{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T03:25:39Z","timestamp":1788492339210,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:00:00Z","timestamp":1759536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82174238"],"award-info":[{"award-number":["82174238"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["RXRC2022003"],"award-info":[{"award-number":["RXRC2022003"]}]},{"name":"Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["XTCX2023001"],"award-info":[{"award-number":["XTCX2023001"]}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"crossref","award":["2022J01530"],"award-info":[{"award-number":["2022J01530"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading to alveolar\u2013capillary barrier disruption and fatal respiratory failure. Methods: We applied an integrative multi-omics strategy combining single-cell transcriptomics, peripheral blood proteomics, and lung tissue proteomics in a lipopolysaccharide (LPS, 10 mg\/kg)-induced mouse ALI model to identify key signaling pathways. Harpagide, an iridoid glycoside identified from our natural compound screen, was evaluated in vivo (40 and 80 mg\/kg) and in vitro (0.1\u20131 mg\/mL). Histopathology, oxidative stress markers (SOD, GSH, and MDA), cytokine levels (IL-6 and IL-1\u03b2), and signaling proteins (HIF-1\u03b1, p-PI3K, p-AKT, Nrf2, and HO-1) were quantitatively assessed. Direct target engagement was probed using surface plasmon resonance (SPR), the cellular thermal shift assay (CETSA), and 100 ns molecular dynamics (MD) simulations. Results: Multi-omics profiling revealed robust activation of HIF-1, PI3K\/AKT, and glutathione-metabolism pathways following the LPS challenge, with HIF-1\u03b1, VEGFA, and AKT as core regulators. Harpagide treatment significantly reduced lung injury scores by ~45% (p &lt; 0.01), collagen deposition by ~50%, and ROS accumulation by &gt;60% relative to LPS (n = 6). The pro-inflammatory cytokines IL-6 and IL-1\u03b2 were reduced by 55\u201370% at the protein level (p &lt; 0.01). Harpagide dose-dependently suppressed HIF-1\u03b1 and p-AKT expression while enhancing Nrf2 and HO-1 levels (p &lt; 0.05). SPR confirmed direct binding of Harpagide to HIF-1\u03b1 (KD = 8.73 \u00b5M), and the CETSA demonstrated enhanced thermal stability of HIF-1\u03b1. MD simulations revealed a stable binding conformation within the inhibitory\/C-TAD region after 50 ns. Conclusions: This study reveals convergent immune\u2013microenvironmental regulatory mechanisms across cellular and tissue levels in ALI and demonstrates the protective effects of Harpagide through multi-pathway modulation. These findings offer new insights into the pathogenesis of ALI and support the development of \u201cone-drug, multilayer co-regulation\u201d strategies for systemic inflammatory diseases.<\/jats:p>","DOI":"10.3390\/ph18101494","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:10:51Z","timestamp":1759738251000},"page":"1494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Harpagide Confers Protection Against Acute Lung Injury Through Multi-Omics Dissection of Immune\u2013Microenvironmental Crosstalk and Convergent Therapeutic Mechanisms"],"prefix":"10.3390","volume":"18","author":[{"given":"Hong","family":"Wang","sequence":"first","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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jicheng","family":"Yang","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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoqi","family":"Song","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhui","family":"Gao","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Pien Tze Huang Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Zhangzhou 363000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Liu","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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5822-999X","authenticated-orcid":false,"given":"Zhiliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Pien Tze Huang Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Zhangzhou 363000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9625-8476","authenticated-orcid":false,"given":"Xianyu","family":"Li","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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1097\/TA.0000000000004046","article-title":"American association for the surgery of trauma\/american college of surgeons committee on trauma clinical protocol for management of acute respiratory distress syndrome and severe hypoxemia","volume":"95","author":"Fawley","year":"2023","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/cc11144","article-title":"Clinical review: Early treatment of acute lung injury-paradigm shift toward prevention and treatment prior to respiratory failure","volume":"16","author":"Levitt","year":"2012","journal-title":"Crit. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1164\/rccm.202311-2011ST","article-title":"An update on management of adult patients with acute respiratory distress syndrome: An official american thoracic society clinical practice guideline","volume":"209","author":"Qadir","year":"2024","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12967-023-04828-7","article-title":"Translational medicine for acute lung injury","volume":"22","author":"Zhang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41392-025-02178-y","article-title":"Deep insight into cytokine storm: From pathogenesis to treatment","volume":"10","author":"Nie","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12931-024-02678-5","article-title":"Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)","volume":"25","author":"Huang","year":"2024","journal-title":"Respir. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cui, T.X., Brady, A.E., Fulton, C.T., Zhang, Y., Rosenbloom, L.M., Goldsmith, A.M., Moore, B.B., and Popova, A.P. (2020). Ccr2 mediates chronic lps-induced pulmonary inflammation and hypoalveolarization in a murine model of bronchopulmonary dysplasia. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.579628"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41423-023-00974-6","article-title":"The chemokines cxcl8 and cxcl12: Molecular and functional properties, role in disease and efforts towards pharmacological intervention","volume":"20","author":"Cambier","year":"2023","journal-title":"Cell. Mol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12931-025-03137-5","article-title":"Pathophysiological mechanisms of ards: A narrative review from molecular to organ-level perspectives","volume":"26","author":"Zhou","year":"2025","journal-title":"Respir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Saha, S., Buttari, B., Panieri, E., Profumo, E., and Saso, L. (2020). An overview of nrf2 signaling pathway and its role in inflammation. Molecules, 25.","DOI":"10.3390\/molecules25225474"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Romero-Dur\u00e1n, M.A., Silva-Garc\u00eda, O., Perez-Aguilar, J.M., and Baizabal-Aguirre, V.M. (2024). Mechanisms of keap1\/nrf2 modulation in bacterial infections: Implications in persistence and clearance. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1508787"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.2147\/JIR.S467882","article-title":"Targeting the ampk\/nrf2 pathway: A novel therapeutic approach for acute lung injury","volume":"17","author":"Huang","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Reddy, N.M., Potteti, H.R., Vegiraju, S., Chen, H., Tamatam, C.M., and Reddy, S.P. (2015). Pi3k-akt signaling via nrf2 protects against hyperoxia-induced acute lung injury, but promotes inflammation post-injury independent of nrf2 in mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129676"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s43657-024-00170-0","article-title":"Multi-omics quality assessment in personalized medicine through european infrastructure for translational medicine (EATRIS): An overview","volume":"5","author":"Baldazzi","year":"2025","journal-title":"Phenomics"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Brownstein, K.J., Thomas, A.L., Nguyen, H.T., Gang, D.R., and Folk, W.R. (2021). Changes in the Harpagide, harpagoside, and verbascoside content of field grown Scrophularia lanceolata and Scrophularia marilandica in response to season and shade. Metabolites, 11.","DOI":"10.3390\/metabo11070464"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1007\/s11064-013-1133-x","article-title":"Harpagophytum procumbens prevents oxidative stress and loss of cell viability in vitro","volume":"38","author":"Schaffer","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lu, Y., Hao, R., Hu, Y., Wei, Y., Xie, Y., Shen, Y., Rui, Q., and Yu, G. (2021). Harpagide alleviate neuronal apoptosis and blood-brain barrier leakage by inhibiting tlr4\/myd88\/nf-\u03bab signaling pathway in angiotensin ii-induced microglial activation in vitro. Chem. Biol. Interact., 348.","DOI":"10.1016\/j.cbi.2021.109653"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.2174\/092986712800229005","article-title":"Anti-inflammatory iridoids of botanical origin","volume":"19","author":"Viljoen","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Surolia, R., and Antony, V.B. (2022). Pathophysiological role of vimentin intermediate filaments in lung diseases. Front. Cell. Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.872759"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.2337\/db09-1105","article-title":"Downregulation of adipose glutathione s-transferase a4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction","volume":"59","author":"Curtis","year":"2010","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, W., Zeng, Q., Wang, B., Lv, C., He, H., Yang, X., Cheng, B., and Tao, X. (2024). Oxidative stress promotes oral carcinogenesis via thbs1-mediated m1-like tumor-associated macrophages polarization. Redox Biol., 76.","DOI":"10.1016\/j.redox.2024.103335"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.neurobiolaging.2008.08.001","article-title":"Overexpression of metal-responsive transcription factor (mtf-1) in drosophila melanogaster ameliorates life-span reductions associated with oxidative stress and metal toxicity","volume":"31","author":"Bahadorani","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1002\/acn3.305","article-title":"Loss of functional opa 1 unbalances redox state: Implications in dominant optic atrophy pathogenesis","volume":"3","author":"Millet","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12077","DOI":"10.1038\/ncomms12077","article-title":"Neutrophils mediate salmonella typhimurium clearance through the gbp4 inflammasome-dependent production of prostaglandins","volume":"7","author":"Tyrkalska","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1515\/nipt-2022-0020","article-title":"Pura sensitizes cells to toxicity induced by oxidative stress","volume":"2","author":"Albukhaytan","year":"2023","journal-title":"Neuroimmune Pharmacol. Ther."