{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:13:04Z","timestamp":1791000784258,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2019,9,21]],"date-time":"2019-09-21T00:00:00Z","timestamp":1569024000000},"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>Visual impairment and blindness are often caused by retinal ischemia-reperfusion (I\/R) injury. We aimed to characterize a new model of I\/R in pigs, in which the intraocular pathways were not manipulated by invasive methods on the ocular system. After 12 min of ischemia followed by 20 h of reperfusion, reactivity of retinal arterioles was measured in vitro by video microscopy. Dihydroethidium (DHE) staining, qPCR, immunohistochemistry, quantification of neurons in the retinal ganglion cell layer, and histological examination was performed. Retinal arterioles of I\/R-treated pigs displayed marked attenuation in response to the endothelium-dependent vasodilator, bradykinin, compared to sham-treated pigs. DHE staining intensity and messenger RNA levels for HIF-1\u03b1, VEGF-A, NOX2, and iNOS were elevated in retinal arterioles following I\/R. Immunoreactivity to HIF-1\u03b1, VEGF-A, NOX2, and iNOS was enhanced in retinal arteriole endothelium after I\/R. Moreover, I\/R evoked a substantial decrease in Brn3a-positive retinal ganglion cells and noticeable retinal thickening. In conclusion, the results of the present study demonstrate that short-time ocular ischemia impairs endothelial function and integrity of retinal blood vessels and induces structural changes in the retina. HIF-1\u03b1, VEGF-A, iNOS, and NOX2-derived reactive oxygen species appear to be involved in the pathophysiology.<\/jats:p>","DOI":"10.3390\/ijms20194685","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T03:26:32Z","timestamp":1569209192000},"page":"4685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Short-Time Ocular Ischemia Induces Vascular Endothelial Dysfunction and Ganglion Cell Loss in the Pig Retina"],"prefix":"10.3390","volume":"20","author":[{"given":"Jenia Kouchek","family":"Zadeh","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6229-1099","authenticated-orcid":false,"given":"Andreas","family":"Garcia-Bardon","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik Kristoffer","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael","family":"Omran","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Vegetative Physiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Patzak","sequence":"additional","affiliation":[{"name":"Institute of Vegetative Physiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University Medical Center, Johanens Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3458-7391","authenticated-orcid":false,"given":"Huige","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University Medical Center, Johanens Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3506-8465","authenticated-orcid":false,"given":"Adrian","family":"Gericke","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,21]]},"reference":[{"key":"ref_1","first-page":"1374","article-title":"Ischemia-reperfusion injury of the retina is linked to necroptosis via the ERK1\/2-RIP3 pathway","volume":"20","author":"Gao","year":"2014","journal-title":"Mol. Vis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3389\/fncel.2017.00254","article-title":"Optic Nerve Degeneration after Retinal Ischemia\/Reperfusion in a Rodent Model","volume":"11","author":"Renner","year":"2017","journal-title":"Front Cell Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0002-9394(99)00359-1","article-title":"Aggressive systematic treatment for central retinal artery occlusion","volume":"128","author":"Rumelt","year":"1999","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","first-page":"138","article-title":"Ocular ischemic syndrome\u2014A systematic review","volume":"18","author":"Skonieczna","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1007\/s00417-005-0140-2","article-title":"Multicenter study of the European assessment group for lysis in the eye (EAGLE) for the treatment of central retinal artery occlusion: Design issues and implications. EAGLE Study report no. 1: EAGLE Study report no. 1","volume":"244","author":"Feltgen","year":"2006","journal-title":"Graefes. Arch. Clin. Exp. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.ophtha.2010.03.061","article-title":"Central retinal artery occlusion: Local intra-arterial fibrinolysis versus conservative treatment, a multicenter randomized trial","volume":"117","author":"Schumacher","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Xu, Z., Alloush, J., Beck, E., and Weisleder, N. (2014). A murine model of myocardial ischemia-reperfusion injury through ligation of the left anterior descending artery. J. Vis. Exp.","DOI":"10.3791\/51329"},{"key":"ref_8","first-page":"1085","article-title":"A model of retinal ischemia-reperfusion injury in rats by subconjunctival injection of endothelin-1","volume":"231","author":"Masuzawa","year":"2006","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Larpthaveesarp, A., and Gonzalez, F.F. (2017). Transient middle cerebral artery occlusion model of neonatal stroke in P10 Rats. J. Vis. Exp.","DOI":"10.3791\/54830-v"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hartsock, M.J., Cho, H., Wu, L., Chen, W.J., Gong, J., and Duh, E.J. (2016). A mouse model of retinal ischemia-reperfusion injury through elevation of intraocular pressure. J. Vis. Exp.","DOI":"10.3791\/54065"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1167\/iovs.11-8753","article-title":"Acute retinal ischemia inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production","volume":"53","author":"Hein","year":"2012","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"ref_12","first-page":"717","article-title":"Early activation of caspase-1 after retinal ischemia and reperfusion injury in mice","volume":"117","author":"Zheng","year":"2004","journal-title":"Chin. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1442-9071.2007.01533.x","article-title":"Neuroprotective effect of topically applied brimonidine tartrate 0.2% in endothelin-1-induced optic nerve ischaemia model","volume":"35","author":"Aktas","year":"2007","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.exer.2008.06.014","article-title":"Molecular and histological changes following central retinal artery occlusion in a mouse model","volume":"87","author":"Dadon","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9208489","DOI":"10.1155\/2017\/9208489","article-title":"Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger (Edaravone)","volume":"2017","author":"Masuda","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2174\/1389557516666151120114605","article-title":"The role oxidative stress in the pathogenesis of eye diseases: Current status and a dual role of physical activity","volume":"16","author":"Kruk","year":"2015","journal-title":"Mini. Rev. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6","article-title":"Pathophysiology of ischaemia-reperfusion injury","volume":"190","author":"Carden","year":"2000","journal-title":"J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00005-014-0310-1","article-title":"The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis","volume":"63","author":"Kowalczyk","year":"2015","journal-title":"Arch. Immunol. Ther. Exp. (Warsz)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00417-011-1617-9","article-title":"The parameters of the porcine eyeball","volume":"249","author":"Sanchez","year":"2011","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.exer.2005.03.014","article-title":"The pig eye as a novel model of glaucoma","volume":"81","author":"Garcia","year":"2005","journal-title":"Exp. Eye Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1463-5224.2011.00937.x","article-title":"Morphology of retinal vessels in the optic disk in a Gottingen minipig experimental glaucoma model","volume":"15","author":"Galdos","year":"2012","journal-title":"Vet. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/cne.901960204","article-title":"The topography of primate retina: A study of the human, bushbaby, and new- and old-world monkeys","volume":"196","author":"Stone","year":"1981","journal-title":"J. Comp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.jneumeth.2011.11.022","article-title":"Simple model of forebrain ischemia in mouse","volume":"204","author":"Onken","year":"2012","journal-title":"J. Neurosci. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chiang, T., Messing, R.O., and Chou, W.H. (2011). Mouse model of middle cerebral artery occlusion. J. Vis. Exp.","DOI":"10.3791\/2761"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/0304-3940(92)90731-L","article-title":"Retinal ischemia induced by occlusion of both common carotid arteries in rats as demonstrated by electroretinography","volume":"144","author":"Block","year":"1992","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1038\/eye.2016.185","article-title":"Microvascular endothelial function and severity of primary open angle glaucoma","volume":"30","author":"Bukhari","year":"2016","journal-title":"Eye"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1755-3768.2007.01167.x","article-title":"Endothelial dysfunction in glaucoma","volume":"87","author":"Resch","year":"2009","journal-title":"Acta Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5207","DOI":"10.1167\/iovs.14-14301","article-title":"Dynamic responses in retinal vessel caliber with flicker light stimulation in eyes with diabetic retinopathy","volume":"55","author":"Lim","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cheng, L., Yu, H., Yan, N., Lai, K., and Xiang, M. (2017). Hypoxia-inducible factor-1alpha target genes contribute to retinal neuroprotection. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00020"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1002\/glia.21068","article-title":"Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy","volume":"58","author":"Mishra","year":"2010","journal-title":"Glia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/IAE.0000000000001133","article-title":"Towards a treatment for diabetic retinopathy: Intravitreal toxicity and preclinical safety evaluation of inducible nitric oxide synthase inhibitors","volume":"37","author":"Carr","year":"2017","journal-title":"Retina"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1159\/000443098","article-title":"iNOS Induces vascular endothelial cell migration and apoptosis via autophagy in ischemia\/reperfusion injury","volume":"38","author":"Zhu","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7061","DOI":"10.1167\/iovs.13-12883","article-title":"Involvement of Nox2 NADPH oxidase in retinal neovascularization","volume":"54","author":"Chan","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.exer.2019.04.021","article-title":"Responses of retinal arterioles and ciliary arteries in pigs with acute respiratory distress syndrome (ARDS)","volume":"184","author":"Zadeh","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1002\/jcp.22640","article-title":"Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia","volume":"226","author":"Yuan","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Nanduri, J., Vaddi, D.R., Khan, S.A., Wang, N., Makarenko, V., Semenza, G.L., and Prabhakar, N.R. (2015). HIF-1alpha activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119762"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/978-1-4614-3209-8_35","article-title":"Hypoxia-inducible factor (HIF)\/vascular endothelial growth factor (VEGF) signaling in the retina","volume":"801","author":"Kurihara","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_38","first-page":"575","article-title":"Early retinal inflammatory biomarkers in the middle cerebral artery occlusion model of ischemic stroke","volume":"22","author":"Ritzel","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1242\/dev.01646","article-title":"Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis","volume":"132","author":"Pan","year":"2005","journal-title":"Development"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/cne.20516","article-title":"Topography of pig retinal ganglion cells","volume":"486","author":"Garca","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF00346285","article-title":"Distribution of retinal ganglion cells in five mammalian species (pig, sheep, ox, horse, dog)","volume":"150","author":"Hebel","year":"1976","journal-title":"Anat. Embryol. (Berl)"},{"key":"ref_42","first-page":"451","article-title":"Metabolic changes in the retina after experimental microembolism in the miniature pig (author\u2019s transl)","volume":"172","author":"Bardy","year":"1978","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1017\/S0952523800010427","article-title":"Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal Muller cells","volume":"7","author":"Osborne","year":"1991","journal-title":"Vis. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0161-6420(80)35283-4","article-title":"Central retinal artery occlusion and retinal tolerance time","volume":"87","author":"Hayreh","year":"1980","journal-title":"Ophthalmology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S0014-4835(03)00214-8","article-title":"Central retinal artery occlusion. retinal survival time","volume":"78","author":"Hayreh","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1136\/bjo.64.11.818","article-title":"Experimental occlusion of the central artery of the retina. IV: Retinal tolerance time to acute ischaemia","volume":"64","author":"Hayreh","year":"1980","journal-title":"Br. J. Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1124\/pr.57.1.2","article-title":"International union of pharmacology. XLV. Classification of the kinin receptor family: From molecular mechanisms to pathophysiological consequences","volume":"57","author":"Marceau","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1167\/iovs.08-3168","article-title":"Role of calcium-activated potassium channels with small conductance in bradykinin-induced vasodilation of porcine retinal arterioles","volume":"50","author":"Dalsgaard","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_49","first-page":"152","article-title":"Sodium nitroprusside: Twenty years and counting","volume":"81","author":"Friederich","year":"1995","journal-title":"Anesth. Analg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1111\/j.1476-5381.1981.tb16814.x","article-title":"Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations","volume":"73","author":"Coleman","year":"1981","journal-title":"Br. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1167\/iovs.08-3267","article-title":"Brn3a as a marker of retinal ganglion cells: Qualitative and quantitative time course studies in naive and optic nerve-injured retinas","volume":"50","author":"Agudo","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.exer.2011.02.008","article-title":"Axotomy-induced retinal ganglion cell death in adult mice: Quantitative and topographic time course analyses","volume":"92","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4822","DOI":"10.1167\/iovs.09-3600","article-title":"Cholinergic responses of ophthalmic arteries in M3 and M5 muscarinic acetylcholine receptor knockout mice","volume":"50","author":"Gericke","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"20322","DOI":"10.1038\/srep20322","article-title":"The gatekeepers in the mouse ophthalmic artery: Endothelium-dependent mechanisms of cholinergic vasodilation","volume":"6","author":"Manicam","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5222","DOI":"10.1038\/s41598-019-41425-5","article-title":"The M1 muscarinic acetylcholine receptor subtype is important for retinal neuron survival in aging mice","volume":"9","author":"Laspas","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6260","DOI":"10.1038\/s41598-017-06702-1","article-title":"Decelerated neurodegeneration after intravitreal injection of alpha-synuclein antibodies in a glaucoma animal model","volume":"7","author":"Teister","year":"2017","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4685\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:22:45Z","timestamp":1760188965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4685"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,21]]},"references-count":58,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20194685"],"URL":"https:\/\/doi.org\/10.3390\/ijms20194685","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,21]]}}}