Journal of Dental Research最新文献

{"title":"MFN2–PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs","authors":"Y. Chen, Y.M. Xu, L.L. Zhu, Z.Y. Shan, Z.G. Yao, H. Zhao","doi":"10.1177/00220345261427294","DOIUrl":"https://doi.org/10.1177/00220345261427294","url":null,"abstract":"With aging, the morphology and function of the parotid glands are impaired, and the current mechanism is unknown. The integrity of mitochondria-associated membranes (MAMs), the structure connecting mitochondria and the endoplasmic reticulum (ER), is compromised during aging. This study investigated the effects of aging on MAMs and ER stress in the parotid glands of mice. Here, aged mice presented abnormalities in gland morphology and mitochondrial morphology and reduced MAMs integrity. Protein kinase R-like endoplasmic reticulum kinase (PERK) signaling is the primary mediator of ER stress, which is activated in the parotid glands of aged mice. Furthermore, aging-induced MFN2 downregulation disrupts mitochondrial dynamics. In addition, aging reduces MAMs function by blocking the MFN2–PERK interaction. Treatment with 4-phenylbutyric acid (4-PBA) improved MAMs integrity, inhibited the PERK pathway, and reduced apoptosis. Like 4-PBA, GSK2606414, a pharmacological antagonist of PERK, regulates ER stress and MAMs. Collectively, our data highlight disruption of the MFN2–PERK axis-mediated ER–mitochondrion connection as a cause of aging-induced parotid gland dysfunction.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"44 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of KLF4 in Neutrophil Aging in Periodontitis with Metabolic Syndrome.","authors":"C Li,Y Zhou,H Gou,Q Xiao,Y Chen,Y Xu","doi":"10.1177/00220345261429954","DOIUrl":"https://doi.org/10.1177/00220345261429954","url":null,"abstract":"Metabolic syndrome (MetS) and periodontitis (PD) are major interconnected health burdens, and the inflammatory interplay between them remains elusive. Neutrophils, central to periodontal immunity, can undergo functional alterations contributing to disease exacerbation. This study investigates the role of Krüppel-like factor 4 (KLF4) in regulating neutrophil aging during the exacerbation of PD by MetS. The analysis of clinical human samples and murine models revealed that MetS enhances the infiltration of senescent neutrophils into periodontal tissues. These neutrophils exhibit a heightened proinflammatory phenotype, including increased secretion of senescence-associated secretory phenotype factors, enhanced formation of neutrophil extracellular traps, and a metabolic reprogramming toward a glycolytic shift. Bioinformatics identified KLF4 as a key downregulated gene in comorbid MetS and PD. Adoptive transfer of MetS-derived or Klf4-deficient neutrophils into mice with periodontitis aggravated periodontal inflammation and alveolar bone destruction. In vitro, KLF4 knockdown in human neutrophil-like cell lines promoted metabolic reprogramming and proinflammatory phenotype. Through virtual docking and molecular dynamics simulations, we identified rosiglitazone as a candidate compound predicted to stabilize KLF4. This compound alleviated periodontal damage and improved insulin resistance in mice by mitigating the neutrophil aging phenotype and suppressing proinflammatory responses. Critically, all of these therapeutic effects were abolished in Klf4-deficient models. These results indicate that KLF4 is associated with the regulation of neutrophil aging through which MetS exacerbates periodontitis, highlighting KLF4 activation as a promising therapeutic strategy.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"85 1","pages":"220345261429954"},"PeriodicalIF":7.6,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Contribution of the Hypoxia Inducible Factor-1α Axis to Periodontitis","authors":"A. Fadl, A. Leask","doi":"10.1177/00220345261426978","DOIUrl":"https://doi.org/10.1177/00220345261426978","url":null,"abstract":"Periodontitis is a complex, multifactorial inflammatory condition characterized by progressive destruction of the periodontal supporting structures. It profoundly affects oral health, esthetics, and masticatory function and is increasingly recognized as a contributing risk factor for systemic disorders. Deep periodontal pockets establish a severely hypoxic microenvironment induced by periodontal pathogens, increased oxygen consumption of infiltrated inflammatory cells, and accompanying periodontal vascular changes. The cellular response to hypoxia is centrally regulated by hypoxia-inducible factor 1 alpha (HIF-1α), which is also recognized as a critical factor driving the progression of periodontal tissue destruction. In vivo and in vitro studies have shown the upregulation of HIF-1α in both animal periodontitis models and clinical samples from individuals with periodontitis, where its expression