{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T13:26:50Z","timestamp":1781184410729,"version":"3.54.1"},"reference-count":88,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,12,6]],"date-time":"2020-12-06T00:00:00Z","timestamp":1607212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, University and Research (MIUR)","award":["PRIN 2015JXE7E8"],"award-info":[{"award-number":["PRIN 2015JXE7E8"]}]},{"name":"Italian Ministry of Economic Development (MISE) PON-Innovative PhD Program XXXIII","award":["E37H18000340006"],"award-info":[{"award-number":["E37H18000340006"]}]},{"name":"PIACERI 2020\/2022","award":["Linea Intervento 2, University of Catania"],"award-info":[{"award-number":["Linea Intervento 2, University of Catania"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics\/Generalized Born Surface Area (MM\/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2\u2032(3\u2032)-O-(4-Benzoylbenzoyl)adenosine-5\u2032-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG\/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1\u03b2, IL-6, TNF-\u03b1, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG\/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and\/or counteracting the BRB dysfunctions elicited by HG conditions.<\/jats:p>","DOI":"10.3390\/ijms21239305","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T12:24:39Z","timestamp":1607343879000},"page":"9305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Dihydrotanshinone, a Natural Diterpenoid, Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor"],"prefix":"10.3390","volume":"21","author":[{"given":"Claudia Giuseppina","family":"Fresta","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1571-5327","authenticated-orcid":false,"given":"Giuseppe","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"},{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Fidilio","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Bianca Maria","family":"Platania","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2451-1158","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Musso","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9867-6054","authenticated-orcid":false,"given":"Filippo","family":"Caraci","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"},{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Drago","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95125 Catania, Italy"},{"name":"Center for Research in Ocular Pharmacology-CERFO, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bucolo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95125 Catania, Italy"},{"name":"Center for Research in Ocular Pharmacology-CERFO, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/09286580701396720","article-title":"Overview of epidemiologic studies of diabetic retinopathy","volume":"14","author":"Klein","year":"2007","journal-title":"Ophthalmic Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/ceo.12696","article-title":"Diabetic retinopathy: Global prevalence, major risk factors, screening practices and public health challenges: a review","volume":"44","author":"Ting","year":"2016","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_3","first-page":"302","article-title":"Prevalence of diabetic retinopathy, proliferative diabetic retinopathy and non-proliferative diabetic retinopathy in asian t2dm patients: A systematic review and meta-analysis","volume":"12","author":"Yang","year":"2019","journal-title":"Int. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2883","DOI":"10.1172\/JCI118746","article-title":"Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy","volume":"97","author":"Mizutani","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/sj.bjp.0703393","article-title":"Endothelial dysfunction in diabetes","volume":"130","author":"Verbeuren","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e126747","DOI":"10.1172\/jci.insight.126747","article-title":"Blood-retina barrier failure and vision loss in neuron-specific degeneration","volume":"5","author":"Ivanova","year":"2019","journal-title":"JCI. Insight"},{"key":"ref_7","first-page":"362","article-title":"Diabetes and retinal vascular dysfunction","volume":"9","author":"Shin","year":"2014","journal-title":"J. Ophthalmic. Vis. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.5301\/EJO.2010.6049","article-title":"Blood-retinal barrier","volume":"21","author":"Bernardes","year":"2011","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/978-1-60761-938-3_5","article-title":"The blood-retinal barrier: Structure and functional significance","volume":"686","author":"Runkle","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Cholkar, K., Dasari, S.R., Pal, D., and Mitra, A.K. (2013). Eye: Anatomy, physiology and barriers to drug delivery. Ocul. Transp. Recept., 1\u201336.","DOI":"10.1533\/9781908818317.1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/B978-0-323-02598-0.50013-6","article-title":"Cell biology of the retinal pigment epithelium","volume":"1","author":"Thumann","year":"2006","journal-title":"Retina"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00424-016-1877-7","article-title":"Claudins in cancer: Bench to bedside","volume":"469","author":"Osanai","year":"2017","journal-title":"Pflugers Arch."