Pub Date : 2024-09-01Epub Date: 2024-08-26DOI: 10.1177/00220345241264810
B Sun, Y Xu, H Wang, F Wang, Q Li, Y Chen, Z Wang
Bone aging and decreased autophagic activity are related but poorly explored in the jawbone. This study aimed to characterize the aging jawbones and jawbone-derived stromal cells (JBSCs) and determine the role of autophagy in jawbone mass decline. We observed that the jawbones of older individuals and mice exhibited similar age-related bone loss. Furthermore, leptin receptor (LepR)-lineage cells served as the primary source for in vitro cultured and expanded JBSCs, referred to as LepR-Cre+/JBSCs. RNA-sequencing data from the jawbones and LepR-Cre+/JBSCs showed the upregulated expression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway during aging. Through single-cell transcriptomics, we identified a decrease in the proportion of osteogenic lineage cells and the activation of the PI3K/AKT pathway in LepR-lineage cells in aging bone tissues. Reduced basal autophagic activity, diminished autophagic flux, and decreased osteogenesis occurred in the jawbones and LepR-Cre+/JBSCs from older mice (O-mice; O-JBSCs). Pharmacologic and constitutive autophagy activation alleviated the impaired osteogenesis in O-JBSCs. In addition, the suppression of mTOR-induced autophagy improved the aging phenotype of O-JBSCs. The activation of autophagy in LepR-Cre+/JBSCs using chemical autophagic activators reduced the alveolar bone resorption in O-mice. Therefore, our study demonstrated that ATG molecules and pathways are crucial in jawbone aging, providing novel approaches to understanding age-related jawbone loss.
{"title":"Autophagy Regulates Age-Related Jawbone Loss via LepR<sup>+</sup> Stromal Cells.","authors":"B Sun, Y Xu, H Wang, F Wang, Q Li, Y Chen, Z Wang","doi":"10.1177/00220345241264810","DOIUrl":"10.1177/00220345241264810","url":null,"abstract":"<p><p>Bone aging and decreased autophagic activity are related but poorly explored in the jawbone. This study aimed to characterize the aging jawbones and jawbone-derived stromal cells (JBSCs) and determine the role of autophagy in jawbone mass decline. We observed that the jawbones of older individuals and mice exhibited similar age-related bone loss. Furthermore, leptin receptor (LepR)-lineage cells served as the primary source for in vitro cultured and expanded JBSCs, referred to as LepR-Cre<sup>+</sup>/JBSCs. RNA-sequencing data from the jawbones and LepR-Cre<sup>+</sup>/JBSCs showed the upregulated expression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway during aging. Through single-cell transcriptomics, we identified a decrease in the proportion of osteogenic lineage cells and the activation of the PI3K/AKT pathway in LepR-lineage cells in aging bone tissues. Reduced basal autophagic activity, diminished autophagic flux, and decreased osteogenesis occurred in the jawbones and LepR-Cre<sup>+</sup>/JBSCs from older mice (O-mice; O-JBSCs). Pharmacologic and constitutive autophagy activation alleviated the impaired osteogenesis in O-JBSCs. In addition, the suppression of mTOR-induced autophagy improved the aging phenotype of O-JBSCs. The activation of autophagy in LepR-Cre+/JBSCs using chemical autophagic activators reduced the alveolar bone resorption in O-mice. Therefore, our study demonstrated that ATG molecules and pathways are crucial in jawbone aging, providing novel approaches to understanding age-related jawbone loss.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1028-1038"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-05DOI: 10.1177/00220345241263320
M Wänman, S Betnér, A Esberg, C K Holm, C Isehed, A Holmlund, P Palmqvist, A Lövgren, S Lindquist, L Hänström, U H Lerner, E Kindstedt, P Lundberg