correlates positively with deteriorating clinical periodontal parameters. Experimental and clinical studies using mouse conditional knockout models, selective small-molecule inhibitors, and human-derived materials have demonstrated clear causal roles for hypoxia-driven HIF-1α signaling in the progression of periodontitis. This conclusion is supported by mechanistic evidence demonstrating that HIF-1α induces aberrant neovascularization, enhances osteoclastogenesis leading to subsequent alveolar bone resorption, and promotes M1 macrophage polarization along with proinflammatory cytokine production. Hypoxia, via HIF-1α, synergistically acts with periodontal pathogens to amplify periodontal inflammation and oxidative stress, driving persistent extracellular matrix destruction in periodontal tissues. This critical review summarizes recent findings, using in vitro and in vivo approaches using animal and human-derived materials, on the role of hypoxia, primarily through the HIF-1α pathway, in periodontitis pathogenesis as well as the potential of hypoxia-based strategies and targeted modulation of HIF-1α signaling through HIF-1α stabilizers for managing periodontitis and promoting periodontal regeneration, while highlighting the existing gaps in our understanding and the limitations of current research, which can serve as a foundation for guiding future studies in this area.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"8 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Cluster-Randomized Clinical Trial of Silver Diamine Fluoride vs Atraumatic Restoration in Older Adults","authors":"S. Nelson, J.M. Albert, D. Selvaraj, P. Milgrom, H. Momotaz, S. Curtan, K. Hickey, P. Weishampel, G. Bales, A. Dubaniewicz, J. Chao","doi":"10.1177/00220345261429949","DOIUrl":"https://doi.org/10.1177/00220345261429949","url":null,"abstract":"Untreated dental caries, a chronic disease linked to systemic health, is common among older adults due to a lack of dental insurance and affordable dental care. Minimally invasive interventions such as silver diamine fluoride (SDF) and atraumatic restorative treatments (ARTs) have been recommended by the World Health Organization to control caries where evidence is lacking in older adults. This cluster-randomized clinical trial tested the noninferiority of SDF vs ART in caries arrest (primary) and prevention (secondary) at 52 wk. Older adults ≥62 y living in 33 subsidized housing facilities were enrolled at baseline, with follow-up visits at 26 and 52 wk. Participants in the intervention arm received biannual topical application of 38% SDF, and the control arm received ART with glass ionomer cement (+2.5% sodium fluoride varnish). Caries arrest and new caries were determined through examinations conducted by hygienists utilizing criteria from the International Caries Detection and Assessment System. The noninferiority margin was 10% of the effectiveness of the control treatment. Among a total of 568 enrolled participants (intervention: 18 sites, <jats:italic toggle=\"yes\">n</jats:italic> = 346; control: 15 sites, <jats:italic toggle=\"yes\">n</jats:italic> = 222), 51% were female and 66% were Black; the mean ± SD age was 69.6 ± 6.8 y. Caries arrest at 52 wk was 88% in the intervention arm vs 92% in the control arm (difference, −0.04; 95% CI, −0.08 to 0.01). After adjusting for sociodemographics, a linear model with generalized estimating equations yielded an estimated treatment difference of −0.05 (95% CI, −0.09 to −0.01). The mean number of new decayed/carious lesions at 52 wk was 0.67 ± 1.72 for the intervention arm and 0.66 ± 1.71 for the control arm (difference, 0.01; 95% CI, −0.31 to 0.32). Results for both outcomes indicated noninferiority of 38% SDF at 52 wk. Findings support the use of a simple topical biannual 38% SDF treatment to control caries in clinical and public health settings, which can be delivered by dental and medical clinicians (ClinicalTrials.gov NCT03916926).","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"1 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological Appraisal of Tooth Loss and Dementia Mortality","authors":"G. Wang","doi":"10.1177/00220345261428077","DOIUrl":"https://doi.org/10.1177/00220345261428077","url":null,"abstract":"","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"11 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding Fluoride Hesitancy: A Qualitative Scoping Review","authors":"S.M.S. Chen, Y.J. Ong, L.Y. Soh, A.H.C. Tay, D.Y. Chow, J.R.H. Tay","doi":"10.1177/00220345261428043","DOIUrl":"https://doi.org/10.1177/00220345261428043","url":null,"abstract":"Fluoride is widely regarded within dentistry and public health as a safe and effective measure for preventing dental caries. Public ambivalence toward fluoride has intensified in recent years, reflected in ongoing disputes over