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.yexcr.2017.03.061","article-title":"Interplay between tight junctions & adherens junctions","volume":"358","author":"Campbell","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_14","first-page":"1","article-title":"Importance of integrity of cell-cell junctions for the mechanics of confluent mdck ii cells","volume":"8","author":"Janshoff","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"790902","DOI":"10.1155\/2014\/790902","article-title":"Hyperglycemia induces toll-like receptor-2 and -4 expression and activity in human microvascular retinal endothelial cells: Implications for diabetic retinopathy","volume":"2014","author":"Rajamani","year":"2014","journal-title":"J. Diabetes Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"224","DOI":"10.2337\/db06-0427","article-title":"Inhibition of caspase-1\/interleukin-1\u03b2 signaling prevents degeneration of retinal capillaries in diabetes and galactosemia","volume":"56","author":"Vincent","year":"2007","journal-title":"Diabetes"},{"key":"ref_17","first-page":"1418","article-title":"Tnf-\u03b1 mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations","volume":"15","author":"Joussen","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/S0140-6736(94)92029-X","article-title":"Leucocyte-endothelial interactions and regulation of leucocyte migration","volume":"343","author":"Adams","year":"1994","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10836","DOI":"10.1073\/pnas.96.19.10836","article-title":"Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition","volume":"96","author":"Miyamoto","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s10735-007-9159-5","article-title":"Adhesion molecules (icam-1 and vcam-1) and diabetic retinopathy in type 2 diabetes","volume":"39","author":"Khalfaoui","year":"2008","journal-title":"J. Mol. Histol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1089\/ars.2009.2743","article-title":"Mammalian mitochondrial complex i: Biogenesis, regulation, and reactive oxygen species generation","volume":"12","author":"Koopman","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8562408","DOI":"10.1155\/2019\/8562408","article-title":"Oxidative stress as the main target in diabetic retinopathy pathophysiology","volume":"2019","author":"Cecilia","year":"2019","journal-title":"J. Diabetes Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.visres.2017.05.009","article-title":"The inner blood-retinal barrier: Cellular basis and development","volume":"139","author":"Ramos","year":"2017","journal-title":"Vis. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"212532","DOI":"10.7573\/dic.212532","article-title":"The role of anti-vascular endothelial growth factor (anti-vegf) in the management of proliferative diabetic retinopathy","volume":"7","author":"Zhao","year":"2018","journal-title":"Drugs Context"},{"key":"ref_25","first-page":"469","article-title":"Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis","volume":"39","author":"Shibuya","year":"2006","journal-title":"J. Biochem. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1517\/13543784.2011.578068","article-title":"A potential therapeutic role for p2x7 receptor (p2x7r) antagonists in the treatment of inflammatory diseases","volume":"20","author":"Arulkumaran","year":"2011","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1161\/01.RES.0000012582.11979.8B","article-title":"Inhibition of nitrobenzylthioinosine-sensitive adenosine transport by elevated d-glucose involves activation of p2y2 purinoceptors in human umbilical vein endothelial cells","volume":"90","author":"Parodi","year":"2002","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C1213","DOI":"10.1152\/ajpcell.00265.2011","article-title":"Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal m\u00fcller cell line rmc-1","volume":"301","author":"Trueblood","year":"2011","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sathanoori, R., Sw\u00e4rd, K., Olde, B., and Erlinge, D. (2015). The atp receptors p2x7 and p2x4 modulate high glucose and palmitate-induced inflammatory responses in endothelial cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0133346"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shibata, M., Ishizaki, E., Zhang, T., Fukumoto, M., Barajas-Espinosa, A., Li, T., and Puro, D.G. (2018). Purinergic vasotoxicity: Role of the pore\/oxidant\/katp channel\/ca2+ pathway in p2x7-induced cell death in retinal capillaries. Vision, 2.","DOI":"10.3390\/vision2030025"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"141","DOI":"10.4239\/wjd.v5.i2.141","article-title":"Role of p2x7 receptors in the development of diabetic retinopathy","volume":"5","author":"Sugiyama","year":"2014","journal-title":"World. J. Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.bcp.2019.07.010","article-title":"Blood-retinal barrier protection against high glucose damage: The role of p2x7 receptor","volume":"168","author":"Platania","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Fresta, C.G., Fidilio, A., Caruso, G., Caraci, F., Giblin, F.J., Leggio, G.M., Salomone, S., Drago, F., and Bucolo, C. (2020). A new human blood\u2013retinal barrier model based on endothelial cells, pericytes, and astrocytes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051636"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.cell.2019.09.017","article-title":"Full-length p2x(7) structures reveal how palmitoylation prevents channel desensitization","volume":"179","author":"McCarthy","year":"2019","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113908","DOI":"10.1016\/j.bcp.2020.113908","article-title":"Novel indole derivatives targeting hur-mrna complex to counteract high glucose damage in retinal endothelial cells","volume":"175","author":"Platania","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bcp.2017.05.001","article-title":"P2x7 receptor antagonism: Implications in diabetic retinopathy","volume":"138","author":"Platania","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.pathophys.2017.07.001","article-title":"Diabetic retinopathy: Breaking the barrier","volume":"24","author":"Eshaq","year":"2017","journal-title":"Pathophysiology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.exer.2011.12.003","article-title":"A novel co-culture model of the blood-retinal barrier based on primary retinal endothelial cells, pericytes and astrocytes","volume":"96","author":"Hoeben","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1089\/jop.2019.0017","article-title":"Organ-on-a-chip technologies for advanced blood-retinal barrier models","volume":"36","author":"Ragelle","year":"2020","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Caruso, G., Musso, N., Costantino, A., Lazzarino, G., Tascedda, F., Gulisano, M., Lunte, S.M., and Caraci, F. (2020). Microfluidics as a novel tool for biological and toxicological assays in drug discovery processes: Focus on microchip electrophoresis. Micromachines, 11.","DOI":"10.3390\/mi11060593"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fphar.2017.00123","article-title":"The p2x7 receptor-interleukin-1 liaison","volume":"8","author":"Giuliani","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5594","DOI":"10.1167\/iovs.17-21973","article-title":"Assessment of neurotrophins and inflammatory mediators in vitreous of patients with diabetic retinopathy","volume":"58","author":"Boss","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9402198","DOI":"10.1155\/2017\/9402198","article-title":"Association between aqueous cytokines and diabetic retinopathy stage","volume":"2017","author":"Wu","year":"2017","journal-title":"J. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jphs.2018.11.001","article-title":"Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: A systematic review of real-world studies","volume":"138","author":"Bucolo","year":"2018","journal-title":"J. Pharmacol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"C568","DOI":"10.1152\/ajpcell.00380.2004","article-title":"Regulation of p2x7-induced pore formation and cell death in pericyte-containing retinal microvessels","volume":"288","author":"Sugiyama","year":"2005","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1113\/jphysiol.2003.047977","article-title":"Atp: A vasoactive signal in the pericyte-containing microvasculature of the rat retina","volume":"551","author":"Kawamura","year":"2003","journal-title":"J. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00592-019-01343-4","article-title":"Pharmacological blockade of the p2x7 receptor reverses retinal damage in a rat model of type 1 diabetes","volume":"56","author":"Clapp","year":"2019","journal-title":"Acta Diabetol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.exer.2014.08.009","article-title":"Purines in the eye: Recent evidence for the physiological and pathological role of purines in the rpe, retinal neurons, astrocytes, m\u00fcller cells, lens, trabecular meshwork, cornea and lacrimal gland","volume":"127","author":"Sanderson","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3109\/02713683.2013.836541","article-title":"From mechanosensitivity to inflammatory responses: New players in the pathology of glaucoma","volume":"39","author":"Ryskamp","year":"2014","journal-title":"Curr. Eye Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1002\/glia.22695","article-title":"Mechanosensitive release of adenosine 5\u2019-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: A mechanism for purinergic