The sequalae of periodontitis include irreversible degradation of tooth-supporting structures and circulatory spread of inflammatory mediators. However, the serum protein profile in periodontitis is not well described, which is partly attributable to the limited number of studies based on large and well-characterized periodontitis cohorts. This study aims to identify novel, circulating inflammation-related proteins associated with periodontitis within the PerioGene North case-control study, which includes 478 cases with severe periodontitis and 509 periodontally healthy controls. The serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and a panel of 45 inflammation-related proteins were analyzed using targeted proteomics. A distinguishable serum protein profile was evident in periodontitis cases. The protein pattern could separate cases from controls with a sensitivity of 0.81 and specificity of 0.81 (area under the curve = 0.87). Adjusted levels for hs-CRP and 24 of the 45 proteins were different between cases and controls. High levels of hs-CRP and matrix metalloproteinase-12, and low levels of epidermal growth factor (EGF) and oxidized low-density lipoprotein receptor 1 (OLR-1) were detected among the cases. Furthermore, the levels of C-C motif chemokine-19, granulocyte colony-stimulating factor-3 (CSF-3), interleukin-7 (IL-7), and hs-CRP were significantly higher in cases with a high degree of gingival inflammation. The levels of CSF-3 and tumor necrosis factor ligand superfamily member-10 TNFSF-10 were higher in cases with many deep periodontal pockets. The PerioGene North study includes detailed clinical periodontal data and uncovers a distinct serum protein profile in periodontitis. The findings of lower EGF and OLR-1 among the cases are highlighted, as this has not been presented before. The role of EGF and OLR-1 in periodontitis pathogenesis and as possible future biomarkers should be further explored.
{"title":"The PerioGene North Study Uncovers Serum Proteins Related to Periodontitis.","authors":"M Wänman, S Betnér, A Esberg, C K Holm, C Isehed, A Holmlund, P Palmqvist, A Lövgren, S Lindquist, L Hänström, U H Lerner, E Kindstedt, P Lundberg","doi":"10.1177/00220345241263320","DOIUrl":"10.1177/00220345241263320","url":null,"abstract":"<p><p>The sequalae of periodontitis include irreversible degradation of tooth-supporting structures and circulatory spread of inflammatory mediators. However, the serum protein profile in periodontitis is not well described, which is partly attributable to the limited number of studies based on large and well-characterized periodontitis cohorts. This study aims to identify novel, circulating inflammation-related proteins associated with periodontitis within the PerioGene North case-control study, which includes 478 cases with severe periodontitis and 509 periodontally healthy controls. The serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and a panel of 45 inflammation-related proteins were analyzed using targeted proteomics. A distinguishable serum protein profile was evident in periodontitis cases. The protein pattern could separate cases from controls with a sensitivity of 0.81 and specificity of 0.81 (area under the curve = 0.87). Adjusted levels for hs-CRP and 24 of the 45 proteins were different between cases and controls. High levels of hs-CRP and matrix metalloproteinase-12, and low levels of epidermal growth factor (EGF) and oxidized low-density lipoprotein receptor 1 (OLR-1) were detected among the cases. Furthermore, the levels of C-C motif chemokine-19, granulocyte colony-stimulating factor-3 (CSF-3), interleukin-7 (IL-7), and hs-CRP were significantly higher in cases with a high degree of gingival inflammation. The levels of CSF-3 and tumor necrosis factor ligand superfamily member-10 TNFSF-10 were higher in cases with many deep periodontal pockets. The PerioGene North study includes detailed clinical periodontal data and uncovers a distinct serum protein profile in periodontitis. The findings of lower EGF and OLR-1 among the cases are highlighted, as this has not been presented before. The role of EGF and OLR-1 in periodontitis pathogenesis and as possible future biomarkers should be further explored.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"999-1007"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-26DOI: 10.1177/00220345241264792
P Mulimani, N A Mazzawi, A J Goldstein, A M Obenaus, S M Baggett, D Truong, T E Popowics, N J Sniadecki
