{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T07:55:51Z","timestamp":1770537351786,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T00:00:00Z","timestamp":1366070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonal antibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeability properties. In this study, we demonstrated that the combination of bevacizumab and plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18 (p-PEDF-SAINT-18) has a favorable antiangiogenic effect on corneal NV. Four groups (Group A: 0 \u03bcg + 0 \u03bcg, B: 0.1 \u03bcg + 0.1 \u03bcg, C: 1 \u03bcg + 1 \u03bcg, and D: 10 \u03bcg + 10 \u03bcg) of bevacizumab + p-PEDF-SAINT-18 were prepared and implanted into the rat subconjunctival substantia propria 1.5 mm from the limbus on the temporal side. Then, 1 \u03bcg of p-bFGF-SAINT-18 was prepared and implanted into the rat corneal stroma 1.5 mm from the limbus on the same side. The inhibition of NV was observed and quantified from days 1 to 60. Biomicroscopic examination, western blot analysis and immunohistochemistry were used to analyze the 18-kDa bFGF, 50-kDa PEDF and VEGF protein expression. No inhibition activity for normal limbal vessels was noted. Subconjunctival injection with the combination of bevacizumab and p-PEDF-SAINT-18 successfully inhibited corneal NV. The bFGF and PEDF genes were successfully expressed as shown by western blot analysis, and a mild immune response to HLA-DR was shown by immunohistochemistry. We concluded that the combination of bevacizumab and p-PEDF-SAINT-18 may have more potent and prolonged antiangiogenic effects, making it possible to reduce the frequency of subconjunctival.Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonalantibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeabilityproperties. In this study, we demonstrated that the combination of bevacizumaband plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18(p-PEDF-SAINT-18) has a favorable antiangiogenic effect on corneal NV. Four groups(Group A: 0 \u03bcg + 0 \u03bcg, B: 0.1 \u03bcg + 0.1 \u03bcg, C: 1 \u03bcg + 1 \u03bcg, and D: 10 \u03bcg + 10 \u03bcg) ofbevacizumab + p-PEDF-SAINT-18 were prepared and implanted into the ratsubconjunctival substantia propria 1.5 mm from the limbus on the temporal side. Then, 1 \u03bcgof p-bFGF-SAINT-18 was prepared and implanted into the rat corneal stroma 1.5 mm fromthe limbus on the same side. The inhibition of NV was observed and quantified from days1 to 60. Biomicroscopic examination, western blot analysis and immunohistochemistry wereused to analyze the 18-kDa bFGF, 50-kDa PEDF and VEGF protein expression. Noinhibition activity for normal limbal vessels was noted. Subconjunctival injection with thecombination of bevacizumab and p-PEDF-SAINT-18 successfully inhibited corneal NV.The bFGF and PEDF genes were successfully expressed as shown by western blot analysis,and a mild immune response to HLA-DR was shown by immunohistochemistry. Weconcluded that the combination of bevacizumab and p-PEDF-SAINT-18 may have morepotent and prolonged antiangiogenic effects, making it possible to reduce the frequency ofsubconjunctival bevacizumab administration combined with a relatively safe profile andlow toxicity.<\/jats:p>","DOI":"10.3390\/ijms14048291","type":"journal-article","created":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T11:36:50Z","timestamp":1366112210000},"page":"8291-8305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Inhibition of Corneal Neovascularization with the Combination of Bevacizumab and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 (p-PEDF-SAINT-18) Vector in a Rat Corneal Experimental Angiogenesis Model"],"prefix":"10.3390","volume":"14","author":[{"given":"Chien-Neng","family":"Kuo","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"},{"name":"Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Township, Taoyuan County 33302, Taiwan"},{"name":"Chang Gung University of Science and Technology, No.2, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"},{"name":"Department of Ophthalmology, Changhua Christian Hospital, Yun Lin Branch, No.375, Shichang S. Rd., Xiluo Township, Yunlin County 64866, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7026-3944","authenticated-orcid":false,"given":"Chung-Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medical and Health Sciences, Fooyin University, No.151, Jinxue Rd., Daliao Dist., Kaohsiung City 83102, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"San-Ni","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Changhua Christian Hospital. No.135, Nanxiao St., Changhua City, Changhua County 50006, Taiwan"},{"name":"School of Medicine, Chung-Shan Medical University, Taichung City 50000, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin-Cheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Gene Therapy Laboratory, E-DA Hospital, I-Shou University, No.1, Sec. 1, Syuecheng Rd., Dashu District, Kaohsiung City 84001, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Ju","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"},{"name":"Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Township, Taoyuan County 33302, Taiwan"},{"name":"Chang Gung University of Science and Technology, No.2, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Hsiung","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"},{"name":"Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Township, Taoyuan County 33302, Taiwan"},{"name":"Chang Gung University of Science and Technology, No.2, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao-Fen","family":"Chen","sequence":"additional","affiliation":[{"name":"Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Township, Taoyuan County 33302, Taiwan"},{"name":"Chang Gung University of Science and Technology, No.2, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"},{"name":"Department of Radiation