{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:32:56Z","timestamp":1784687576257,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T00:00:00Z","timestamp":1612569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Dry eye disease (DED) is a multifactorial condition caused by tear deficiency and accompanied by ocular surface damage. Recent data support a key role of oxidative and inflammatory processes in the pathogenesis of DED. Hyaluronic acid (HA) is widely used in artificial tears to treat DED by improving ocular hydration and reducing surface friction. Crocin (Cr), the main constituent of saffron, is a renowned compound that exhibits potent antioxidant and anti-inflammatory effects. The present study was undertaken to assess the viscosity and muco-adhesiveness of a photoactivated formulation with crosslinked HA (cHA), Cr, and liposomes (cHA-Cr-L). Our aim was also to evaluate whether cHA-Cr-L may exert cytoprotective effects against oxidative and inflammatory processes in human corneal epithelial cells (HCECs). Viscosity was measured using a rotational rheometer, and then the muco-adhesiveness was evaluated. Under hyperosmolarity (450 mOsm), the HCECs were treated with cHA-Cr-L. Interleukin-1\u03b2 (IL-1\u03b2) and tumor necrosis factor \u03b1 (TNF\u03b1) were quantified by quantitative real-time polymerase chain reaction (RT-qPCR). The levels of reactive oxygen species (ROS) were measured using the DCF assay. The combined action of cHA-Cr-L produced a higher viscosity and muco-adhesiveness compared to the control. The anti-inflammatory effect of cHA-Cr-L was achieved through a significant reduction of IL-1\u03b2 and TNF\u03b1 (p &lt; 0.001). The results also showed that cHA-Cr-L reduces ROS production under conditions of hyperosmolarity (p &lt; 0.001). We conclude that cHA-Cr-L has potential as a therapeutic agent in DED, which should be further investigated.<\/jats:p>","DOI":"10.3390\/molecules26040849","type":"journal-article","created":{"date-parts":[[2021,2,7]],"date-time":"2021-02-07T14:07:19Z","timestamp":1612706839000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Crosslinked Hyaluronic Acid with Liposomes and Crocin Confers Cytoprotection in an Experimental Model of Dry Eye"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3887-0303","authenticated-orcid":false,"given":"Sawan","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-7199","authenticated-orcid":false,"given":"Sergio","family":"Davinelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Mencucci","sequence":"additional","affiliation":[{"name":"Eye Clinic, Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Fusi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0744-0722","authenticated-orcid":false,"given":"Gianluca","family":"Scuderi","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, NESMOS Department, St. Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8477-6188","authenticated-orcid":false,"given":"Ciro","family":"Costagliola","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-5586","authenticated-orcid":false,"given":"Giovanni","family":"Scapagnini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e412","DOI":"10.1111\/aos.13526","article-title":"Dry eye disease and oxidative stress","volume":"96","author":"Seen","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_3","first-page":"240","article-title":"Dry eye: An inflammatory ocular disease","volume":"9","author":"Hessen","year":"2014","journal-title":"J. Ophthalmic. Vis. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.exer.2003.09.003","article-title":"The role of the lacrimal functional unit in the pathophysiology of dry eye","volume":"78","author":"Stern","year":"2004","journal-title":"Exp. Eye Res"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1590\/S0004-27492008000700017","article-title":"Rationale for anti-inflammatory therapy in dry eye syndrome","volume":"71","author":"Pflugfelder","year":"2008","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"Des163","DOI":"10.1167\/iovs.17-23402","article-title":"Potential Role of Oxidative Stress in Ocular Surface Inflammation and Dry Eye Disease","volume":"59","author":"Dogru","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jtos.2017.05.006","article-title":"TFOS DEWS II Management and Therapy Report","volume":"15","author":"Jones","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1517\/17425247.2013.796360","article-title":"Applications of poloxamers in ophthalmic pharmaceutical formulations: An overview","volume":"10","author":"Almeida","year":"2013","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1046\/j.1440-1681.2000.03288.x","article-title":"Biopharmaceutical considerations in topical ocular drug delivery","volume":"27","author":"Davies","year":"2000","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gra\u00e7a, A., Gon\u00e7alves, L.M., Raposo, S., Ribeiro, H.M., and Marto, J. (2018). Useful In Vitro Techniques to Evaluate the Mucoadhesive Properties of Hyaluronic Acid-Based Ocular Delivery Systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10030110"},{"key":"ref_11","first-page":"3409","article-title":"Cytoprotective effects of hyaluronic acid and Carbomer 934P in ocular surface epithelial cells","volume":"43","author":"Debbasch","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_12","first-page":"78","article-title":"Hyaluronic Acid in Inflammation and Tissue Regeneration","volume":"28","author":"Litwiniuk","year":"2016","journal-title":"Wounds"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1167\/tvst.8.6.2","article-title":"Physicochemical Properties of Hyaluronic Acid-Based Lubricant Eye Drops","volume":"8","author":"Aragona","year":"2019","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fallacara, A., Vertuani, S., Panozzo, G., Pecorelli, A., Valacchi, G., and Manfredini, S. (2017). Novel Artificial Tears Containing Cross-Linked Hyaluronic Acid: An In Vitro Re-Epithelialization Study. Molecules, 22.","DOI":"10.3390\/molecules22122104"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1089\/jop.2017.0052","article-title":"Relevance