{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:54:11Z","timestamp":1776401651822,"version":"3.51.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Diabetic foot infection (DFI) remains a leading cause of morbidity and mortality in diabetic patients, with Pseudomonas aeruginosa serving as a predominant pathogen due to its arsenal of virulence factors. Among these, the siderophore pyoverdine (PVD) is critical for bacterial iron acquisition and pathogenesis; however, its direct impact on the vascular endothelial barrier\u2014particularly under hyperglycemic conditions\u2014remains poorly understood. In this study, we employed Human Umbilical Vein Endothelial Cells (HUVECs) as a model to systematically evaluate the effects of PVD and high glucose (HG) on endothelial integrity. Transcriptomic analysis (RNA-seq) revealed that PVD significantly reshaped the gene expression profile of HUVECs, characterized by a marked upregulation of iron homeostasis-related genes, such as TFRC, indicating a state of apparent intracellular iron deficiency. Functional enrichment analysis further highlighted alterations in the extracellular matrix (ECM) and pathways associated with barrier function.\n                    <jats:italic>In vitro<\/jats:italic>\n                    assays demonstrated that PVD exposure reduced cell viability, triggered reactive oxygen species (ROS) bursts, and induced a loss of mitochondrial membrane potential. Ultrastructural observations via transmission electron microscopy confirmed pathological changes, including mitochondrial swelling, cristae disorganization, and cytoplasmic vacuolation. Functional assessments showed that PVD significantly increased the transendothelial flux of FITC-dextran and downregulated the expression of the tight junction proteins ZO-1 and Claudin-5, indicating compromised barrier integrity. Notably, these deleterious effects\u2014including oxidative stress, mitochondrial damage, and barrier dysfunction\u2014were significantly exacerbated under HG conditions. Collectively, our findings suggest that PVD impairs the vascular endothelial barrier by disrupting eukaryotic iron homeostasis and activating oxidative stress, leading to the downregulation of junctional proteins. This study identifies PVD as a key mediator of vascular injury in DFI and provides a theoretical rationale for targeting iron metabolism and oxidative stress as a therapeutic strategy.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1719170","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:15:05Z","timestamp":1776399305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pyoverdine-induced iron dysregulation exacerbates vascular endothelial barrier dysfunction under hyperglycemic conditions"],"prefix":"10.3389","volume":"17","author":[{"given":"Guixiang","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, Ningxia, China"]},{"name":"People\u2019s Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University","place":["Yinchuan, Ningxia, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiyuan","family":"Xin","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, Ningxia, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, Ningxia, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junxia","family":"Yan","sequence":"additional","affiliation":[{"name":"People\u2019s Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University","place":["Yinchuan, Ningxia, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weidong","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Ningxia Medical University","place":["Yinchuan, Ningxia, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1530\/joe-22-0238","article-title":"Diabetes-related foot disease: new insights with an antipodean focus","volume":"257","author":"Hamilton","year":"2023","journal-title":"J Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1128\/iai.00945-15","article-title":"Pseudomonas aeruginosa triggers macrophage autophagy to escape intracellular killing by activation of the NLRP3 inflammasome","volume":"84","author":"Deng","year":"2016","journal-title":"Infect Immun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2018.07.003","article-title":"Updates on the pathogenicity status of Pseudomonas aeruginosa","volume":"24","author":"Azam","year":"2019","journal-title":"Drug Discov Today"},{"key":"B5","doi-asserted-by":"publisher","first-page":"3128","DOI":"10.3390\/ijms22063128","article-title":"Pseudomonas aeruginosa: An audacious pathogen with an adaptable arsenal of virulence factors","volume":"22","author":"Jurado-Mart\u00edn","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00248-013-0297-x","article-title":"Pseudomonas aeruginosa biofilms in disease","volume":"68","author":"Mulcahy","year":"2014","journal-title":"Microb Ecol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13649","article-title":"Impact of wound microbiology on limb preservation in patients with diabetic foot infection","volume":"13","author":"Hung","year":"2022","journal-title":"J Diabetes Invest"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/2304018","article-title":"Emerging roles of redox-mediated angiogenesis and oxidative stress in dermatoses","volume":"2019","author":"Xian","year":"2019","journal-title":"Oxid Med Cell Longevity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/1040841x.2023.2282459","article-title":"Natural and synthetic molecules with potential to enhance biofilm formation and virulence properties in Pseudomonas aeruginosa","volume":"50","author":"Jeong","year":"2024","journal-title":"Crit Rev Microbiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.1c07103","article-title":"In situ photo-cross-linking hydrogel accelerates diabetic wound healing through restored hypoxia-inducible factor 1-alpha pathway and regulated inflammation","volume":"13","author":"Pang","year":"2021","journal-title":"ACS Appl Mater Interfaces"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202200521","article-title":"Immunoregulation in diabetic wound repair with a photoenhanced glycyrrhizic acid hydrogel scaffold","volume":"34","author":"Qian","year":"2022","journal-title":"Adv Mater (Deerfield Beach Fla)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202255971","article-title":"Pseudomonas aeruginosa LecB suppresses immune responses by inhibiting transendothelial migration","volume":"24","author":"Sponsel","year":"2023","journal-title":"EMBO Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-020-00478-1","article-title":"Pseudomonas aeruginosa virulence proteins pseudolysin and protease IV impede cutaneous wound healing","volume":"100","author":"Prasad","year":"2020","journal-title":"Lab Investig A J Tech Methods Pathol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/978-3-031-08491-1_2","article-title":"Iron