involvement in chronic strain","volume":"62","author":"Beckel","year":"2014","journal-title":"Glia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"114199","DOI":"10.1016\/j.bcp.2020.114199","article-title":"P2x7 receptor antagonism preserves retinal ganglion cells in glaucomatous mice","volume":"180","author":"Romano","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fphar.2018.00030","article-title":"Recent advances in cns p2x7 physiology and pharmacology: Focus on neuropsychiatric disorders","volume":"9","author":"Bhattacharya","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16478","DOI":"10.1038\/srep16478","article-title":"Dihydrotanshinone-i interferes with the rna-binding activity of hur affecting its post-transcriptional function","volume":"5","author":"Lal","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"19059","DOI":"10.1038\/s41598-019-55723-5","article-title":"Discovery of ganoderma lucidum triterpenoids as potential inhibitors against dengue virus ns2b-ns3 protease","volume":"9","author":"Bharadwaj","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"13587","DOI":"10.1038\/s41598-019-49984-3","article-title":"Fragment-based discovery of the first nonpeptidyl inhibitor of an s46 family peptidase","volume":"9","author":"Sakamoto","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.4155\/fmc-2018-0448","article-title":"Synthesis, in vitro and in silico studies of ho-1 inducers and lung antifibrotic agents","volume":"11","author":"Vanella","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1242\/jcs.175968","article-title":"P2x7 receptor activation regulates rapid unconventional export of transglutaminase-2","volume":"128","author":"Adamczyk","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fphar.2018.00039","article-title":"Non-nucleotide agonists triggering p2x7 receptor activation and pore formation","volume":"9","author":"Giuliani","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1002\/jcp.25510","article-title":"Vip family members prevent outer blood retinal barrier damage in a model of diabetic macular edema","volume":"232","author":"Maugeri","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1001\/archopht.118.10.1364","article-title":"Alterations of the blood-retinal barrier and retinal thickness in preclinical retinopathy in subjects with type 2 diabetes","volume":"118","author":"Lobo","year":"2000","journal-title":"Arch. Ophthalmol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"44785","DOI":"10.1074\/jbc.M406563200","article-title":"Establishment and characterization of cultured epithelial cells lacking expression of zo-1","volume":"279","author":"Umeda","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1091\/mbc.e05-07-0650","article-title":"Zonula occludens-1 function in the assembly of tight junctions in madin-darby canine kidney epithelial cells","volume":"17","author":"McNeil","year":"2006","journal-title":"Mol. Biol. Cell."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.exer.2013.07.018","article-title":"Vegf but not plgf disturbs the barrier of retinal endothelial cells","volume":"115","author":"Deissler","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"29393","DOI":"10.1038\/srep29393","article-title":"Dipeptidyl peptidase-4 inhibitor increases vascular leakage in retina through ve-cadherin phosphorylation","volume":"6","author":"Lee","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"605946","DOI":"10.1155\/2015\/605946","article-title":"Blockade of vascular endothelial growth factor receptor 1 prevents inflammation and vascular leakage in diabetic retinopathy","volume":"2015","author":"He","year":"2015","journal-title":"J. Ophthalmol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.sjopt.2018.05.002","article-title":"Role of oxidative stress, inflammation, hypoxia and angiogenesis in the development of diabetic retinopathy","volume":"32","year":"2018","journal-title":"Saudi J. Ophthalmol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3940241","DOI":"10.1155\/2017\/3940241","article-title":"Ischemic retinopathies: Oxidative stress and inflammation","volume":"2017","author":"Rivera","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_68","first-page":"247861","article-title":"Peroxynitrite mediates diabetes-induced endothelial dysfunction: Possible role of rho kinase activation","volume":"2010","author":"Tawfik","year":"2010","journal-title":"Exp. Diabetes. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/s41433-018-0032-4","article-title":"Diabetic retinopathy and endothelin system: Microangiopathy versus endothelial dysfunction","volume":"32","author":"Sorrentino","year":"2018","journal-title":"Eye (Lond.)"