{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:38:40Z","timestamp":1790206720984,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T00:00:00Z","timestamp":1772841600000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100017847","name":"Medline Industries","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017847","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006379","name":"Office of Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Wound Repair Regeneration"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A novel folinic acid (FA) wound treatment (FAWT) significantly (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) improved healing (re\u2010epithelialization) of chronic diabetic foot ulcers (DFUs). In a double\u2010blind RCT, 10 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910) chronic DFU subjects received daily topical treatment in either the Control group [(\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095); PluroGel] or the FAWT group [(\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095); PluroGel with FA 2.5%]. After 12\u2009weeks, FAWT subjects experienced significantly (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) greater %\u2010DFU area reduction (88% [SD: 16]) vs. Control (40% [SD: 39]), respectively. Proteomic analysis of keratinocytes (KCs) pre\u2010 and post\u2010FAWT, using Reverse Phase Proteomic Array (RPPA), documented significantly decreased levels of HMGB1 (High Mobility Group Box1) protein and activated IL\u20101B protein at 12\u2009weeks after FAWT as compared to Control. RPPA also documented significantly decreased activating phosphorylation of SAP\/JNK3 (T183\/Y185) and p38 MAPK (T180\/Y182) levels after FAWT as compared to Control. These findings suggested decreased activation and possible reduction of NFKB\/p65 and p38 MAPK following FAWT that could decrease proinflammatory gene expression. Genomic DNA\u2010methylation analysis of KCs identified significantly decreased FAWT\u2010induced methylation at gene expression regulatory sites for multiple microRNAs (MiRNA) associated with regulating proinflammatory responses. FAWT\u2010induced decreased methylation levels in MiRNAs suggested increased expression and their potential to inhibit protein translation. These MiRNAs are predicted to target multiple mitogen\u2010activated protein kinase (MAPK) pathways. These MAPK pathways mediate signalling from proinflammatory cell surface receptors (such as RAGE, TLRs and IL1R), altering gene expression. FAWT\u2010induced inhibition of MAPK\u2010signalling may lessen NFKB\/p65 and p38 MAPK induction of proinflammatory gene expression, reflected in the significantly decreased protein levels of HMGB1 and IL\u20101B. The data suggest FAWT\u2010induced coordinated expression of multiple anti\u2010inflammatory MiRNAs associated with impaired MAPK\u2010signalling that resulted in decreased expression of HMGB1 and IL1B and this process may facilitate DFUs' transition from an inflammatory state to wound repair, enabling KCs to regulate their proliferative phase, migration and the promotion of DFU re\u2010epithelialization.\n                  <\/jats:p>","DOI":"10.1111\/wrr.70141","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:02:14Z","timestamp":1772967734000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Folinic Acid Improves Healing of Diabetic Foot Ulcers"],"prefix":"10.1111","volume":"34","author":[{"given":"Glenn D.","family":"Hoke","sequence":"first","affiliation":[{"name":"Departments of Surgery\/Plastic Surgery, Richmond Department of Veterans Affairs Medical Center  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8012-748X","authenticated-orcid":false,"given":"Annjanette","family":"Stone","sequence":"additional","affiliation":[{"name":"Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-7295","authenticated-orcid":false,"given":"Michael A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics University of Arkansas for Medical Sciences  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4808-9660","authenticated-orcid":false,"given":"Weleetka C.","family":"Carter","sequence":"additional","affiliation":[{"name":"Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan R.","family":"Newsom","sequence":"additional","affiliation":[{"name":"Departments of Surgery\/Plastic Surgery, Richmond Department of Veterans Affairs Medical Center  Richmond Virginia USA"},{"name":"Department of Surgery\/Plastic Surgery Virginia Commonwealth University Health System  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-7001","authenticated-orcid":false,"suffix":"Jr.","given":"Joseph V.","family":"Boykin","sequence":"additional","affiliation":[{"name":"Departments of Surgery\/Plastic Surgery, Richmond Department of Veterans Affairs Medical Center  Richmond Virginia USA"},{"name":"Department of Surgery\/Plastic Surgery Virginia Commonwealth University Health System  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.10578"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0239236"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2018.06.003"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1586927"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/wrr.12804"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.4161\/15592294.2014.967584"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.05.064"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/5240127"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2019_270"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77335-0"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts124"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky691"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz240"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1629-z"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz757"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05005"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad431"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab297"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.93120"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1044662"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2013.05.002"},{"key":"e_1_2_11_23_1","first-page":"1.30.1","volume-title":"Current Protocols in Bioinformatics","author":"Stelzer G.","year":"2016"},{"key":"e_1_2_11_24_1","first-page":"27","volume-title":"Chapter Practical Guide to Life Science Databases","author":"Safran M.","year":"2022"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00031\u201010"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2007.01.002"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.12703\/P6\u201097"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/medicina57101053"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202051803"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1025"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1510559"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/biof.5520320129"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj20030816"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119352"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathophysiology32010009"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2025.02.003"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.03.007"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.59)"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1139\/bcb\u20102022\u20100371"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2016.00056"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02950"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells1040699"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2011.06.069"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2531"}],"container-title":["Wound Repair and Regeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/wrr.70141","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/wrr.70141","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/wrr.70141","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T06:17:03Z","timestamp":1777789023000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/wrr.70141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":43,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/wrr.70141"],"URL":"https:\/\/doi.org\/10.1111\/wrr.70141","archive":["Portico"],"relation":{},"ISSN":["1067-1927","1524-475X"],"issn-type":[{"value":"1067-1927","type":"print"},{"value":"1524-475X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2026-02-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70141"}}