In vitro models are invaluable tools for deconstructing the biological complexity of the periodontal ligament (PDL). Model systems that closely reproduce the 3-dimensional (3D) configuration of cell-cell and cell-matrix interactions in native tissue can deliver physiologically relevant insights. However, 3D models of the PDL that incorporate mechanical loading are currently lacking. Hence, we developed a model where periodontal tissue constructs (PTCs) are made by casting PDL cells in a collagen gel suspended between a pair of slender, silicone posts for magnetic tensile loading. Specifically, one of the posts was rigid and the other was flexible with a magnet embedded in its tip so that PTCs could be subjected to tensile loading with an external magnet. Additionally, the deflection of the flexible post could be used to measure the contractile force of PDL cells in the PTCs. Prior to tensile loading, second harmonics generation analysis of collagen fibers in PTCs revealed that incorporation of PDL cells resulted in collagen remodeling. Biomechanical testing of PTCs by tensile loading revealed an elastic response at 4 h, permanent deformation by 1 d, and creep elongation by 1 wk. Subsequently, contractile forces of PDL cells were substantially lower for PTCs under tensile loading. Immunofluorescence analysis revealed that tensile loading caused PDL cells to increase in number, express higher levels of F-actin and α-smooth muscle actin, and become aligned to the tensile axis. Second harmonics generation analysis indicated that collagen fibers in PTCs progressively remodeled over time with tensile loading. Gene expression analysis also confirmed tension-mediated upregulation of the F-actin/Rho pathway and osteogenic genes. Our model is novel in demonstrating the mechanobiological behavior that results in cell-mediated remodeling of the PDL tissue in a 3D context. Hence, it can be a valuable tool to develop therapeutics for periodontitis, periodontal regeneration, and orthodontics.
{"title":"Engineered 3D Periodontal Ligament Model with Magnetic Tensile Loading.","authors":"P Mulimani, N A Mazzawi, A J Goldstein, A M Obenaus, S M Baggett, D Truong, T E Popowics, N J Sniadecki","doi":"10.1177/00220345241264792","DOIUrl":"10.1177/00220345241264792","url":null,"abstract":"<p><p>In vitro models are invaluable tools for deconstructing the biological complexity of the periodontal ligament (PDL). Model systems that closely reproduce the 3-dimensional (3D) configuration of cell-cell and cell-matrix interactions in native tissue can deliver physiologically relevant insights. However, 3D models of the PDL that incorporate mechanical loading are currently lacking. Hence, we developed a model where periodontal tissue constructs (PTCs) are made by casting PDL cells in a collagen gel suspended between a pair of slender, silicone posts for magnetic tensile loading. Specifically, one of the posts was rigid and the other was flexible with a magnet embedded in its tip so that PTCs could be subjected to tensile loading with an external magnet. Additionally, the deflection of the flexible post could be used to measure the contractile force of PDL cells in the PTCs. Prior to tensile loading, second harmonics generation analysis of collagen fibers in PTCs revealed that incorporation of PDL cells resulted in collagen remodeling. Biomechanical testing of PTCs by tensile loading revealed an elastic response at 4 h, permanent deformation by 1 d, and creep elongation by 1 wk. Subsequently, contractile forces of PDL cells were substantially lower for PTCs under tensile loading. Immunofluorescence analysis revealed that tensile loading caused PDL cells to increase in number, express higher levels of F-actin and α-smooth muscle actin, and become aligned to the tensile axis. Second harmonics generation analysis indicated that collagen fibers in PTCs progressively remodeled over time with tensile loading. Gene expression analysis also confirmed tension-mediated upregulation of the F-actin/Rho pathway and osteogenic genes. Our model is novel in demonstrating the mechanobiological behavior that results in cell-mediated remodeling of the PDL tissue in a 3D context. Hence, it can be a valuable tool to develop therapeutics for periodontitis, periodontal regeneration, and orthodontics.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1008-1016"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1177/00220345241262949