water fluoridation. This scoping review synthesizes qualitative evidence on how fluoride hesitancy is constructed and expressed across social and clinical contexts. Qualitative studies examining perceptions, beliefs, and decision-making related to fluoride use were identified through searches of PubMed, Scopus, Embase, and CINAHL to April 2025. Twelve studies met the inclusion criteria. Data were extracted using a standardized charting approach and synthesized through an inductive, grounded theory–informed thematic analysis supported by constant comparison and reflexive memoing. Five interconnected domains of hesitancy were identified: (1) perceptions of fluoride as harmful or toxic; (2) uncertainty about benefits or necessity; (3) mistrust of scientific, professional, or governmental institutions; (4) ethical concerns regarding autonomy, consent, and environmental integrity; and (5) discomfort with specific delivery modalities paired with preferences for alternatives. Hesitancy was shaped not only by information but also by emotional responses, lived experience, parenting norms, online discourse, and interpretations of institutional credibility. Across studies, decisions about fluoride reflected broader efforts to navigate uncertainty, protect children, and maintain control over health choices. Fluoride hesitancy is a multifaceted interpretive process rather than a simple knowledge deficit. Addressing it requires approaches that pair clear scientific communication with attention to trust, autonomy, and the social contexts in which preventive recommendations are received. Strategies that acknowledge experiential perspectives and increase transparency around policy decisions may enhance the credibility and uptake of fluoride guidance, but some degree of hesitancy is likely to persist given wider environments of uneven trust and contested information.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"10 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Target Trial Emulation to Assess Oral Drug Safety","authors":"I. Leiva-Escobar, A. Puzhakkara Chennas, S.L. Reckelkamm, L. Gelberg, S.-E. Baumeister, M. Nolde","doi":"10.1177/00220345261429938","DOIUrl":"https://doi.org/10.1177/00220345261429938","url":null,"abstract":"Trials that use a randomization process are preferred for evaluating causal effect. However, these interventional studies are not always feasible due to ethical, time, and cost constraints. Additionally, they are often criticized for not accurately representing patients seen in clinical practice. Observational studies can help bridge this gap, but they are often affected by several sources of bias. A growing framework known as target trial emulation (TTE) is increasingly being applied to real-world data to minimize these common biases in observational studies and, under certain conditions, allow for causal interpretation. In this study, we assessed the 5-y effect of thiazide monotherapy, an antihypertensive medication known to cause xerostomia, on the risk of developing dental caries. We applied the target trial framework to build a TTE cohort using an active comparator new user design. We compared thiazide vs nonthiazide monotherapy using electronic health records from the All of Us Research Program. Furthermore, we developed 2 naïve cohorts: a prevalent user cohort, which included existing medication users, and a nonaligned cohort, which was affected by immortal time bias. These cohorts helped illustrate the advantages of TTE. In the TTE cohort, we found no significant difference in the 5-y risk of dental caries between groups, with a risk difference of 0.29% (95% CI, −0.36% to 0.95%). In contrast, the naïve cohorts showed directionally opposite effects, with 5-y risk differences of 0.65% (95% CI, 0.22% to 1.09%) in the prevalent user cohort and −0.24% (95% CI, −0.55% to 0.07%) in the nonaligned cohort, highlighting the impact of design-related biases on the observed outcomes. We demonstrated how the TTE framework can help avoid common biases in observational research, enabling researchers to answer important oral health questions.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"84 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Involvement of X-Inactivation in Organogenesis","authors":"M. Kawasaki, K. Kawasaki, M. Fukushima, F. Tisna Sari, V. Utama, A. Kesuma, A. Fujita, J. Nihara, K. Ichikawa, T. Kudo, S. Ghafoor, P.T. Sharpe, Y. Fukusumi, H. Kawachi, T. Maeda, B. Franco, A. Ohazama","doi":"10.1177/00220345261428392","DOIUrl":"https://doi.org/10.1177/00220345261428392","url":null,"abstract":"X-inactivation is the process of dosage compensation to balance X-linked gene expression levels between females (XX) and males (XY). One of the 2 X-chromosomes is randomly selected for inactivation in each cell during embryogenesis and remains inactive