{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:22:42Z","timestamp":1789910562389,"version":"4.0.1"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,6,16]],"date-time":"2024-06-16T00:00:00Z","timestamp":1718496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007194","name":"Wenzhou Municipal Science and Technology Bureau","doi-asserted-by":"publisher","award":["Y20210777"],"award-info":[{"award-number":["Y20210777"]}],"id":[{"id":"10.13039\/501100007194","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>To elucidate whether mitochondrial biogenesis disorder and damage from oxidative stress promote refractory apical periodontitis (RAP) in rat and human.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methodology<\/jats:title><jats:p>Twenty <jats:italic>Enterococcus faecalis<\/jats:italic>\u2010induced RAPs were established in the maxillary first molars of male Wistar rats. Concurrently, 12 periapical lesion specimens from patients presenting with RAP were obtained by apicoectomy. Radiographic examination and histologic analysis were conducted to evaluate periapical bone tissue destruction and morphological changes. The expression of key regulators of mitochondrial biogenesis, PGC\u20101\u03b1 and Nrf2, were detected by immunohistochemistry and double immunofluorescence staining, Western blot and real\u2010time PCR were also assayed. Mitochondrial ROS (mtROS) was identified by MitoSOX staining. Mitochondrial function was detected by the quantification of ATP production, mitochondrial DNA (mtDNA) copy number and activities of mitochondrial respiratory chain complexes. Furthermore, mitochondrial oxidative stress was evaluated by the determination of 3\u2010nitrotyrosine (3\u2010NT), 4\u2010hydroxy\u20102\u2010nonenal (4\u2010HNE) and 8\u2010hydroxy\u2010deoxyguanosine (8\u2010OHdG) expression levels, as well as malondialdehyde (MDA) expression and antioxidant capacity. Student's <jats:italic>t<\/jats:italic>\u2010test was performed to determine significance between the groups; <jats:italic>p\u2009&lt;<\/jats:italic>\u2009.05 was considered significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the maxilla, significantly more bone resorption, greater number of periapical apoptotic cells and Tartrate\u2010resistant acid phosphatase (TRAP)\u2010positive multinucleated cells were observed in the RAP group compared with the control group (<jats:italic>p\u2009&lt;<\/jats:italic>\u2009.01). PGC\u20101\u03b1 and Nrf2 were significantly reduced in rat and human RAP lesions compared to the control group (<jats:italic>p\u2009&lt;<\/jats:italic>\u2009.01) at both the mRNA and protein levels. Double immunofluorescence analysis of PGC\u20101\u03b1 or Nrf2 with TOMM20 also indicated that mitochondrial biogenesis was impaired in RAP group (<jats:italic>p\u2009&lt;<\/jats:italic>\u2009.01). Additionally, mitochondrial dysfunction was observed in RAP group, as reflected by increased mtROS, decreased ATP production, reduced mtDNA copy number and complexes of the mitochondrial respiratory chain. Finally, the expression levels of mitochondrial oxidative stress markers, 3\u2010NT, 4\u2010HNE and 8\u2010OHdG, were significantly increased in the RAP group (<jats:italic>p\u2009&lt;<\/jats:italic>\u2009.01). Consistent with this, systemic oxidative damage was also present in the progression of RAP, including increased MDA expression and decreased antioxidant activity (<jats:italic>p\u2009&lt;<\/jats:italic>\u2009.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Mitochondrial biogenesis disorder and damage from oxidative stress contribute to the development of RAP.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.14106","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T05:50:36Z","timestamp":1718603436000},"page":"1326-1342","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mitochondrial biogenesis disorder and oxidative damage promote refractory apical periodontitis in rat and human"],"prefix":"10.1111","volume":"57","author":[{"given":"Jun","family":"Wang","sequence":"first","affiliation":[{"name":"School and Hospital of Stomatology Wenzhou Medical 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