L Benz, K Heck, D Hevisov, D Kugelmann, P-C Tseng, Z Sreij, F Litzenburger, J Waschke, F Schwendicke, A Kienle, R Hickel, K-H Kunzelmann, E Walter
Endodontic access preparation is one of the initial steps in root canal treatments and can be hindered by the obliteration of pulp canals and formation of tertiary dentin. Until now, methods for direct intraoperative visualization of the 3-dimensional anatomy of teeth have been missing. Here, we evaluate the use of shortwave infrared radiation (SWIR) for navigation during stepwise access preparation. Nine teeth (3 anteriors, 3 premolars, and 3 molars) were explanted en bloc with intact periodontium including alveolar bone and mucosa from the upper or lower jaw of human body donors. Analysis was performed at baseline as well as at preparation depths of 5 mm, 7 mm, and 9 mm, respectively. For reflection, SWIR was used at a wavelength of 1,550 nm from the occlusal direction, whereas for transillumination, SWIR was passed through each sample at the marginal gingiva from the buccal as well as oral side at a wavelength of 1,300 nm. Pulpal structures could be identified as darker areas approximately 2 mm before reaching the pulp chamber using SWIR transillumination, although they were indistinguishable under normal circumstances. Furcation areas in molars appeared with higher intensity than areas with canals. The location of pulpal structures was confirmed by superimposition of segmented micro-computed tomography (µCT) images. By radiomic analysis, significant differences between pulpal and parapulpal areas could be detected in image features. With hierarchical cluster analysis, both segments could be confirmed and associated with specific clusters. The local thickness of µCTs was calculated and correlated with SWIR transillumination images, by which a linear dependency of thickness and intensity could be demonstrated. Lastly, by in silico simulations of light propagation, dentin tubules were shown to be a crucial factor for understanding the visibility of the pulp. In conclusion, SWIR transillumination may allow direct clinical live navigation during endodontic access preparation.
{"title":"Visualization of Pulpal Structures by SWIR in Endodontic Access Preparation.","authors":"L Benz, K Heck, D Hevisov, D Kugelmann, P-C Tseng, Z Sreij, F Litzenburger, J Waschke, F Schwendicke, A Kienle, R Hickel, K-H Kunzelmann, E Walter","doi":"10.1177/00220345241262949","DOIUrl":"https://doi.org/10.1177/00220345241262949","url":null,"abstract":"<p><p>Endodontic access preparation is one of the initial steps in root canal treatments and can be hindered by the obliteration of pulp canals and formation of tertiary dentin. Until now, methods for direct intraoperative visualization of the 3-dimensional anatomy of teeth have been missing. Here, we evaluate the use of shortwave infrared radiation (SWIR) for navigation during stepwise access preparation. Nine teeth (3 anteriors, 3 premolars, and 3 molars) were explanted <i>en bloc</i> with intact periodontium including alveolar bone and mucosa from the upper or lower jaw of human body donors. Analysis was performed at baseline as well as at preparation depths of 5 mm, 7 mm, and 9 mm, respectively. For reflection, SWIR was used at a wavelength of 1,550 nm from the occlusal direction, whereas for transillumination, SWIR was passed through each sample at the marginal gingiva from the buccal as well as oral side at a wavelength of 1,300 nm. Pulpal structures could be identified as darker areas approximately 2 mm before reaching the pulp chamber using SWIR transillumination, although they were indistinguishable under normal circumstances. Furcation areas in molars appeared with higher intensity than areas with canals. The location of pulpal structures was confirmed by superimposition of segmented micro-computed tomography (µCT) images. By radiomic analysis, significant differences between pulpal and parapulpal areas could be detected in image features. With hierarchical cluster analysis, both segments could be confirmed and associated with specific clusters. The local thickness of µCTs was calculated and correlated with SWIR transillumination images, by which a linear dependency of thickness and intensity could be demonstrated. Lastly, by <i>in silico</i> simulations of light propagation, dentin tubules were shown to be a crucial factor for understanding the visibility of the pulp. In conclusion, SWIR transillumination may allow direct clinical live navigation during endodontic access preparation.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345241262949"},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241262706