throughout life. Therefore, females have 2 types of cells: those with paternal X-chromosome activation and those with maternal X-chromosome activation. However, it remains unclear how X-inactivation is involved in palate and tooth development. <jats:italic toggle=\"yes\">Ofd1</jats:italic> is located on the X-chromosome. We found cleft palate in all heterozygous <jats:italic toggle=\"yes\">Ofd1</jats:italic> mutant mice ( <jats:italic toggle=\"yes\">Ofd1</jats:italic> <jats:sup>fl/WT</jats:sup> ; <jats:italic toggle=\"yes\">Wnt1Cre</jats:italic> [HET]), even though some cells should activate the normal X-chromosome due to random X-inactivation. Cells with <jats:italic toggle=\"yes\">Ofd1</jats:italic> mutant X chromosome activation ( <jats:italic toggle=\"yes\">Ofd1</jats:italic> mutant cells) accumulated at the tip of the palatal shelves due to cell segregation caused by a lack of EFNB1 expression, resulting in a cleft palate in all <jats:italic toggle=\"yes\">Ofd1</jats:italic> <jats:sup>fl/WT</jats:sup> ; <jats:italic toggle=\"yes\">Wnt1Cre</jats:italic> (HET) mice. Unlike the palate, <jats:italic toggle=\"yes\">Ofd1</jats:italic> <jats:sup>fl/WT</jats:sup> ; <jats:italic toggle=\"yes\">Wnt1Cre</jats:italic> (HET) mice showed multiple tooth phenotypes, including extra and absent incisors, while a normal number of incisors was also found. Accumulation of <jats:italic toggle=\"yes\">Ofd1</jats:italic> mutant cells also occurred in the tooth mesenchyme, and these clusters of <jats:italic toggle=\"yes\">Ofd1</jats:italic> mutant cells failed to initiate incisor tooth formation due to a lack of Wnt signaling. In contrast to palate development, the location of <jats:italic toggle=\"yes\">Ofd1</jats:italic> mutant cell clusters differed between <jats:italic toggle=\"yes\">Ofd1</jats:italic> <jats:sup>fl/WT</jats:sup> ; <jats:italic toggle=\"yes\">Wnt1Cre</jats:italic> (HET) mice, likely leading to diversity of tooth phenotypes. Thus, X-inactivation exhibits different involvement between palate and tooth development.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"11 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Letter to Editor: “Disability Weights for Global Burden Estimation of Orofacial Pain”","authors":"A. Lövgren, P. Liv, J. Durham, D.A.G. Goncalves, F.P. Kapos, S.F. Kothari, M. Drangsholt, C.C. Peck, C.M. Visscher, L. Ong, P. Svensson","doi":"10.1177/00220345261430278","DOIUrl":"https://doi.org/10.1177/00220345261430278","url":null,"abstract":"","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"52 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exogenous Nitric Oxide in the Treatment of Dental and Oral Diseases","authors":"Q. Zhang, L. Lu, C. Liu, X. Zhao, P. Gao, J. Liu","doi":"10.1177/00220345261429478","DOIUrl":"https://doi.org/10.1177/00220345261429478","url":null,"abstract":"Nitric oxide (NO), a gaseous signaling molecule, is increasingly recognized for its central role in the pathophysiology of dental and oral diseases. Dysregulation of nitric oxide synthase (NOS) and consequent impairment of endogenous NO production have been implicated in a range of oral conditions. Accordingly, exogenous NO therapy has garnered significant interest due to its broad-spectrum antibacterial, potent anti-inflammatory, tissue-regenerative, and potential antitumor effects. This review provides a comprehensive overview of therapeutic advances in exogenous NO for dental and oral diseases, focusing on underlying mechanisms, such as modulation of the cyclic di-guanosine monophosphate pathway, mediation of S-nitrosylation, activation of the soluble guanylate cyclase–cyclic guanosine monophosphate–protein kinase G pathway, and regulation of the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Collectively, these mechanisms confer antimicrobial efficacy, immunomodulation, enhanced periodontal and pulpal tissue repair, and apoptosis induction in oral cancer cells. Various NO delivery platforms, including nanocarriers, hydrogels, implant coatings, and microneedles, are reviewed for their efficacy and application in managing periodontitis, peri-implantitis, dental caries, endodontic and periapical diseases, oral ulcers, orthodontic tooth movement, and oral cancer. Although most of the current evidence is derived from preclinical studies and substantial challenges remain with respect to dosing accuracy and delivery specificity, the unique multitarget properties of exogenous NO highlight its considerable promise as an adjunctive strategy in dental medicine. This review seeks to provide a comprehensive overview that not only advances fundamental understanding of exogenous NO but also promotes its clinical translation for improved management of dental and oral diseases.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"37 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}