{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:04:37Z","timestamp":1774620277320,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"STI2030-Major Projects","award":["2022ZD0211600"],"award-info":[{"award-number":["2022ZD0211600"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01h0zpd94","doi-asserted-by":"publisher","award":["82174210"],"award-info":[{"award-number":["82174210"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific Research Facility Special Foundation for Operation and Maintenance","award":["102160222020040009016"],"award-info":[{"award-number":["102160222020040009016"]}]},{"name":"Scientific Research Facility Special Foundation for Operation and Maintenance","award":["160202001000210007"],"award-info":[{"award-number":["160202001000210007"]}]},{"name":"Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["ZZ14-FL-005"],"award-info":[{"award-number":["ZZ14-FL-005"]}]},{"name":"Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["ZZ13-YQ-073"],"award-info":[{"award-number":["ZZ13-YQ-073"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) involves amyloid and tau pathology with neuroimmune dysregulation, and Yixin Yangshen Granules (YXYS) shows neuroprotective promise, though mechanisms remain unclear. This study aimed to elucidate the multi-target mechanisms of YXYS in AD. Methods: The study began by analyzing a public human AD hippocampal snRNA-seq dataset to identify cell-type-specific pathological pathways and profiled YXYS constituents by UPLC-QTOF-MS. In vitro, YXYS cytoprotection against mitochondrial dysfunction and oxidative stress was tested in A\u03b225\u201335-challenged HT22 cells; in vivo efficacy was assessed in A\u03b21\u201342-induced mice via behavioral and histopathological analyses. Integrated transcriptomic and proteomic profiling of brain tissue, with ELISA, qRT-PCR, and Western blot validation, confirmed pathway targets. Using the intersection of transcriptomic and proteomic targets as biological input, the DTIAM deep learning framework was employed to prioritize active YXYS constituents. Finally, molecular docking and 100-ns dynamics simulations demonstrated direct binding of Ganosporelactone A to HIF\u22121\u03b1. Results: AD snRNA-seq analysis highlighted HIF\u22121 and AGE-RAGE signaling as prominent pathways in the AD hippocampus, particularly enriched in brain microvascular endothelial cells, implicating neurovascular hypoxic and inflammatory stress. In A\u03b2-induced mice, YXYS improved cognition, reduced A\u03b2 pathology, suppressed neuroinflammation, and promoted neuronal survival, consistent with in vitro evidence of restored mitochondrial function. Multi-omics confirmed convergence on HIF\u22121 and AGE-RAGE pathways, with YXYS rebalancing the neuroimmune microenvironment by reducing pro-inflammatory M0 macrophages. Screening against these consensus signaling hubs, deep learning analysis prioritized Ganosporelactone A as the top-ranked modulator, and molecular further demonstrated the stable binding of Ganosporelactone A to HIF\u22121\u03b1, linking YXYS to mitigation of hypoxic stress. Conclusions: Guided by multi-omics and deep learning, our findings suggest that YXYS may alleviate AD-related phenotypes through multi-target modulation of the HIF\u22121 and AGE-RAGE pathways, with associated improvements in neuro-immune homeostasis and reductions in oxidative stress, neuroinflammation, and hypoxia.<\/jats:p>","DOI":"10.3390\/ph19030502","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:12:26Z","timestamp":1773853946000},"page":"502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Yixin Yangshen Granules Target HIF\u22121 Signaling to Modulate the Neuroimmune Microenvironment in Alzheimer\u2019s Disease: Insights from Integrative Multi-Omics and Deep Learning"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0157-7770","authenticated-orcid":false,"given":"Zhihao","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"},{"name":"Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6081-4573","authenticated-orcid":false,"given":"Linshuang","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-1565","authenticated-orcid":false,"given":"Sixia","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Shi","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dasheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Jiangxi University of Chinese Medicine, Nanchang 330004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9299-0256","authenticated-orcid":false,"given":"Junying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuejie","family":"Han","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2803-2974","authenticated-orcid":false,"given":"Dongfeng","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"173554","DOI":"10.1016\/j.ejphar.2020.173554","article-title":"Alzheimer\u2019s disease: Recent treatment strategies","volume":"887","author":"Vaz","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Weinstock, M. (2025). Role of Oxidative Stress and Neuroinflammation in the Etiology of Alzheimer\u2019s Disease: Therapeutic Options. Antioxidants, 14.","DOI":"10.3390\/antiox14070769"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1152\/physrev.00015.2020","article-title":"The complexity of Alzheimer\u2019s disease: An evolving puzzle","volume":"101","author":"Ferrari","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Jarrell, J.T., Gao, L., Cohen, D.S., and Huang, X. (2018). Network Medicine for Alzheimer\u2019s