H Liu, Y Zhang, Y Zhang, Y Huang, Y Yang, Y Zhao, S Chen, J Deng, W Li, B Han
Alveolar bone (AB) remodeling, including formation and absorption, is the foundation of orthodontic tooth movement (OTM). However, the sources and mechanisms underlying new bone formation remain unclear. Therefore, we aimed to understand the potential mechanism of bone formation during OTM, focusing on the leptin receptor+ (Lepr+) osteogenitors and periodontal ligament cells (PDLCs). We demonstrated that Lepr+ cells activated by force-induced PDLC apoptosis served as distinct osteoprogenitors during orthodontic bone regeneration. We investigated bone formation both in vivo and in vitro. Single-cell RNA sequencing analysis and lineage tracing demonstrated that Lepr represents a subcluster of stem cells that are activated and differentiate into osteoblasts during OTM. Targeted ablation of Lepr+ cells in a mouse model disrupted orthodontic force-guided bone regeneration. Furthermore, apoptosis and sequential fluorescent labeling assays revealed that the apoptosis of PDLCs preceded new bone deposition. We found that PDL stem cell-derived apoptotic vesicles activated Lepr+ cells in vitro. Following apoptosis inhibition, orthodontic force-activated osteoprogenitors and osteogenesis were significantly downregulated. Notably, we found that bone formation occurred on the compression side during OTM; this has been first reported here. To conclude, we found a potential mechanism of bone formation during OTM that may provide new insights into AB regeneration.
{"title":"Periodontal Ligament Cell Apoptosis Activates Lepr+ Osteoprogenitors in Orthodontics.","authors":"H Liu, Y Zhang, Y Zhang, Y Huang, Y Yang, Y Zhao, S Chen, J Deng, W Li, B Han","doi":"10.1177/00220345241262706","DOIUrl":"10.1177/00220345241262706","url":null,"abstract":"<p><p>Alveolar bone (AB) remodeling, including formation and absorption, is the foundation of orthodontic tooth movement (OTM). However, the sources and mechanisms underlying new bone formation remain unclear. Therefore, we aimed to understand the potential mechanism of bone formation during OTM, focusing on the leptin receptor+ (Lepr+) osteogenitors and periodontal ligament cells (PDLCs). We demonstrated that Lepr+ cells activated by force-induced PDLC apoptosis served as distinct osteoprogenitors during orthodontic bone regeneration. We investigated bone formation both in vivo and in vitro. Single-cell RNA sequencing analysis and lineage tracing demonstrated that Lepr represents a subcluster of stem cells that are activated and differentiate into osteoblasts during OTM. Targeted ablation of Lepr+ cells in a mouse model disrupted orthodontic force-guided bone regeneration. Furthermore, apoptosis and sequential fluorescent labeling assays revealed that the apoptosis of PDLCs preceded new bone deposition. We found that PDL stem cell-derived apoptotic vesicles activated Lepr+ cells in vitro. Following apoptosis inhibition, orthodontic force-activated osteoprogenitors and osteogenesis were significantly downregulated. Notably, we found that bone formation occurred on the compression side during OTM; this has been first reported here. To conclude, we found a potential mechanism of bone formation during OTM that may provide new insights into AB regeneration.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"937-947"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241261982
K L Adeleye, A R Li, Y Xie, S Pochampally, D Hamilton, F Garcia-Godoy, D D Miller, W Li
Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.