Oncology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Hui","family":"Hung","sequence":"additional","affiliation":[{"name":"Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Township, Taoyuan County 33302, Taiwan"},{"name":"Chang Gung University of Science and Technology, No.2, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"},{"name":"Department of Dermatology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Hsein","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi City 60004, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2013,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1097\/00003226-198706040-00004","article-title":"Corneal neovascularization pathogenesis and inhibition","volume":"6","author":"Epstein","year":"1987","journal-title":"Cornea"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1177\/10454411950060030501","article-title":"The pathophysiology of angiogenesis","volume":"6","author":"Polverini","year":"1995","journal-title":"Crit. Rev. Oral Biol. Med"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1006\/exer.1998.0512","article-title":"The heparin sulfate suleparoide inhibits rat corneal angiogenesis and in vitro neovascularization","volume":"67","author":"Benelli","year":"1998","journal-title":"Exp. Eye Res"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1073\/pnas.91.9.4082","article-title":"Thalidomide is an inhibitor of angiogenesis","volume":"91","author":"Loughnan","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s002800050885","article-title":"Inhibitory effect of suramin in rat models of angiogenesis in vitro and in vivo","volume":"43","author":"Bocci","year":"1999","journal-title":"Cancer Chemother. Pharmacol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1073\/pnas.90.7.2690","article-title":"Genistein, a dietary\u2014Derived inhibitor of in vitro angiogenesis","volume":"90","author":"Fotsis","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e5467","DOI":"10.1371\/journal.pone.0005467","article-title":"Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis","volume":"4","author":"Taniguchi","year":"2009","journal-title":"PLoS One"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e16712","DOI":"10.1371\/journal.pone.0016712","article-title":"Anti-angiogenic and anti-inflammatory effects of SERPINA3K on corneal injury","volume":"6","author":"Liu","year":"2011","journal-title":"PLoS One"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0002-9394(14)75794-0","article-title":"Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy","volume":"118","author":"Adamis","year":"1994","journal-title":"Am. J. Ophthalmol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1056\/NEJM199412013312203","article-title":"Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders","volume":"331","author":"Aiello","year":"1994","journal-title":"N. Engl. J. Med"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1001\/archopht.1994.01090230090028","article-title":"Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy","volume":"112","author":"Malecaze","year":"1994","journal-title":"Arch. Ophthalmol"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10457","DOI":"10.1073\/pnas.92.23.10457","article-title":"Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins","volume":"92","author":"Aiello","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1001\/archopht.1996.01100130062010","article-title":"Inhibition of vascular endothelial growth factor prevents retinal ischemia associated iris neovascularization in a nonhuman primate","volume":"114","author":"Adamis","year":"1996","journal-title":"Arch. Ophthalmol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1136\/bjo.2006.107912","article-title":"Inhibition of experimental corneal neovascularization by bevacizumab (Avastin)","volume":"91","author":"Manzano","year":"2007","journal-title":"Br. J. Ophthalmol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1056\/NEJMoa032691","article-title":"Bevacizumab plusirinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer","volume":"350","author":"Hurwitz","year":"2004","journal-title":"N. Engl. J. Med"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.ophtha.2005.11.019","article-title":"Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration","volume":"113","author":"Avery","year":"2006","journal-title":"Ophthalmology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/00006982-200603000-00004","article-title":"Intravitreal Bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage","volume":"26","author":"Spaide","year":"2006","journal-title":"Retina"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ajo.2007.11.003","article-title":"Inhibition of corneal neovascularization by subconjunctival bevacizumab in an animal model","volume":"145","author":"Papathanassiou","year":"2008","journal-title":"Am. J. Ophthalmol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1111\/j.1600-0420.2007.01049.x","article-title":"Safety, penetration and efficacy of topically applied bevacizumab: Evaluation of eyedrops in corneal neovascularization after chemical burn","volume":"86","author":"Yoeruek","year":"2008","journal-title":"Acta Ophthalmol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.ophtha.2007.01.017","article-title":"Pharmacokinetics of intravitreal bevacizumab (Avastin)","volume":"114","author":"Bakri","year":"2007","journal-title":"Ophthalmology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S1471-4914(02)02362-6","article-title":"PEDF: Anti-angiogenic guardian of ocular function","volume":"8","author":"Bouck","year":"2002","journal-title":"Trends Mol. Med"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.exer.2005.10.016","article-title":"Focus on molecules: Pigment epithelium-derived factor (PEDF)","volume":"82","author":"Becerra","year":"2006","journal-title":"Exp. Eye Res"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/S1471-4914(03)00074-1","article-title":"Therapeutic prospects for PEDF: More than a promising angiogenesis