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial","volume":"182","author":"Singh","year":"2022","journal-title":"JAMA Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1681\/ASN.2020111638","article-title":"Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study","volume":"33","author":"Fishbane","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.2215\/CJN.00550122","article-title":"Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial","volume":"17","author":"Coyne","year":"2022","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1056\/NEJMoa2113380","article-title":"Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis","volume":"385","author":"Singh","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1093\/ndt\/gfab191","article-title":"Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: A Phase 3, randomized, open-label, active-controlled study (DOLOMITES)","volume":"36","author":"Barratt","year":"2021","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1681\/ASN.2020081150","article-title":"Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study","volume":"32","author":"Fishbane","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1056\/NEJMoa2025956","article-title":"Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis","volume":"384","author":"Eckardt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1093\/ndt\/gfab057","article-title":"Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: A Phase 3, randomized, double-blind, placebo-controlled study (ALPS)","volume":"36","author":"Shutov","year":"2021","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1093\/ndt\/gfab055","article-title":"Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: A Phase 3, multicenter, randomized, double-blind study","volume":"36","author":"Nangaku","year":"2021","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2215\/CJN.16011219","article-title":"Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial","volume":"15","author":"Akizawa","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1681\/ASN.2019060623","article-title":"Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan","volume":"31","author":"Akizawa","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMoa1901713","article-title":"Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis","volume":"381","author":"Chen","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1056\/NEJMra1011165","article-title":"Oxygen sensing, homeostasis, and disease","volume":"365","author":"Semenza","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4304","DOI":"10.1073\/pnas.90.9.4304","article-title":"General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia","volume":"90","author":"Wang","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1073\/pnas.90.6.2423","article-title":"Inducible operation of the erythropoietin 3\u2019 enhancer in multiple cell lines: Evidence for a widespread oxygen-sensing mechanism","volume":"90","author":"Maxwell","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6496","DOI":"10.1073\/pnas.91.14.6496","article-title":"Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: Similarities with the erythropoietin 3\u2019 enhancer","volume":"91","author":"Firth","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13333","DOI":"10.1074\/jbc.270.22.13333","article-title":"Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia","volume":"270","author":"Levy","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Watanabe, K., Sato, E., Mishima, E., Miyazaki, M., and Tanaka, T. (2022). What\u2019s New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010570"},{"key":"ref_20","first-page":"2390","article-title":"From Myo-inositol to D-chiro-inositol molecular pathways","volume":"25","author":"Kiani","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.fsi.2018.03.017","article-title":"Dietary myo-inositol deficiency decreased intestinal immune function related to NF-kappaB and TOR signaling in the intestine of young grass carp (Ctenopharyngodon idella)","volume":"76","author":"Li","year":"2018","journal-title":"Fish Shellfish Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1080\/17425255.2016.1206887","article-title":"Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease","volume":"12","author":"Bizzarri","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.aninu.2017.07.002","article-title":"Effect of phytase superdosing, myo-inositol and available phosphorus concentrations on performance and bone mineralisation in broilers","volume":"3","author":"Lee","year":"2017","journal-title":"Anim. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.3382\/ps\/pex186","article-title":"Effects of a high dose of microbial phytase and myo-inositol supplementation on growth performance, tibia mineralization, nutrient digestibility, litter moisture content, and foot problems in broiler chickens fed phosphorus-deficient diets","volume":"96","author":"Farhadi","year":"2017","journal-title":"Poult. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1042\/BST0371139","article-title":"Investigation of the H+-myo-inositol transporter (HMIT) as a neuronal regulator of phosphoinositide signalling","volume":"37","author":"Kew","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D590","DOI":"10.1093\/nar\/gky962","article-title":"New approach for understanding genome variations in KEGG","volume":"47","author":"Kanehisa","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Di Daniel, E., Mok, M.H., Mead, E., Mutinelli, C., Zambello, E., Caberlotto, L.L., Pell, T.J., Langmead, C.J., Shah, A.J., and Duddy, G. (2009). Evaluation of expression and function of the H+\/myo-inositol transporter HMIT. BMC Cell Biol., 10.","DOI":"10.1186\/1471-2121-10-54"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/s41580-022-00490-x","article-title":"Phosphoinositides as membrane organizers","volume":"23","author":"Posor","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41580-019-0129-z","article-title":"PI3K isoforms in cell signalling and vesicle trafficking","volume":"20","author":"Bilanges","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1056\/NEJMra1704560","article-title":"Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer","volume":"379","author":"Goncalves","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"978940","DOI":"10.3389\/fmicb.2022.978940","article-title":"Mixed silage with Chinese cabbage waste enhances antioxidant ability by increasing ascorbate and aldarate metabolism through rumen Prevotellaceae UCG-004 in Hu sheep","volume":"13","author":"Li","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chatree, S., Thongmaen, N., Tantivejkul, K., Sitticharoon, C., and Vucenik, I. (2020). Role of Inositols and Inositol Phosphates in Energy Metabolism. Molecules, 25.","DOI":"10.3390\/molecules25215079"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"F1087","DOI":"10.1152\/ajprenal.00340.2016","article-title":"Insulin resistance in chronic kidney disease: A systematic review","volume":"311","author":"Spoto","year":"2016","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1053\/j.ajkd.2020.05.028","article-title":"Adiposity, Physical Function, and Their Associations With Insulin Resistance, Inflammation, and Adipokines in CKD","volume":"77","author":"Navaneethan","year":"2021","journal-title":"Am. J. Kidney Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"638","DOI":"10.2215\/CJN.01290214","article-title":"Insulin resistance in CKD","volume":"9","author":"Leyking","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"Faul","year":"2007","journal-title":"Behav. Res. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.3758\/BRM.41.4.1149","article-title":"Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses","volume":"41","author":"Faul","year":"2009","journal-title":"Behav. Res. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"601","DOI":"10.4097\/kjae.2017.70.6.601","article-title":"Introduction of a pilot study","volume":"70","author":"In","year":"2017","journal-title":"Korean J. Anesthesiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j..2002.384.doc.x","article-title":"Design and analysis of pilot studies: Recommendations for good practice","volume":"10","author":"Lancaster","year":"2004","journal-title":"J. Eval. Clin. Pract."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108272","DOI":"10.1016\/j.pharmthera.2022.108272","article-title":"Future perspectives of anemia management in chronic kidney disease using hypoxia-inducible factor-prolyl hydroxylase inhibitors","volume":"239","author":"Sugahara","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1056\/NEJMoa2113379","article-title":"Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis","volume":"385","author":"Singh","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1159\/000513103","article-title":"Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial","volume":"52","author":"Nangaku","year":"2021","journal-title":"Am. J. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kumakura, S., Sato, E., Sekimoto, A., Hashizume, Y., Yamakage, S., Miyazaki, M., Ito, S., Harigae, H., and Takahashi, N. (2021). Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease. Toxins, 13.","DOI":"10.3390\/toxins13010050"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"17115","DOI":"10.18632\/oncotarget.15081","article-title":"Investigations in the possibility of early detection of colorectal cancer by gas chromatography\/triple-quadrupole mass spectrometry","volume":"8","author":"Nishiumi","year":"2017","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Nishiumi, S., Kobayashi, T., Ikeda, A., Yoshie, T., Kibi, M., Izumi, Y., Okuno, T., Hayashi, N., Kawano, S., and Takenawa, T. (2012). A novel serum metabolomics-based diagnostic approach for colorectal cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040459"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bae, J.E., Min, D., Choi, J.Y., Choi, H., Kim, J.B., Park, N.Y., Jo, D.S., Kim, Y.H., Na, H.W., and Kim, Y.J. (2021). Primary Ciliogenesis by 2-Isopropylmalic Acid Prevents PM2.5-Induced Inflammatory Response and MMP-1 Activation in Human Dermal Fibroblasts and a 3-D-Skin Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010941"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8583","DOI":"10.1038\/s41598-023-35225-1","article-title":"GC-MS based untargeted metabolomics reveals the metabolic response of earthworm (Eudrilus eugeniae) after chronic combinatorial exposure to three different pesticides","volume":"13","author":"Malla","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jchromb.2008.04.049","article-title":"Standardizing GC-MS metabolomics","volume":"871","author":"Kanani","year":"2008","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12752\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:32:50Z","timestamp":1760128370000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12752"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,13]]},"references-count":48,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612752"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612752","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,8,13]]}}}