{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:33:28Z","timestamp":1784043208930,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,19]],"date-time":"2019-05-19T00:00:00Z","timestamp":1558224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>We previously found the instillation of sericin to be useful as therapy for keratopathy with or without diabetes mellitus. In this study, we investigated whether a combination of solid magnesium hydroxide nanoparticles (MHN) enhances epithelial corneal wound healing by sericin using rabbits, normal rats and type 2 diabetes mellitus rats with debrided corneal epithelium (ex vivo and in vivo studies). Ophthalmic formulations containing sericin and MHN (N-Ser) were prepared using a bead mill method. The mean particle size of the N-Ser was 110.3 nm at the time of preparation, and 148.1 nm one month later. The instillation of N-Ser had no effect on the amount of lacrimal fluid in normal rabbits (in vivo), but the MHN in N-Ser was found to expand the intercellular space in ex vivo rat corneas. In addition, the instillation of N-Ser increased the phosphorylation of Extracellular Signal-regulated Kinase (ERK)1\/2, a factor involved in cell adhesion and cell proliferation in the corneal epithelium, in comparison with the instillation of sericin alone. The combination with MHN enhanced epithelial corneal wound healing by sericin in rat debrided corneal epithelium (in vivo). This study provides significant information to prepare potent drugs to cure severe keratopathy, such as diabetic keratopathy.<\/jats:p>","DOI":"10.3390\/nano9050768","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T11:05:07Z","timestamp":1558350307000},"page":"768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Therapeutic Potential of a Combination of Magnesium Hydroxide Nanoparticles and Sericin for Epithelial Corneal Wound Healing"],"prefix":"10.3390","volume":"9","author":[{"given":"Noriaki","family":"Nagai","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshie","family":"Iwai","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Deguchi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Otake","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3690-2332","authenticated-orcid":false,"given":"Kazutaka","family":"Kanai","sequence":"additional","affiliation":[{"name":"Department of Small Animal Internal Medicine, School of Veterinary Medicine, University of Kitasato, Towada, Aomori 034-8628, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Okamoto Eye Clinic, 5-11-12-312 Izumicho, Suita, Osaka 564-0041, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fuchu Hospital, 1-10-17 Hikocho, Izumi, Osaka 594-0076, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,19]]},"reference":[{"key":"ref_1","first-page":"1442","article-title":"The X, Y, Z hypothesis of corneal epithelial maintenance","volume":"24","author":"Thoft","year":"1983","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","first-page":"5","article-title":"Corneal epithelial wound healing","volume":"51","author":"Agrawal","year":"2003","journal-title":"Indian J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1590\/S0004-27492008000700016","article-title":"The corneal epithelium: Clinical relevance of cytokine-mediated responses to maintenance of corneal health","volume":"71","author":"Reinach","year":"1995","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.4252\/wjsc.v6.i4.391","article-title":"Limbal stem cells: Central concepts of corneal epithelial homeostasis","volume":"6","author":"Yoon","year":"2014","journal-title":"World J. Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"643","DOI":"10.3892\/mmr.2016.5314","article-title":"TNF-enhances vascular cell-adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-\u03baB, ERK and JNK signaling pathways","volume":"14","author":"Lu","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9798374","DOI":"10.1155\/2016\/9798374","article-title":"Limbal stem cell deficiency: Current treatment options and emerging therapies","volume":"2016","author":"Haagdorens","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1159\/000343775","article-title":"Comparative study of the effects of recombinant human epidermal growth factor and basic fibroblast growth factor on corneal epithelial wound healing and neovascularzation in vivo and in vitro","volume":"49","author":"Yan","year":"2013","journal-title":"Ophthalmic Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"296","DOI":"10.4252\/wjsc.v6.i3.296","article-title":"Mesenchymal stem cells: Potential role in corneal wound repair and transplantation","volume":"6","author":"Li","year":"2014","journal-title":"World J. Stem Cells"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Mora, C., Mrowiec, A., Garc\u00eda-Vizca\u00edno, E.M., Alcaraz, A., Cenis, J.L., and Nicol\u00e1s, F.J. (2012). Fibroin and sericin from Bombyx mori silk stimulate cell migration through upregulation and phosphorylation of c-Jun. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042271"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1016\/j.biomaterials.2013.01.019","article-title":"The promotion of osseointegration of titanium surfaces by coating with silk protein sericin","volume":"34","author":"Nayak","year":"2013","journal-title":"Biomaterials"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1023\/A:1023993400608","article-title":"Sericin, a protein derived from silkworms, accelerates the proliferation of several mammalian cell lines including a hybridoma","volume":"40","author":"Terada","year":"2002","journal-title":"Cytotechnology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1263\/jbb.100.667","article-title":"Preparation of silk protein sericin as mitogenic factor for better mammalian cell culture","volume":"100","author":"Terada","year":"2005","journal-title":"J. Biosci. Bioeng."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1007\/s00253-015-6576-3","article-title":"Viability and proliferation of L929, tumour and hybridoma cells in the culture media containing sericin protein as a supplement or serum substitute","volume":"99","author":"Cao","year":"2015","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.repbio.2015.11.001","article-title":"In vitro culture medium (IVC) supplementation with sericin improves developmental competence of ovine zygotes","volume":"16","author":"Aghaz","year":"2016","journal-title":"Reprod. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.progpolymsci.2007.05.013","article-title":"Silk as a biomaterial","volume":"32","author":"Vapory","year":"2007","journal-title":"Prog. Polym. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1089\/bio.2013.0078","article-title":"Evaluation of Sericin as a Fetal Bovine Serum-Replacing Cryoprotectant during Freezing of Human Mesenchymal Stromal Cells and Human Osteoblast-Like Cells","volume":"12","author":"Verdanova","year":"2014","journal-title":"Biopreserv. Biobank."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1271\/bbb.69.403","article-title":"Sericin enhances attachment of cultured human skin fibroblasts","volume":"69","author":"Tsubouchi","year":"2005","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1007\/s10529-005-7177-5","article-title":"A sericin-derived peptide protects sf9 insect cells from death caused by acute serum deprivation","volume":"27","author":"Takahashi","year":"2005","journal-title":"Biotechnol. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nagai, N., Fukuoka, Y., Ishii, M., Otake, H., Yamamoto, T., Taga, A., Okamoto, N., and Shimomura, Y. (2018). Instillation of Sericin Enhances Corneal Wound Healing through the ERK Pathway in Rat Debrided Corneal Epithelium. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041123"},{"key":"ref_20","unstructured":"Goto, H., Yamada, M., Yoshikawa, K., and Iino, M. (2006). Presented at the Ganka-Kaigyoui Notameno Gimon Nanmon Kaiketusaku, Shindan to Chiryosha Co."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.exer.2017.10.002","article-title":"Co-instillation of nano-solid magnesium hydroxide enhances corneal permeability of dissolved timolol","volume":"165","author":"Nagai","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nagai, N., Yamaoka, S., Fukuoka, Y., Ishii, M., Otake, H., Kanai, K., Okamoto, N., and Shimomura, Y. (2018). Enhancement in Corneal Permeability of Dissolved Carteolol by its Combination with Magnesium Hydroxide Nanoparticles. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010282"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"177","DOI":"10.5650\/jos.ess13082","article-title":"Improved corneal toxicity and permeability of tranilast by the preparation of ophthalmic formulations containing its nanoparticles","volume":"63","author":"Nagai","year":"2014","journal-title":"J. Oleo Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29329","DOI":"10.3390\/ijms161226166","article-title":"Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia\/Reperfusion-Induced Injury Model","volume":"16","author":"Nagai","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1248\/bpb.32.933","article-title":"Enhancing effect of sericin on corneal wound healing in rat debrided corneal epithelium","volume":"32","author":"Nagai","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1248\/bpb.32.1594","article-title":"Enhancing effects of sericin on corneal wound healing in Otsuka long-evans Tokushima Fatty rats as a model of human type 2 diabetes","volume":"32","author":"Nagai","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.5966\/sctm.2015-0039","article-title":"A comparative study of the therapeutic potential of mesenchymal stem cells and limbal epithelial stem cells for ocular surface reconstruction","volume":"4","author":"Holan","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.preteyeres.2015.07.002","article-title":"Progress in corneal wound healing","volume":"49","author":"Ljubimov","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S75","DOI":"10.1097\/ICO.0b013e31812f6d8e","article-title":"Deviated mechanism of wound healing in diabetic corneas","volume":"26","author":"Chikama","year":"2007","journal-title":"Cornea"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ajo.2006.05.002","article-title":"Is autologous serum a tonic for the ailing corneal epithelium?","volume":"142","author":"Pflugfelder","year":"2006","journal-title":"Am. J. Ophthalmol."},{"key":"ref_31","first-page":"180","article-title":"Diabetic keratopathy","volume":"79","author":"Schultz","year":"1981","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_32","first-page":"358","article-title":"Ocular surface changes in type II diabetic patients with proliferative diabetic retinopathy","volume":"8","author":"Gao","year":"2015","journal-title":"Int. J. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1442-9071.2010.02435.x","article-title":"New therapeutic approaches in the treatment of diabetic keratopathy: A review","volume":"39","author":"Abdelkader","year":"2011","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/0026-0495(95)90249-X","article-title":"Which is the primary etiologic event in Otsuka Long-Evans Tokushima Fatty rats, a model of spontaneous non-insulin-dependent diabetes mellitus, insulin resistance, or impaired insulin secretion?","volume":"44","author":"Ishida","year":"1995","journal-title":"Metabolism"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1007\/BF00402172","article-title":"Insulin resistance in skeletal muscle of the male Otsuka Long-Evans Tokushima Fatty rat, a new model of NIDDM","volume":"38","author":"Sato","year":"1995","journal-title":"Diabetologia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1067\/mlc.2001.116843","article-title":"Inhibition of neuronal nitric oxide synthase ameliorates renal hyperfiltration in streptozotocin-induced diabetic rat","volume":"138","author":"Ito","year":"2001","journal-title":"J. Lab. Clin. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1538\/expanim.55.17","article-title":"Neuronal nitric oxide synthase and cyclooxygenase-2 in diabetic nephropathy of type 2 diabetic OLETF rats","volume":"55","author":"Yabuki","year":"2006","journal-title":"Exp. Anim."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"441","DOI":"10.5650\/jos.59.441","article-title":"Kinetic Analysis of the Rate of Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rats, a Model of Type 2 Diabetes Mellitus","volume":"59","author":"Nagai","year":"2010","journal-title":"J. Oleo Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/15216540050022386","article-title":"Cells on the move: A dialogue between polarization and motility","volume":"49","author":"Manes","year":"2000","journal-title":"IUBMB. Life"},{"key":"ref_40","unstructured":"Albert, D.M., and Jakobiec, F.A. (1994). Agents That Affect Corneal Wound Healing: Modulation of Structure and Function, Saunders Press."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0006-8993(00)02864-X","article-title":"Cellular dynamics of corneal wound re-epithelialization in the rat. III. Mitotic activity","volume":"882","author":"Zagon","year":"2000","journal-title":"Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3892\/mmr.2014.2154","article-title":"Ocular albinism type 1-induced melanoma cell migration is mediated through the RAS\/RAF\/MEK\/ERK signaling pathway","volume":"10","author":"Bai","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Galan, A., Dergham, P., Escoll, P., de-la-Hera, A., D\u2019Onofrio, P.M., Magharious, M.M., Koeberle, P.D., Frade, J.M., and Saragovi, H.U. (2014). Neuronal injury external to the retina rapidly activates retinal glia, followed by elevation of markers for cell cycle re-entry and death in retinal ganglion cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101349"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s10571-015-0198-2","article-title":"Upregulation of homer1a promoted retinal ganglion cell survival after retinal ischemia and reperfusion via interacting with Erk pathway","volume":"35","author":"Fei","year":"2015","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/bs.pmbts.2015.05.002","article-title":"Corneal epithelial wound healing","volume":"134","author":"Liu","year":"2015","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1385\/IR:21:2-3:83","article-title":"Molecular signaling mechanisms of cell migration and invasion","volume":"21","author":"Stupack","year":"2000","journal-title":"Immunol. Res."},{"key":"ref_47","first-page":"153","article-title":"Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions","volume":"22","author":"Pearson","year":"2001","journal-title":"Endocr. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nature01745","article-title":"JNK phosphorylates paxillin and regulates cell migration","volume":"424","author":"Huang","year":"2003","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15090","DOI":"10.1074\/jbc.M606094200","article-title":"Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1\/2, p38, and phosphatidylinositol 3-kinase signaling pathways","volume":"282","author":"Fitsialos","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Gouveia, R.M., Vajda, F., Wibowo, J.A., Figueiredo, F., and Connon, C.J. (2019). YAP, \u0394Np63, and \u03b2-Catenin Signaling Pathways Are Involved in the Modulation of Corneal Epithelial Stem Cell Phenotype Induced by Substrate Stiffness. Cells, 8.","DOI":"10.3390\/cells8040347"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/s41467-019-09331-6","article-title":"Assessment of corneal substrate biomechanics and its effect on epithelial stem cell maintenance and differentiation","volume":"10","author":"Gouveia","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/9\/5\/768\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:53:28Z","timestamp":1760187208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/9\/5\/768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,19]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["nano9050768"],"URL":"https:\/\/doi.org\/10.3390\/nano9050768","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,19]]}}}