of Lipid-Based Products in the Management of Dry Eye Disease","volume":"33","author":"Garrigue","year":"2017","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.clae.2009.12.007","article-title":"Effect of a liposomal spray on the pre-ocular tear film","volume":"33","author":"Craig","year":"2010","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Vickackaite, V., Romani, A., Pannacci, D., and Favaro, G. (2004). Photochemical and thermal degradation of a naturally occurring dye used in artistic painting. A chromatographic, spectrophotometric and fluorimetric study on saffron. Int. J. Photoenergy, 6.","DOI":"10.1155\/S1110662X04000224"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.biopha.2017.12.090","article-title":"A comprehensive review of the pharmacological potential of Crocus sativus and its bioactive apocarotenoids","volume":"98","author":"Bukhari","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1007\/s13197-013-1238-x","article-title":"Evaluation of antioxidant activities of bioactive compounds and various extracts obtained from saffron (Crocus sativus L.): A review","volume":"52","author":"Rahaiee","year":"2015","journal-title":"J. Food Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1097\/OPX.0b013e3181824de3","article-title":"Precorneal residence time of artificial tears measured in dry eye subjects","volume":"85","author":"Paugh","year":"2008","journal-title":"Optom Vis Sci"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"M\u00fcller-Lierheim, W.G.K. (2020). Why Chain Length of Hyaluronan in Eye Drops Matters. Diagnostics, 10.","DOI":"10.3390\/diagnostics10080511"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.addr.2005.07.005","article-title":"The use of mucoadhesive polymers in ocular drug delivery","volume":"57","author":"Ludwig","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Thacker, M., Tseng, C.L., Chang, C.Y., Jakfar, S., Chen, H.Y., and Lin, F.H. (2020). Mucoadhesive Bletilla striata Polysaccharide-Based Artificial Tears to Relieve Symptoms and Inflammation in Rabbit with Dry Eyes Syndrome. Polymers, 12.","DOI":"10.3390\/polym12071465"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.jtos.2013.07.003","article-title":"Role of hyperosmolarity in the pathogenesis and management of dry eye disease: Proceedings of the OCEAN group meeting","volume":"11","author":"Baudouin","year":"2013","journal-title":"Ocul. Surf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.ophtha.2017.07.010","article-title":"The Pathophysiology of Dry Eye Disease: What We Know and Future Directions for Research","volume":"124","author":"Pflugfelder","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Heitmar, R., Brown, J., and Kyrou, I. (2019). Saffron (Crocus sativus L.) in Ocular Diseases: A Narrative Review of the Existing Evidence from Clinical Studies. Nutrients, 11.","DOI":"10.3390\/nu11030649"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kojima, T., Nagata, T., Kudo, H., M\u00fcller-Lierheim, W.G.K., van Setten, G.-B., Dogru, M., and Tsubota, K. (2020). The Effects of High Molecular Weight Hyaluronic Acid Eye Drop Application in Environmental Dry Eye Stress Model Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103516"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s12031-017-0899-8","article-title":"Crocin Inhibits Oxidative Stress and Pro-inflammatory Response of Microglial Cells Associated with Diabetic Retinopathy Through the Activation of PI3K\/Akt Signaling Pathway","volume":"61","author":"Yang","year":"2017","journal-title":"J. Mol. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/S1542-0124(12)70185-4","article-title":"Antioxidant defenses in the ocular surface","volume":"7","author":"Chen","year":"2009","journal-title":"Ocul. Surf."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3109\/10715762.2011.645206","article-title":"Oxidative stress, as measured by protein oxidation, is increased in primary Sj\u00f8gren\u2019s syndrome","volume":"46","author":"Norheim","year":"2012","journal-title":"Free Radic. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1097\/ICO.0b013e31826a5de1","article-title":"A new mouse model of dry eye disease: Oxidative stress affects functional decline in the lacrimal gland","volume":"31","author":"Uchino","year":"2012","journal-title":"Cornea"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1167\/iovs.12-10325","article-title":"Evaluation of lipid oxidative stress status in Sj\u00f6gren syndrome patients","volume":"54","author":"Wakamatsu","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S1119","DOI":"10.1016\/j.arabjc.2013.02.004","article-title":"Evaluation of antioxidant activity of crocin, podophyllotoxin and kaempferol by chemical, biochemical and electrochemical assays","volume":"10","author":"Dar","year":"2017","journal-title":"Arab. J. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.neulet.2004.02.067","article-title":"Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of alpha-tocopherol","volume":"362","author":"Ochiai","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.carbpol.2016.07.106","article-title":"Optimization of hyaluronan-based eye drop formulations","volume":"153","author":"Salzillo","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.exer.2004.02.015","article-title":"Phenotypic characterization of human corneal epithelial cells expanded ex vivo from limbal explant and single cell cultures","volume":"79","author":"Kim","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Deng, R., Hua, X., Li, J., Chi, W., Zhang, Z., Lu, F., Zhang, L., Pflugfelder, S.C., and Li, D.Q. (2015). Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126561"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/849\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:20:20Z","timestamp":1760160020000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/849"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,6]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26040849"],"URL":"https:\/\/doi.org\/10.3390\/molecules26040849","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,6]]}}}