{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T17:05:21Z","timestamp":1767978321267,"version":"3.49.0"},"reference-count":57,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,8]],"date-time":"2020-06-08T00:00:00Z","timestamp":1591574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.<\/jats:p>","DOI":"10.3390\/ijms21114095","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T05:16:14Z","timestamp":1591679774000},"page":"4095","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6097-0517","authenticated-orcid":false,"given":"Samiksha","family":"Wasnik","sequence":"first","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolei","family":"Tang","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"},{"name":"Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY 11548, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongzheng","family":"Bi","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"},{"name":"School of Basic Medicine, Zhengzhou University, Zhengzhou 450051, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5204-1152","authenticated-orcid":false,"given":"Amir","family":"Abdipour","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edmundo","family":"E. Carreon","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Sutjiadi","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Lyu","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jintao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"},{"name":"Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Wilson","sequence":"additional","affiliation":[{"name":"The Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Baylink","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.5812\/nephropathol.10449","article-title":"Acute kidney injury: Global health alert","volume":"2","author":"Burdmann","year":"2013","journal-title":"J. Nephropathol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hosohata, K. (2016). Role of Oxidative Stress in Drug-Induced Kidney Injury. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17111826"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s00467-017-3695-3","article-title":"Acute kidney injury: Emerging pharmacotherapies in current clinical trials","volume":"33","author":"Benoit","year":"2018","journal-title":"Pediatr. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nrneph.2015.3","article-title":"Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD","volume":"11","author":"Ferenbach","year":"2015","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1681\/ASN.2015030309","article-title":"Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments","volume":"27","author":"Basile","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.semnephrol.2016.01.006","article-title":"Targeting Inflammation in So-Called Acute Kidney Injury","volume":"36","author":"Mulay","year":"2016","journal-title":"Semin. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.4161\/org.20342","article-title":"Four danger response programs determine glomerular and tubulointerstitial kidney pathology: Clotting, inflammation, epithelial and mesenchymal healing","volume":"8","author":"Anders","year":"2012","journal-title":"Organogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nri3743","article-title":"Regulated cell death and inflammation: An auto-amplification loop causes organ failure","volume":"14","author":"Linkermann","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1517\/17460440902946389","article-title":"Animal models of renal dysfunction: Acute kidney injury","volume":"4","author":"Heyman","year":"2009","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chen, Y., Du, Y., Li, Y., Wang, X., Gao, P., Yang, G., Fang, Y., Meng, Y., and Zhao, X. (2015). Panaxadiol Saponin and Dexamethasone Improve Renal Function in Lipopolysaccharide-Induced Mouse Model of Acute Kidney Injury. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134653"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Li, C.H., Tang, X., Wasnik, S., Wang, X., Zhang, J., Xu, Y., Lau, K.W., Nguyen, H.B., and Baylink, D.J. (2019). Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4529-7"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20287","DOI":"10.1038\/srep20287","article-title":"Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20931","DOI":"10.1038\/srep20931","article-title":"LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3\/angiopoietins\/Tie-2 and HIF-2alpha\/Notch3 pathways","volume":"6","author":"Zeng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Choudhury, S., Bae, S., Ke, Q., Lee, J.Y., Singh, S.S., St-Arnaud, R., Monte, F.D., and Kang, P.M. (2014). Abnormal calcium handling and exaggerated cardiac dysfunction in mice with defective vitamin d signaling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108382"},{"key":"ref_16","first-page":"202","article-title":"Evaluation of insulin-like growth factor-1 influence on PECAM-1 and ICAM-1 adhesion molecules expression on human umbilical endothelial cells surface","volume":"24","author":"Szczepanski","year":"2008","journal-title":"Pol. Merkur. Lek."