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Their single or combined inhibition's molecular and cellular effects were assessed in human keratinocytes (HaCaT cells) and in vivo using a mouse model of type 1 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>As primary outcomes, we screened for proteome changes in HaCaT cells by LC-MS\/MS after transfection with miR-146a-5p or miR-29a-3p inhibitors individually or in combination and following stimulation with TNF-\u03b1. Moreover, as a secondary outcome, we collected the data and cryopreserved and paraffin-embedded skin biopsies to estimate the tissue response to miRNA inhibition using immunofluorescence and histological analysis. Cryopreserved biopsies were also used for the LC-MS\/MS proteome profiling to identify targets and cellular pathways involved in observed tissue changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a panel of extracellular matrix proteins, mainly laminins, whose levels changed after transfection with miR-146a-5p or miR-29a-3p inhibitors in HaCaT cells, counteracting TNF-\u03b1 effects. There was a difference in wound closure rate in vivo between the dual inhibition of miR-146a-5p and miR-29a-3p and scramble controls on day 8 (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.01) and day 9 (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.05), although not at day 10. Histological analysis at day 10 shows a loose papillary layer in the scramble inhibition group, indicating incomplete wound closure compared with dual miRNA inhibition. Moreover, the dual action of the inhibitors decreased inflammation at day 3 and day 10 (both\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.001) and reactive oxygen species formation (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.01) 3 days post wounding, while increasing the angiogenesis on day 3 (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.01) and day 10 (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.001). This was consistent with cytoskeletal rearrangements and collagen alterations observed in proteome profiling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>These findings demonstrate that dual inhibition of miR-146a-5p and miR-29a-3p in vitro synergises in a bidirectional manner, resulting either in intermediate effects or in cancelling each other\u2019s activity for the levels of specific proteins of basal lamina that impair proliferation and cell motility, compared with the individual inhibitors. Topical supplementation of miR-146a-5p and miR-29a-3p inhibitors to diabetic mouse wounds resulted in a reduction in wound size on days 8 and 9, which correspond to the later stages of healing, but did not lead to complete healing by day 10. However, dual inhibition demonstrates favourable effects on high oxidative stress, elevated inflammation and poor angiogenesis. These effects are superior to single miRNA inhibition, suggesting that combined miRNA inhibition could be a promising therapeutic strategy for diabetic wound healing. Nevertheless, further studies in humans are warranted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06522-3","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T01:26:48Z","timestamp":1756862808000},"page":"214-229","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Improved wound healing by dual inhibition of miR-146a-5p and miR-29a-3p supports a network action of dysregulated miRNAs in diabetic skin"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0404-5241","authenticated-orcid":false,"given":"Marija","family":"Petkovic","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-9861","authenticated-orcid":false,"given":"Ermelindo C.","family":"Leal","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7557-5376","authenticated-orcid":false,"given":"Anja E.","family":"S\u00f8rensen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3932-5921","authenticated-orcid":false,"given":"Per T.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9835-1009","authenticated-orcid":false,"given":"Jesper T.","family":"Wengel","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4706-5322","authenticated-orcid":false,"given":"Rosa R.","family":"Jersie-Christensen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4177-3267","authenticated-orcid":false,"given":"Jesper T.","family":"Troelsen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6264-3632","authenticated-orcid":false,"given":"Eugenia","family":"Carvalho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3598-2775","authenticated-orcid":false,"given":"Louise T.","family":"Dalgaard","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"issue":"18","key":"6522_CR1","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1111\/bph.15139","volume":"177","author":"X Nie","year":"2020","unstructured":"Nie X, Zhao J, Ling H, Deng Y, Li X, He Y (2020) Exploring microRNAs in diabetic chronic cutaneous ulcers: Regulatory mechanisms and therapeutic potential. 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Persson for her dedicated and skilled technical expertise, and H. Jenssen for providing HaCaT cells. Some of the preliminary data were presented at the EASD in Barcelona (2019):\n                      \n                      and virtually (Vienna) in (2020):\n                      \n                      . The graphical abstract and Fig.\n                      \n                      c were created with BioRender.com (Petkovic, M. (2025)\n                      \n                      ; M. (2025)\n                      \n                      ).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [\n                      \n                      ] partner repository with the dataset identifier PXD060087.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by Roskilde University. This work was supported by a research grant from the Danish Diabetes and Endocrine Academy, funded by the Novo Nordisk Foundation, grant number NNF22SA0079901 and the Novo Nordisk grant NNF24OC0089436 to MP; the Danish Diabetes Academy, funded by the Novo Nordisk Foundation, grant number NNF17SA0031406 to AES; the Novo Nordisk Foundation, grant number NNF23OC0081177 to LTD; the Portuguese Foundation for Science and Technology (FCT), grant number DL57\/2016\/CP1448\/CT0024 to ECL; the National Institute on Aging (USA), grant number 5P30-AG028718 to EC; the European Foundation for the Study of Diabetes (EFSD), European Research Program in Microvascular Complications in Diabetes supported by Novartis to EC and LTD; the European Regional Development Fund (ERDF)\/Centro 2020 Regional Operational Programme project Healthy Aging 2020-CENTRO-01-0145-FEDER-000012-N2323 and the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation\/FCT projects: POCI-01-0145-FEDER-007440, UIDB\/04539\/2020, UIDP\/04539\/2020 and LA\/P\/0058\/2020 to CIBB\u2019s Associate Laboratory, University of Coimbra.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"LTD, EC, ECL and MP conceived the ideas for the study. MP wrote the manuscript and researched data; ECL and AES researched data and reviewed\/edited the manuscript. JTT, PTJ, JTW\u00a0and RRJ-C researched data, and EC reviewed\/edited the manuscript. LTD researched data and reviewed\/edited the manuscript. All authors reviewed and approved the final version of the manuscript. LTD and EC are the guarantors of this work and, as such, had full access to all data reported in the study, thus taking responsibility for the data integrity and the data accuracy.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}