{"title":"Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma.","authors":"K L Adeleye, A R Li, Y Xie, S Pochampally, D Hamilton, F Garcia-Godoy, D D Miller, W Li","doi":"10.1177/00220345241261982","DOIUrl":"10.1177/00220345241261982","url":null,"abstract":"<p><p>Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC<sub>50</sub> values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl</sup>/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"926-936"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241259954
F V Bitencourt, A Andersen, L Bjerg, A Sandbæk, H Li, G G Nascimento, R Spin-Neto, M A Peres, F R M Leite
Conflicting evidence suggests a link between diabetes-related microvascular complications and periodontitis. Reliable estimates have been hindered by small sample sizes and residual confounding. Moreover, the combined effects of microvascular complications and dyslipidemia on periodontitis have not been explored. Therefore, this study aimed to investigate the association between individual and combined diabetic microvascular complications (i.e., neuropathy and retinopathy) and moderate/severe periodontitis in a Danish population-based study. In addition, we assessed whether dyslipidemia modified these associations. This study comprised 15,922 participants with type 2 diabetes from the Health in Central Denmark study. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for individual and joint microvascular diabetes complications. The models adjusted for potential confounders, including sociodemographic factors, lifestyle behaviors, and health conditions. Inverse probability of treatment weighting (IPTW) balanced measured confounders between periodontitis and nonperiodontitis participants. Sensitivity analyses tested the findings' robustness by estimating E-values for unmeasured confounding and varying microvascular complication definitions. After IPTW, adjusted models revealed that diabetic neuropathy (OR 1.36, 95% CI 1.14 to 1.63) and retinopathy (OR 1.21, 95% CI 1.03 to 1.43) were significantly associated with moderate/severe periodontitis. Moreover, the coexistence of microvascular complications increased the odds 1.5-fold for moderate/severe periodontitis (OR 1.51, 95% CI 1.23 to 1.85). An effect modification of dyslipidemia on an additive scale was found, indicated by a positive relative excess risk due to interaction of 0.24 for neuropathy, 0.11 for retinopathy, and 0.44 for both complications. Sensitivity analysis ruled out unmeasured confounders and microvascular complication definitions as explanatory factors. Diabetic neuropathy and retinopathy, individually and combined, were associated with moderate/severe periodontitis. In addition, dyslipidemia had an additive positive effect modification on diabetic microvascular complications, elevating the odds of moderate/severe periodontitis. These findings may aid in identifying at-risk subgroups for diabetes-related microvascular complications and periodontitis, optimizing efforts to mitigate disease burden.
相互矛盾的证据表明,糖尿病相关微血管并发症与牙周炎之间存在联系。由于样本量小和残余混杂因素,可靠的估计结果受到阻碍。此外,尚未探讨微血管并发症和血脂异常对牙周炎的综合影响。因此,本研究旨在通过一项基于丹麦人群的研究,探讨糖尿病微血管并发症(即神经病变和视网膜病变)与中度/重度牙周炎之间的关联。此外,我们还评估了血脂异常是否会改变这些关联。这项研究包括丹麦中部健康研究中的 15,922 名 2 型糖尿病患者。我们采用多叉逻辑回归法估算了单个和联合微血管糖尿病并发症的几率比(OR)和 95% 置信区间(CI)。模型调整了潜在的混杂因素,包括社会人口因素、生活方式行为和健康状况。反向治疗概率加权(IPTW)平衡了牙周炎和非牙周炎参与者之间的测量混杂因素。敏感性分析通过估算未测量混杂因素的 E 值和不同的微血管并发症定义来检验研究结果的稳健性。IPTW调整后的模型显示,糖尿病神经病变(OR 1.36,95% CI 1.14-1.63)和视网膜病变(OR 1.21,95% CI 1.03-1.43)与中度/重度牙周炎显著相关。此外,同时存在微血管并发症会使中度/重度牙周炎的几率增加 1.5 倍(OR 1.51,95% CI 1.23 至 1.85)。研究还发现,血脂异常对并发症的影响具有叠加效应,神经病变、视网膜病变和两种并发症的交互作用导致的正向相对超额风险分别为 0.24、0.11 和 0.44。敏感性分析排除了作为解释因素的未测量混杂因素和微血管并发症定义。糖尿病神经病变和视网膜病变单独或合并与中度/重度牙周炎有关。此外,血脂异常对糖尿病微血管并发症也有叠加的积极影响,提高了中度/重度牙周炎的几率。这些发现有助于确定糖尿病相关微血管并发症和牙周炎的高危亚群,从而优化减轻疾病负担的工作。