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"10555","DOI":"10.1038\/ncomms10555","article-title":"Neutrophil p2x7 receptors mediate nlrp3 inflammasome-dependent il-1\u03b2 secretion in response to atp","volume":"7","author":"Karmakar","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s11302-018-9631-6","article-title":"Hypoxic expression of nlrp3 and vegf in cultured retinal pigment epithelial cells: Contribution of p2y(2) receptor signaling","volume":"14","author":"Doktor","year":"2018","journal-title":"Purinergic. Signal."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.freeradbiomed.2010.01.006","article-title":"Linking oxidative stress to inflammation: Toll-like receptors","volume":"48","author":"Gill","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.phrs.2019.02.017","article-title":"Dihydrotanshinone exhibits an anti-inflammatory effect in vitro and in vivo through blocking tlr4 dimerization","volume":"142","author":"Yuan","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/bph.12314","article-title":"Pharmacological characterization of a novel centrally permeable p2x7 receptor antagonist: Jnj-47965567","volume":"170","author":"Bhattacharya","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/epi.13783","article-title":"Neuroinflammatory targets and treatments for epilepsy validated in experimental models","volume":"58","author":"Aronica","year":"2017","journal-title":"Epilepsia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e920738","DOI":"10.12659\/MSM.920738","article-title":"Dihydrotanshinone i alleviates spinal cord injury via suppressing inflammatory response, oxidative stress and apoptosis in rats","volume":"26","author":"Yu","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/ijc.32207","article-title":"Highly-expressed p2x7 receptor promotes growth and metastasis of human hos\/mnng osteosarcoma cells via pi3k\/akt\/gsk3\u03b2\/\u03b2-catenin and mtor\/hif1\u03b1\/vegf signaling","volume":"145","author":"Zhang","year":"2019","journal-title":"Int. J. Cancer."},{"key":"ref_78","first-page":"2408","article-title":"Vegf-initiated blood-retinal barrier breakdown in early diabetes","volume":"42","author":"Qaum","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40942-019-0179-6","article-title":"Serum vascular endothelial growth factor is a biomolecular biomarker of severity of diabetic retinopathy","volume":"5","author":"Ahuja","year":"2019","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1167\/iovs.09-4489","article-title":"Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice","volume":"51","author":"Bobbie","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6518","DOI":"10.1167\/iovs.13-11763","article-title":"Effects of high glucose-induced cx43 downregulation on occludin and zo-1 expression and tight junction barrier function in retinal endothelial cells","volume":"54","author":"Tien","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1046\/j.1464-5491.2002.00694.x","article-title":"Intercellular adhesion molecule-1 (icam-1) polymorphism is associated with diabetic retinopathy in type 2 diabetes mellitus","volume":"19","author":"Kamiuchi","year":"2002","journal-title":"Diabet. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"114110","DOI":"10.1016\/j.bcp.2020.114110","article-title":"Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (gitr)","volume":"178","author":"Platania","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1021\/jm030331x","article-title":"Structural interaction fingerprint (sift): A novel method for analyzing three-dimensional protein-ligand binding interactions","volume":"47","author":"Deng","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.bcp.2017.06.130","article-title":"Sulodexide prevents activation of the pla2\/cox-2\/vegf inflammatory pathway in human retinal endothelial cells by blocking the effect of age\/rage","volume":"142","author":"Giurdanella","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Rueden, C.T., Schindelin, J., Hiner, M.C., DeZonia, B.E., Walter, A.E., Arena, E.T., and Eliceiri, K.W. (2017). Imagej2: Imagej for the next generation of scientific image data. BMC Bioinform., 18.","DOI":"10.1186\/s12859-017-1934-z"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Caruso, G., Fresta, C.G., Fidilio, A., O\u2019Donnell, F., Musso, N., Lazzarino, G., Grasso, M., Amorini, A.M., Tascedda, F., and Bucolo, C. (2019). Carnosine decreases pma-induced oxidative stress and inflammation in murine macrophages. Antioxidants, 8.","DOI":"10.3390\/antiox8080281"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3389\/fphar.2019.00693","article-title":"Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by abeta1-42 oligomers in mice: A key role of transforming growth factor-beta1","volume":"10","author":"Torrisi","year":"2019","journal-title":"Front. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:41:39Z","timestamp":1760179299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,6]]},"references-count":88,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21239305"],"URL":"https:\/\/doi.org\/10.3390\/ijms21239305","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,6]]}}}