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1161\/01.CIR.0000144309.87183.FB","article-title":"Insulin-like growth factor-1 as a vascular protective factor","volume":"110","author":"Conti","year":"2004","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1210\/endo.132.1.8419119","article-title":"Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity","volume":"132","author":"Nesbitt","year":"1993","journal-title":"Endocrinology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1074\/jbc.C111.328559","article-title":"Phospholipase Cgamma-2 and intracellular calcium are required for lipopolysaccharide-induced Toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation","volume":"287","author":"Chiang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1084\/jem.20111355","article-title":"TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation","volume":"209","author":"Tauseef","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1189\/jlb.0406248","article-title":"Potent inhibition of store-operated Ca2+ influx and superoxide production in HL60 cells and polymorphonuclear neutrophils by the pyrazole derivative BTP2","volume":"81","author":"Steinckwich","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1007\/s10753-017-0522-8","article-title":"BTP2, a Store-Operated Calcium Channel Inhibitor, Attenuates Lung Ischemia-Reperfusion Injury in Rats","volume":"40","author":"Zhang","year":"2017","journal-title":"Inflammation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12881","DOI":"10.1038\/s41598-017-13343-x","article-title":"Unveiling some FDA-approved drugs as inhibitors of the store-operated Ca(2+) entry pathway","volume":"7","author":"Rahman","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","first-page":"887","article-title":"Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation","volume":"123","author":"Gandhirajan","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1172\/JCI68093","article-title":"Calcium flux and endothelial dysfunction during acute lung injury: A STIMulating target for therapy","volume":"123","author":"Seeley","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1478-811X-7-25","article-title":"Novel inhibitors of the calcineurin\/NFATc hub-alternatives to CsA and FK506?","volume":"7","author":"Sieber","year":"2009","journal-title":"Cell. Commun. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1055\/s-2007-978719","article-title":"Cellular actions of insulin-like growth factor binding proteins","volume":"31","author":"Ferry","year":"1999","journal-title":"Horm. Metab. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1210\/er.2001-0033","article-title":"Cellular actions of the insulin-like growth factor binding proteins","volume":"23","author":"Firth","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaaw2108","DOI":"10.1126\/sciadv.aaw2108","article-title":"Cyclooxygenase 2 augments osteoblastic but suppresses chondrocytic differentiation of CD90(+) skeletal stem cells in fracture sites","volume":"5","author":"Wasnik","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_30","first-page":"60","article-title":"Insulin-like growth factor binding protein (IGFBP)-3-bound IGF-I and IGFBP-3-bound IGF-II in growth hormone deficiency","volume":"52","author":"Belgorosky","year":"1999","journal-title":"Horm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fimmu.2020.00195","article-title":"The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases","volume":"11","author":"Park","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1074\/jbc.M117.812289","article-title":"Toll-like receptor 4-induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca(2+) leakage promote cardiac contractile dysfunction in sepsis","volume":"293","author":"Yang","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-3-319-18440-1_18","article-title":"Lipopolysaccharide-Induced Ionized Hypocalcemia and Acute Kidney Injury in Carotid Chemo\/Baro-Denervated Rats","volume":"860","author":"Fernandez","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kandasamy, K., Bezavada, L., Escue, R.B., and Parthasarathi, K. (2013). Lipopolysaccharide induces endoplasmic store Ca2+-dependent inflammatory responses in lung microvessels. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063465"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1152\/physrev.00020.2014","article-title":"Store-Operated Calcium Channels","volume":"95","author":"Prakriya","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-065X.2009.00810.x","article-title":"Capacitative calcium entry: From concept to molecules","volume":"231","author":"Putney","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1073\/pnas.0712288105","article-title":"Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai\/TRPC model for SOCE\/Icrac channels","volume":"105","author":"Liao","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.molcel.2017.05.028","article-title":"Intracellular Ca(2+) Sensing: Its Role in Calcium Homeostasis and Signaling","volume":"66","author":"Bagur","year":"2017","journal-title":"Mol. Cell."