{"title":"Periodontitis and Diabetes Complications: A Danish Population-Based Study.","authors":"F V Bitencourt, A Andersen, L Bjerg, A Sandbæk, H Li, G G Nascimento, R Spin-Neto, M A Peres, F R M Leite","doi":"10.1177/00220345241259954","DOIUrl":"10.1177/00220345241259954","url":null,"abstract":"<p><p>Conflicting evidence suggests a link between diabetes-related microvascular complications and periodontitis. Reliable estimates have been hindered by small sample sizes and residual confounding. Moreover, the combined effects of microvascular complications and dyslipidemia on periodontitis have not been explored. Therefore, this study aimed to investigate the association between individual and combined diabetic microvascular complications (i.e., neuropathy and retinopathy) and moderate/severe periodontitis in a Danish population-based study. In addition, we assessed whether dyslipidemia modified these associations. This study comprised 15,922 participants with type 2 diabetes from the Health in Central Denmark study. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for individual and joint microvascular diabetes complications. The models adjusted for potential confounders, including sociodemographic factors, lifestyle behaviors, and health conditions. Inverse probability of treatment weighting (IPTW) balanced measured confounders between periodontitis and nonperiodontitis participants. Sensitivity analyses tested the findings' robustness by estimating E-values for unmeasured confounding and varying microvascular complication definitions. After IPTW, adjusted models revealed that diabetic neuropathy (OR 1.36, 95% CI 1.14 to 1.63) and retinopathy (OR 1.21, 95% CI 1.03 to 1.43) were significantly associated with moderate/severe periodontitis. Moreover, the coexistence of microvascular complications increased the odds 1.5-fold for moderate/severe periodontitis (OR 1.51, 95% CI 1.23 to 1.85). An effect modification of dyslipidemia on an additive scale was found, indicated by a positive relative excess risk due to interaction of 0.24 for neuropathy, 0.11 for retinopathy, and 0.44 for both complications. Sensitivity analysis ruled out unmeasured confounders and microvascular complication definitions as explanatory factors. Diabetic neuropathy and retinopathy, individually and combined, were associated with moderate/severe periodontitis. In addition, dyslipidemia had an additive positive effect modification on diabetic microvascular complications, elevating the odds of moderate/severe periodontitis. These findings may aid in identifying at-risk subgroups for diabetes-related microvascular complications and periodontitis, optimizing efforts to mitigate disease burden.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"870-877"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-24DOI: 10.1177/00220345241257866
P Huang, R X Jiang, F Wang, W W Qiao, Y T Ji, L Y Meng, Z Bian
Located at the interface of the dentin-pulp complex, the odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis and the underlying mechanisms remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in healthy human third molars, mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. In addition, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in odontoblast-mediated reactionary dentinogenesis, mice with a conditional knockout of Piezo1 in odontoblasts were generated, and no significant differences in teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair by odontoblasts. In summary, these findings suggest that PIEZO1 enhances the mineralization capacity of hOBLCs in vitro via the Ca2+/PI3K-Akt/SEMA3A signaling pathway and contributes to reactionary dentinogenesis in vivo.