inhibitor","volume":"9","author":"Barnstable","year":"2003","journal-title":"Trends Mol. Med"},{"key":"ref_24","first-page":"821","article-title":"Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF induced migration and growth","volume":"43","author":"Duh","year":"2002","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0031-6997(24)01359-0","article-title":"Signal transduction and signal modulation by cell adhesion receptors: The role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins","volume":"50","author":"Aplin","year":"1998","journal-title":"Pharmacol. Rev"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1126\/science.1082015","article-title":"Role of Raf in vascular protection from distinct apoptotic stimuli","volume":"301","author":"Alavi","year":"2003","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/425139a","article-title":"Cardiovascular biology: Signalling silenced","volume":"425","author":"Conway","year":"2003","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.mehy.2004.05.016","article-title":"How PEDF prevents angiogenesis: A hypothesized pathway","volume":"64","author":"Ren","year":"2005","journal-title":"Med. Hypotheses"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1242\/jcs.01686","article-title":"Pigment epithelium-derived factor inhibits fibroblast-growth-factor-2-induced capillary morphogenesis of endothelial cells through Fyn","volume":"118","author":"Kanda","year":"2005","journal-title":"J. Cell Sci"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.mvr.2012.02.006","article-title":"PEDF-derived peptide inhibits corneal angiogenesis by suppressing VEGF expression","volume":"84","author":"Matsui","year":"2012","journal-title":"Microvasc Res"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3870","DOI":"10.1167\/iovs.07-1418","article-title":"Vascular endothelial growth factor mediates corneal nerve repair","volume":"49","author":"Yu","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1080\/02713680802382963","article-title":"A novel vector system for gene transfer into the cornea using a partially dried plasmid expressing 18 basic fibroblast growth factor-synthetic amphiphile INTeraction-18 (SAINT-18) complex","volume":"33","author":"Kuo","year":"2008","journal-title":"Curr. Eye Res"},{"key":"ref_33","first-page":"1625","article-title":"A model of angiogenesis in the mouse cornea","volume":"37","author":"Kenyon","year":"1996","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/nrc909","article-title":"VEGF and the quest for tumour angiogenesis factors","volume":"2","author":"Ferrara","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1097\/00055735-200108000-00002","article-title":"Corneal neovascularization","volume":"12","author":"Chang","year":"2001","journal-title":"Curr. Opin. Ophthalmol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e26432","DOI":"10.1371\/journal.pone.0026432","article-title":"Targeted decorin gene therapy delivered with adeno-associated virus effectively retards corneal neovascularization in vivo","volume":"6","author":"Mohan","year":"2011","journal-title":"PLoS One"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.exer.2009.06.021","article-title":"Inhibition of corneal neovascularization with plasmid pigment epithelium-derived factor (p-PEDF) delivered by synthetic amphiphile INTeraction-18 (SAINT-18) vector in an experimental model of rat corneal angiogenesis","volume":"89","author":"Kuo","year":"2009","journal-title":"Exp. Eye Res"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.ajo.2007.03.007","article-title":"Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab","volume":"143","author":"Peters","year":"2007","journal-title":"Am. J. Ophthalmol"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1016\/j.ophtha.2008.02.013","article-title":"The effect of topical bevacizumab on corneal neovascularization","volume":"115","author":"Kim","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s00417-009-1099-1","article-title":"Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization","volume":"247","author":"Koenig","year":"2009","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol"},{"key":"ref_41","first-page":"725","article-title":"Conjunctival and episcleral blood vessels are permeable to blood-borne horseradish peroxidase","volume":"24","author":"Raviola","year":"1983","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.addr.2006.07.025","article-title":"Transscleral drug delivery to the posterior eye: Prospects of pharmacokinetic modeling","volume":"58","author":"Ranta","year":"2006","journal-title":"Adv. Drug Deliv. Rev"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.exer.2005.08.007","article-title":"A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide","volume":"82","author":"Robinson","year":"2006","journal-title":"Exp. Eye Res"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1167\/iovs.07-0593","article-title":"Modeling of corneal and retinal pharmacokinetics after periocular drug administration","volume":"49","author":"Amrite","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1167\/iovs.06-0570","article-title":"Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis","volume":"48","author":"Bock","year":"2007","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/ICO.0b013e31815cf67d","article-title":"Inhibition of experimental corneal neovascularization by using subconjunctival injection of bevacizumab (Avastin)","volume":"27","author":"Kim","year":"2008","journal-title":"Cornea"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/4\/8291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:46:09Z","timestamp":1760219169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/4\/8291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,4,16]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,4]]}},"alternative-id":["ijms14048291"],"URL":"https:\/\/doi.org\/10.3390\/ijms14048291","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,4,16]]}}}