},{"key":"ref_26","first-page":"e926281","article-title":"Peroxiredoxin2 (prdx2) reduces oxidative stress and apoptosis of myocardial cells induced by acute myocardial infarction by inhibiting the tlr4\/nuclear factor kappa b (nf-\u03bab) signaling pathway","volume":"26","author":"Li","year":"2020","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/s41590-020-0736-z","article-title":"Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection","volume":"21","author":"Xie","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7703","DOI":"10.1038\/s41467-022-35492-y","article-title":"Locally organised and activated fth1hi neutrophils aggravate inflammation of acute lung injury in an il-10-dependent manner","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1179\/135100009X12525712409490","article-title":"A role for acute-phase serum amyloid a and high-density lipoprotein in oxidative stress, endothelial dysfunction and atherosclerosis","volume":"14","author":"Hua","year":"2009","journal-title":"Redox Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shin, H.J., Jeong, E.A., Lee, J.Y., An, H.S., Jang, H.M., Ahn, Y.J., Lee, J., Kim, K.E., and Roh, G.S. (2021). Lipocalin-2 deficiency reduces oxidative stress and neuroinflammation and results in attenuation of kainic acid-induced hippocampal cell death. Antioxidants, 10.","DOI":"10.3390\/antiox10010100"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156626","DOI":"10.1016\/j.phymed.2025.156626","article-title":"Naoqing formula alleviates cerebral ischemia\/reperfusion injury induced inflammatory injury by regulating csf3 mediated jak\/stat pathway and macrophage polarization","volume":"140","author":"Ye","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/toxsci\/kfy309","article-title":"Role of macrophages in acute lung injury and chronic fibrosis induced by pulmonary toxicants","volume":"168","author":"Laskin","year":"2019","journal-title":"Toxicol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1159\/000492651","article-title":"Cd38 deficiency protects heart from high fat diet-induced oxidative stress via activating sirt3\/foxo3 pathway","volume":"48","author":"Wang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1161\/CIRCULATIONAHA.116.022668","article-title":"Necrotic cell sensor clec4e promotes a proatherogenic macrophage phenotype through activation of the unfolded protein response","volume":"134","author":"Basatemur","year":"2016","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3892\/mmr.2020.11702","article-title":"S100a8 silencing attenuates inflammation, oxidative stress and apoptosis in bv2 cells induced by oxygen-glucose deprivation and reoxygenation by upregulating gab1 expression","volume":"23","author":"Hu","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2407223","DOI":"10.1155\/2022\/2407223","article-title":"Regulation of transactivation at c-tad domain of hif-1\u03b1 by factor-inhibiting hif-1\u03b1 (fih-1): A potential target for therapeutic intervention in cancer","volume":"2022","author":"Rani","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109289","DOI":"10.1016\/j.clim.2023.109289","article-title":"Targeting immunometabolism against acute lung injury","volume":"249","author":"Ning","year":"2023","journal-title":"Clin. Immunol."},{"key":"ref_38","first-page":"1","article-title":"Biomarkers for patients with trauma associated acute respiratory distress syndrome","volume":"4","author":"Xu","year":"2017","journal-title":"Mil. Med. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.canlet.2009.03.004","article-title":"Pi3k\/akt activity has variable cell-specific effects on expression of hif target genes, ca9 and vegf, in human cancer cell lines","volume":"282","author":"Shafee","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e1447","DOI":"10.1002\/cti2.1447","article-title":"Hypoxia-inducible factor-1\u03b1 regulates the interleukin-6 production by b cells in rheumatoid arthritis","volume":"12","author":"Fan","year":"2023","journal-title":"Clin. Transl. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jneuroim.2006.01.014","article-title":"Evidence that hypoxia-inducible factor-1 (hif-1) mediates transcriptional activation of interleukin-1\u03b2 (il-1\u03b2) in astrocyte cultures","volume":"174","author":"Zhang","year":"2006","journal-title":"J. Neuroimmunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.redox.2018.08.014","article-title":"Identification of a functional antioxidant response element at the hif1a locus","volume":"19","author":"Lacher","year":"2018","journal-title":"Redox Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Toth, R.K., and Warfel, N.A. (2017). Strange bedfellows: Nuclear factor, erythroid 2-like 2 (nrf2) and hypoxia-inducible factor 1 (hif-1) in tumor hypoxia. Antioxidants, 6.","DOI":"10.3390\/antiox6020027"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s12276-024-01180-8","article-title":"Hypoxia, oxidative stress, and the interplay of hifs and nrf2 signaling in cancer","volume":"56","author":"Bae","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_45","first-page":"886","article-title":"Relationships between serum hif-1\u03b1 and vegf levels and clinical prognosis of acute respiratory distress syndrome","volume":"19","year":"2019","journal-title":"Transl. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7682","DOI":"10.12659\/MSM.909909","article-title":"Attenuation of lipopolysaccharide-induced acute lung injury by cyclosporine-A via suppression of mitochondrial DNA","volume":"24","author":"Xiao","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s43657-023-00153-7","article-title":"Reference materials for improving reliability of multiomics profiling","volume":"4","author":"Ren","year":"2024","journal-title":"Phenomics"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kang, Z., Huang, Q., Zhen, N., Xuan, N., Zhou, Q., Zhao, J., Cui, W., Zhang, Z., and Tian, B. (2024). Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1382449"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/10\/1494\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T04:20:12Z","timestamp":1759810812000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/10\/1494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,4]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ph18101494"],"URL":"https:\/\/doi.org\/10.3390\/ph18101494","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,4]]}}}