{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T18:27:19Z","timestamp":1778956039021,"version":"3.51.4"},"reference-count":75,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T00:00:00Z","timestamp":1542672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CHE-1411993"],"award-info":[{"award-number":["CHE-1411993"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM103638"],"award-info":[{"award-number":["P20GM103638"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["NFP0075515"],"award-info":[{"award-number":["NFP0075515"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Neuropsychopharmacology Research Program 2017","award":["RC-06-05"],"award-info":[{"award-number":["RC-06-05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human amylin is a 37-residue peptide hormone (hA1-37) secreted by \u03b2-cells of the pancreas and, along with insulin, is directly associated with type 2 diabetes mellitus (T2DM). Amyloid deposits within the islets of the pancreas represent a hallmark of T2DM. Additionally, amylin aggregates have been found in blood vessels and\/or brain of patients with Alzheimer\u2019s disease, alone or co-deposited with \u03b2-amyloid. The purpose of this study was to investigate the neuroprotective potential of human amylin in the context of endothelial-neuronal \u201ccross-talk\u201d. We initially performed dose-response experiments to examine cellular toxicity (quantified by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] MTT assay) of different hA17\u201329 concentrations in endothelial cells (RBE4). In the culture medium of these cells, we also measured heat shock protein B5 (HspB5) levels by ELISA, finding that even a sub-toxic concentration of hA17\u201329 (3 \u00b5M) produced an increase of HspB5. Using a cell medium of untreated and RBE4 challenged for 48 h with a sub-toxic concentration of hA17\u201329, we determined the potential beneficial effect of their addition to the medium of neuroblastoma SH-SY5Y cells. These cells were subsequently incubated for 48 h with a toxic concentration of hA17\u201329 (20 \u00b5M). We found a complete inhibition of hA17\u201329 toxicity, potentially related to the presence in the conditioned medium not only of HspB5, but also of vascular endothelial growth factor (VEGF). Pre-treating SH-SY5Y cells with the anti-Flk1 antibody, blocking the VEGF receptor 2 (VEGFR2), significantly decreased the protective effects of the conditioned RBE4 medium. These data, obtained by indirectly measuring VEGF activity, were strongly corroborated by the direct measurement of VEGF levels in conditioned RBE4 media as detected by ELISA. Altogether, these findings highlighted a novel role of sub-toxic concentrations of human amylin in promoting the secretion of proteic factors by endothelial cells (HspB5 and VEGF) that support the survival and proliferation of neuron-like cells.<\/jats:p>","DOI":"10.3390\/ijms19113659","type":"journal-article","created":{"date-parts":[[2018,11,21]],"date-time":"2018-11-21T11:23:27Z","timestamp":1542799407000},"page":"3659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Sub-Toxic Human Amylin Fragment Concentrations Promote the Survival and Proliferation of SH-SY5Y Cells via the Release of VEGF and HspB5 from Endothelial RBE4 Cells"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1571-5327","authenticated-orcid":false,"given":"Giuseppe","family":"Caruso","sequence":"first","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia G.","family":"Fresta","sequence":"additional","affiliation":[{"name":"Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66045, USA"},{"name":"Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Lazzarino","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Clinical Biochemistry, Catholic University of the Sacred Heart, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donatella A.","family":"Distefano","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Parlascino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan M.","family":"Lunte","sequence":"additional","affiliation":[{"name":"Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66045, USA"},{"name":"Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA"},{"name":"Department of Chemistry, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-7279","authenticated-orcid":false,"given":"Giuseppe","family":"Lazzarino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Caraci","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, 94018 Troina, Italy"},{"name":"Department of Drug Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1007\/s001250051079","article-title":"Transgenic overexpression of human islet amyloid polypeptide inhibits insulin secretion and glucose elimination after gastric glucose gavage in mice","volume":"41","author":"Ahren","year":"1998","journal-title":"Diabetologia"},{"key":"ref_2","first-page":"101S","article-title":"The physiology of amylin and insulin","volume":"32","author":"Martin","year":"2006","journal-title":"Diabetes Educ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17243","DOI":"10.1016\/S0021-9258(19)77825-9","article-title":"An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing","volume":"263","author":"Sanke","year":"1988","journal-title":"J. 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