homeostasis in Pseudomonas aeruginosa: Targeting iron acquisition and storage as an antimicrobial strategy","volume":"1386","author":"Llamas","year":"2022","journal-title":"Adv Exp Med Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2018.1449508","article-title":"Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response","volume":"9","author":"Kang","year":"2018","journal-title":"Virulence"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424954112","article-title":"Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa","volume":"112","author":"Kirienko","year":"2015","journal-title":"PNAS"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.03.003","article-title":"Pseudomonas aeruginosa disrupts Caenorhabditis elegans iron homeostasis, causing a hypoxic response and death","volume":"13","author":"Kirienko","year":"2013","journal-title":"Cell Host Microbe"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00271","article-title":"Diabetes and sepsis: Risk, recurrence, and ruination","volume":"8","author":"Frydrych","year":"2017","journal-title":"Front Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"9464","DOI":"10.1038\/s41598-021-88273-w","article-title":"Genetic factors affect the susceptibility to bacterial infections in diabetes","volume":"11","author":"Simonsen","year":"2021","journal-title":"Sci Rep"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2174\/1566524020999200831124534","article-title":"Innate immunity alterations in type 2 diabetes mellitus: Understanding infection susceptibility","volume":"21","author":"de Lourdes Ochoa-Gonz\u00e1lez","year":"2021","journal-title":"Curr Mol Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"396","DOI":"10.21203\/rs.3.rs-1154535\/v1","article-title":"Distribution and drug sensitivity of pathogenic bacteria in diabetic foot ulcer patients with necrotizing fasciitis at a diabetic foot center in China","volume":"22","author":"Li","year":"2022","journal-title":"BMC Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41392-022-01056-1","article-title":"Pseudomonas aeruginosa: Pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41396-019-0442-8","article-title":"In-vivo microscopy reveals the impact of Pseudomonas aeruginosa social interactions on host colonization","volume":"13","author":"Rezzoagli","year":"2019","journal-title":"ISME J"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-022-12347-6","article-title":"Pseudomonas aeruginosa virulence attenuation by inhibiting siderophore functions","volume":"107","author":"Jeong","year":"2023","journal-title":"Appl Microbiol Biotechnol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03319-7","article-title":"Caenorhabditis elegans: A model to understand host-microbe interactions","volume":"77","author":"Kumar","year":"2020","journal-title":"Cell Mol Life Sci: CMLS"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006876","article-title":"A conserved mitochondrial surveillance pathway is required for defense against Pseudomonas aeruginosa","volume":"13","author":"Tjahjono","year":"2017","journal-title":"PloS Genet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12915-020-00812-5","article-title":"The evolutionarily conserved ESRE stress response network is activated by ROS and mitochondrial damage","volume":"18","author":"Tjahjono","year":"2020","journal-title":"BMC Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1451-9","article-title":"Sequential inactivation of Rho GTPases and Lim kinase by Pseudomonas aeruginosa toxins ExoS and ExoT leads to endothelial monolayer breakdown","volume":"71","author":"Huber","year":"2014","journal-title":"Cell Mol Life Sci: CMLS"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.607796","article-title":"Acacetin protects against high glucose-induced endothelial cells injury by preserving mitochondrial function via activating Sirt1\/Sirt3\/AMPK signals","volume":"11","author":"Han","year":"2020","journal-title":"Front Pharmacol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s12989-022-00462-1","article-title":"Combined exposure to fine particulate matter and high glucose aggravates endothelial damage by increasing inflammation and mitophagy: the involvement of vitamin D","volume":"19","author":"Lai","year":"2022","journal-title":"Part Fibre Toxicol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1186\/s12967-025-06320-w","article-title":"Single-cell analysis identifies MKI67(+) microglia as drivers of neovascularization in proliferative diabetic retinopathy","volume":"23","author":"Zou","year":"2025","journal-title":"J Transl Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.22038\/IJBMS.2023.71019.15425","article-title":"Alpha-mangostin decreases high glucose-induced damage on human umbilical vein endothelial cells by increasing autophagic protein expression","volume":"27","author":"Eisvand","year":"2024","journal-title":"Iranian J Basic Med Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03693-23","article-title":"In vitro lung epithelial cell model reveals novel roles for Pseudomonas aeruginosa siderophores","volume":"12","author":"Kang","year":"2024","journal-title":"Microbiol Spectr"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/8416763","article-title":"Oxidative stress: Harms and benefits for human health","volume":"2017","author":"Pizzino","year":"2017","journal-title":"Oxid Med Cell Longevity"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.3390\/jcm9061995","article-title":"Oxidative stress and new pathogenetic mechanisms in endothelial dysfunction: Potential diagnostic biomarkers and therapeutic targets","volume":"9","author":"Scioli","year":"2020","journal-title":"J Clin Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00313-x","article-title":"NAD(+) metabolism and its roles in cellular processes during ageing","volume":"22","author":"Covarrubias","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3820","DOI":"10.3390\/ijms21113820","article-title":"Mitochondrial OXPHOS biogenesis: Co-regulation of protein synthesis, import, and assembly pathways","volume":"21","author":"Tang","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.736735","article-title":"Modulation of microenvironment signals by proteolytic shedding of cell surface extracellular matrix receptors","volume":"9","author":"Itoh","year":"2021","journal-title":"Front Cell Dev Biol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1719170\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:15:07Z","timestamp":1776399307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1719170\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":38,"alternative-id":["10.3389\/fendo.2026.1719170"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1719170","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]},"article-number":"1719170"}}