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1161\/circ.116.suppl_16.II_283-a","article-title":"NFkb blockade attenuate cytokines and oxidative stress in the paraventricular nucleus and decreases neurohumoral excitation in spontaneously hypertensive rats","volume":"116","author":"Mariappan","year":"2007","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ramaswami, S., Ghosh, C.C., Juvekar, A.P., Le, H.D., Soe, K., and Vancurova, I. (2009). Role of Acetylation in the NFkB Dependent Transcription of Proinflammatory Cytokines in Stimulated Human Macrophages. FASEB J., 23.","DOI":"10.1096\/fasebj.23.1_supplement.700.5"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"260","DOI":"10.12688\/f1000research.13426.1","article-title":"NFAT control of immune function: New Frontiers for an Abiding Trooper","volume":"7","author":"Vaeth","year":"2018","journal-title":"F1000Research"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4951","DOI":"10.1172\/JCI126108","article-title":"Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury","volume":"129","author":"Mehrotra","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.bcp.2009.04.029","article-title":"Inflammatory cytokines in vascular dysfunction and vascular disease","volume":"78","author":"Sprague","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nm.3893","article-title":"Inflammasomes: Mechanism of action, role in disease, and therapeutics","volume":"21","author":"Guo","year":"2015","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"784","DOI":"10.3892\/ijmm.2014.2054","article-title":"Lipopolysaccharides upregulate calcium concentration in mouse uterine smooth muscle cells through the T-type calcium channels","volume":"35","author":"Zhang","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1582-4934.2011.01395.x","article-title":"Orais and STIMs: Physiological mechanisms and disease","volume":"16","author":"Woodard","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Meng, K., Xu, J., Zhang, C., Zhang, R., Yang, H., Liao, C., and Jiao, J. (2014). Calcium sensing receptor modulates extracellular calcium entry and proliferation via TRPC3\/6 channels in cultured human mesangial cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098777"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"H130","DOI":"10.1152\/ajpheart.00298.2008","article-title":"Chronic treatment with insulin-like growth factor I enhances myocyte contraction by upregulation of Akt-SERCA2a signaling pathway","volume":"295","author":"Kim","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1469-7793.2001.0433a.x","article-title":"Ca(2+) signalling and PKCalpha activate increased endothelial permeability by disassembly of VE-cadherin junctions","volume":"533","author":"Sandoval","year":"2001","journal-title":"J. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-019-2315-y","article-title":"Vascular endothelial cadherin shedding is more severe in sepsis patients with severe acute kidney injury","volume":"23","author":"Yu","year":"2019","journal-title":"Crit. Care"},{"key":"ref_51","first-page":"97","article-title":"Vascular permeability factor\/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis","volume":"237","author":"Dvorak","year":"1999","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"21695","DOI":"10.1074\/jbc.M000805200","article-title":"Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways","volume":"275","author":"Miele","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1186\/cc12540","article-title":"Impact of sepsis-associated cytokine storm on plasma NGAL during acute kidney injury in a model of polymicrobial sepsis","volume":"17","author":"Otto","year":"2013","journal-title":"Crit. Care."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Tanase, D.M., Gosav, E.M., Radu, S., Costea, C.F., Ciocoiu, M., Carauleanu, A., Lacatusu, C.M., Maranduca, M.A., Floria, M., and Rezus, C. (2019). The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205238"},{"key":"ref_55","first-page":"58","article-title":"Acute kidney injury: Current concepts and new insights","volume":"8","author":"Koza","year":"2016","journal-title":"J. Inj. Violence Res."},{"key":"ref_56","unstructured":"Radu, M., and Chernoff, J. (2013). An in vivo assay to test blood vessel permeability. J. Vis. Exp."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1681\/ASN.2007040419","article-title":"HIF activation protects from acute kidney injury","volume":"19","author":"Weidemann","year":"2008","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4095\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:36:49Z","timestamp":1760175409000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4095"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,8]]},"references-count":57,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21114095"],"URL":"https:\/\/doi.org\/10.3390\/ijms21114095","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,8]]}}}