Disease and Traditional Chinese Medicine. Molecules, 23.","DOI":"10.3390\/molecules23051143"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113208","DOI":"10.1016\/j.biopha.2022.113208","article-title":"Signal pathways in the treatment of Alzheimer\u2019s disease with traditional Chinese medicine","volume":"152","author":"Ding","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15620","DOI":"10.18632\/aging.203125","article-title":"Formulated Chinese medicine Shaoyao Gancao Tang reduces NLRP1 and NLRP3 in Alzheimer\u2019s disease cell and mouse models for neuroprotection and cognitive improvement","volume":"13","author":"Chiu","year":"2021","journal-title":"Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8189","DOI":"10.1007\/s00210-024-03188-3","article-title":"Oxidative stress-mediated neuroinflammation in Alzheimer\u2019s disease","volume":"397","author":"Firdous","year":"2024","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2","DOI":"10.31083\/j.jin2201002","article-title":"A Review of the Pathogenesis and Chinese Medicine Intervention of Alzheimer\u2019s Disease","volume":"22","author":"Zhao","year":"2022","journal-title":"J. Integr. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.2147\/DDDT.S380612","article-title":"The Role of Traditional Chinese Medicine Natural Products in \u03b2-Amyloid Deposition and Tau Protein Hyperphosphorylation in Alzheimer\u2019s Disease","volume":"17","author":"Yan","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.yrtph.2016.04.006","article-title":"Cereboost, an American ginseng extract, improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection","volume":"78","author":"Shin","year":"2016","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yang, Y., Chen, W., Lin, Z., Wu, Y., Li, Y., and Xia, X. (2024). Panax notoginseng saponins prevent dementia and oxidative stress in brains of SAMP8 mice by enhancing mitophagy. BMC Complement. Med. Ther., 24.","DOI":"10.1186\/s12906-024-04403-7"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.fitote.2019.01.013","article-title":"Aromatic constituents from Ganoderma lucidum and their neuroprotective and anti-inflammatory activities","volume":"134","author":"Lu","year":"2019","journal-title":"Fitoterapia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"116222","DOI":"10.1016\/j.biopha.2024.116222","article-title":"Therapeutic potential of the medicinal mushroom Ganoderma lucidum against Alzheimer\u2019s disease","volume":"172","author":"Chen","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","first-page":"330","article-title":"Effect of Ganoderma Lucidum Preparation on the Behavior, Biochemistry, and Autoimmune Parameters of Mouse Models of APP\/PS1 Double Transgenic Alzheimer\u2019s Disease","volume":"39","author":"Qin","year":"2017","journal-title":"Zhongguo Yi Xue Ke Xue Yuan Xue Bao"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13020-024-00900-6","article-title":"A review on traditional Chinese medicine natural products and acupuncture intervention for Alzheimer\u2019s disease based on the neuroinflammatory","volume":"19","author":"Chen","year":"2024","journal-title":"Chinese Medicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112719","DOI":"10.1016\/j.biopha.2022.112719","article-title":"Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: Applications for natural compounds from medicinal herbs","volume":"148","author":"Zhu","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ye, Y., Li, Q., Pan, C.-S., Yan, L., Sun, K., Wang, X.-Y., Yao, S.-Q., Fan, J.-Y., and Han, J.-Y. (2022). QiShenYiQi inhibits tissue plasminogen activator\u2013induced brain edema and hemorrhage after ischemic stroke in mice. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.759027"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tran, M.N., Kim, S., Nguyen, Q.H.N., and Lee, S. (2022). Molecular mechanisms underlying qi-invigorating effects in traditional medicine: Network pharmacology-based study on the unique functions of qi-invigorating herb group. Plants, 11.","DOI":"10.3390\/plants11192470"},{"key":"ref_20","unstructured":"Chinese Pharmacopoeia Commission (2020). Pharmacopoeia of the People\u2019s Republic of China, China Medical Science Press."},{"key":"ref_21","first-page":"35","article-title":"Experience of Han Xuejie in Treating Qi Deficiency and Blood Stasis Syndrome during the Recovery Period of Cerebral Infarction with Yiqi Yangxin Powder","volume":"5","author":"Ren","year":"2022","journal-title":"West. Tradit. Chin. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s11655-022-3570-3","article-title":"Yixin Ningshen Tablet Alleviates Comorbidity of Myocardial Infarction and Depression by Enhancing Myocardial Energy Metabolism and Increasing Availability of Monoamine Neurotransmitter","volume":"28","author":"Jiang","year":"2022","journal-title":"Chin. J. Integr. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1536\/ihj.22-715","article-title":"Yixin Granules Reduce Myocardial Inflammation and Fibrosis in Rats with Heart Failure by Inhibiting the Expression of ADAMTS8","volume":"64","author":"Li","year":"2023","journal-title":"Int. Heart J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-inducible factors in physiology and medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1007\/s00018-009-0141-0","article-title":"Contribution of hypoxia to Alzheimer\u2019s disease: Is HIF-1\u03b1 a mediator of neurodegeneration?","volume":"66","author":"Ogunshola","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10873","DOI":"10.1074\/jbc.M608856200","article-title":"Hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1)-mediated hypoxia increases BACE1 expression and \u03b2-amyloid generation","volume":"282","author":"Zhang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103501","DOI":"10.1016\/j.amsu.2022.103501","article-title":"Doxorubicin induced immune abnormalities and inflammatory responses via HMGB1, HIF1-\u03b1 and VEGF pathway in progressive of cardiovascular damage","volume":"76","author":"Syukri","year":"2022","journal-title":"Ann. Med. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shi, J., Wang, J., Jia, N., and Sun, Q. (2022). A network pharmacology study on mechanism of resveratrol in treating preeclampsia via regulation of AGE-RAGE and HIF-1 signalling pathways. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1044775"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Voirin, A.C., Chatard, M., Briancon-Marjollet, A., Pepin, J.L., Perek, N., and Roche, F. (2023). Loss of Blood-Brain Barrier Integrity in an In Vitro Model Subjected to Intermittent Hypoxia: Is Reversion Possible with a HIF-1\u03b1 Pathway Inhibitor?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24055062"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shen, C.Y., Lu, C.H., Wu, C.H., Li, K.J., Kuo, Y.M., Hsieh, S.C., and Yu, C.L. (2020). The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases. Molecules, 25.","DOI":"10.3390\/molecules25235591"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bhattacharya, R., Alam, M.R., Kamal, M.A., Seo, K.J., and Singh, L.R. (2023). AGE-RAGE axis culminates into multiple pathogenic processes: A central road to neurodegeneration. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1155175"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.2174\/1871527313666140806144831","article-title":"Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress","volume":"13","author":"Cuevas","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e20025","DOI":"10.1016\/j.heliyon.2023.e20025","article-title":"Network analysis and experimental approach to investigate the potential therapeutic mechanism of zishen yutai pills on premature ovarian insufficiency","volume":"9","author":"Song","year":"2023","journal-title":"Heliyon"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e22007","DOI":"10.1016\/j.heliyon.2023.e22007","article-title":"Dendrobium mixture ameliorates hepatic injury induced by insulin resistance in vitro and in vivo through the downregulation of AGE\/RAGE\/Akt signaling pathway","volume":"9","author":"Zhuang","year":"2023","journal-title":"Heliyon"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1536\/ihj.20-315","article-title":"HIF-1\/AKT Signaling-Activated PFKFB2 Alleviates Cardiac Dysfunction and Cardiomyocyte Apoptosis in Response to Hypoxia","volume":"62","author":"Gao","year":"2021","journal-title":"Int. Heart J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Long, H.Z., Cheng, Y., Zhou, Z.W., Luo, H.Y., Wen, D.D., and Gao, L.C. (2021). PI3K\/AKT Signal Pathway: A Target of Natural Products in the Prevention and Treatment of Alzheimer\u2019s Disease and Parkinson\u2019s Disease. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.648636"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"114371","DOI":"10.1016\/j.expneurol.2023.114371","article-title":"Long-term voluntary exercise inhibited AGE\/RAGE and microglial activation and reduced the loss of dendritic spines in the hippocampi of APP\/PS1 transgenic mice","volume":"363","author":"Wang","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/s41586-021-04369-3","article-title":"A human brain vascular atlas reveals diverse mediators of Alzheimer\u2019s risk","volume":"603","author":"Yang","year":"2022","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"155776","DOI":"10.1016\/j.phymed.2024.155776","article-title":"Xiezhuo Tiaozhi formula inhibits macrophage pyroptosis in the non-alcoholic fatty liver disease by targeting the SIRT1 pathway","volume":"131","author":"Tian","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.peptides.2009.12.016","article-title":"Functional characterization of two human receptor activity-modifying protein 3 variants","volume":"31","author":"Bailey","year":"2010","journal-title":"Peptides"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"54","DOI":"10.2174\/138920310790274626","article-title":"Conformations and biological activities of amyloid \u03b2 peptide 25-35","volume":"11","author":"Millucci","year":"2010","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Sanchez-Rodriguez, I., Gruart, A., Delgado-Garcia, J.M., Jimenez-Diaz, L., and Navarro-Lopez, J.D. (2019). Role of GirK Channels in Long-Term Potentiation of Synaptic Inhibition in an In Vivo Mouse Model of Early Amyloid-\u03b2 Pathology. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051168"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5545","DOI":"10.1093\/bioinformatics\/btaa1005","article-title":"DeepPurpose: A deep learning library for drug-target interaction prediction","volume":"36","author":"Huang","year":"2021","journal-title":"Bioinformatics"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T12:59:01Z","timestamp":1774616341000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ph19030502"],"URL":"https:\/\/doi.org\/10.3390\/ph19030502","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,18]]}}}