{"title":"PIEZO1 Promotes Odontoblast-Mediated Reactionary Dentinogenesis via SEMA3A.","authors":"P Huang, R X Jiang, F Wang, W W Qiao, Y T Ji, L Y Meng, Z Bian","doi":"10.1177/00220345241257866","DOIUrl":"10.1177/00220345241257866","url":null,"abstract":"<p><p>Located at the interface of the dentin-pulp complex, the odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis and the underlying mechanisms remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in healthy human third molars, mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca<sup>2+</sup>/PI3K-Akt/SEMA3A signaling pathway. In addition, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in <i>PIEZO1</i>-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in odontoblast-mediated reactionary dentinogenesis, mice with a conditional knockout of <i>Piezo1</i> in odontoblasts were generated, and no significant differences in teeth phenotypes were observed between the control and conditional knockout (<i>cKO</i>) mice. Nevertheless, <i>cKO</i> mice exhibited reduced reactionary dentin formation and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair by odontoblasts. In summary, these findings suggest that PIEZO1 enhances the mineralization capacity of hOBLCs in vitro via the Ca<sup>2+</sup>/PI3K-Akt/SEMA3A signaling pathway and contributes to reactionary dentinogenesis in vivo.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"889-898"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-31DOI: 10.1177/00220345241255593
F C Setzer, J Li, A A Khan
Endodontics is the dental specialty foremost concerned with diseases of the pulp and periradicular tissues. Clinicians often face patients with varying symptoms, must critically assess radiographic images in 2 and 3 dimensions, derive complex diagnoses and decision making, and deliver sophisticated treatment. Paired with low intra- and interobserver agreement for radiographic interpretation and variations in treatment outcome resulting from nonstandardized clinical techniques, there exists an unmet need for support in the form of artificial intelligence (AI), providing automated biomedical image analysis, decision support, and assistance during treatment. In the past decade, there has been a steady increase in AI studies in endodontics but limited clinical application. This review focuses on critically assessing the recent advancements in endodontic AI research for clinical applications, including the detection and diagnosis of endodontic pathologies such as periapical lesions, fractures and resorptions, as well as clinical treatment outcome predictions. It discusses the benefits of AI-assisted diagnosis, treatment planning and execution, and future directions including augmented reality and robotics. It critically reviews the limitations and challenges imposed by the nature of endodontic data sets, AI transparency and generalization, and potential ethical dilemmas. In the near future, AI will significantly affect the everyday endodontic workflow, education, and continuous learning.
{"title":"The Use of Artificial Intelligence in Endodontics.","authors":"F C Setzer, J Li, A A Khan","doi":"10.1177/00220345241255593","DOIUrl":"10.1177/00220345241255593","url":null,"abstract":"<p><p>Endodontics is the dental specialty foremost concerned with diseases of the pulp and periradicular tissues. Clinicians often face patients with varying symptoms, must critically assess radiographic images in 2 and 3 dimensions, derive complex diagnoses and decision making, and deliver sophisticated treatment. Paired with low intra- and interobserver agreement for radiographic interpretation and variations in treatment outcome resulting from nonstandardized clinical techniques, there exists an unmet need for support in the form of artificial intelligence (AI), providing automated biomedical image analysis, decision support, and assistance during treatment. In the past decade, there has been a steady increase in AI studies in endodontics but limited clinical application. This review focuses on critically assessing the recent advancements in endodontic AI research for clinical applications, including the detection and diagnosis of endodontic pathologies such as periapical lesions, fractures and resorptions, as well as clinical treatment outcome predictions. It discusses the benefits of AI-assisted diagnosis, treatment planning and execution, and future directions including augmented reality and robotics. It critically reviews the limitations and challenges imposed by the nature of endodontic data sets, AI transparency and generalization, and potential ethical dilemmas. In the near future, AI will significantly affect the everyday endodontic workflow, education, and continuous learning.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"853-862"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241258459
H S Schuch, M Furtado, A D P Chiavegatto Filho, H W Elani
In 2020, the Brazilian federal government launched the "Prevent Brazil" program to incentivize cities to improve their performance across 7 health care indicators, including prenatal dental care. Our study examines the impact of this policy on the use of oral health care among pregnant women in Brazil. We used a series of cross-sectional data from the Brazilian Public Health System from 2018 to 2023. We linked publicly available data from the Brazilian Ministry of Health and the Brazilian Institute of Geography and Statistics. Our outcome was the proportion of pregnant women receiving prenatal care who had at least 1 dental visit during the past year. Covariates included city-level socioeconomic (income and literacy), demographic (gender, race, and urban areas), and workforce variables (number of dentists working in the public health system per city/year). We estimated the impact of the policy on prenatal dental visits nationwide and stratified by geographic region using interrupted time-series analysis. Our analyses included 99.9% of all Brazilian cities (n = 5,562). The use of oral health care among pregnant women increased from 15% in 2018 to 69% in 2023. Adjusted estimates show that, after initiation of the Prevent Brazil, dental care use among pregnant women increased nationally at a rate of 4.6 percentage points per 4-mo period (95% confidence interval [CI] 4.5; 4.7). The policy's largest impact was in the North and Northeast regions, which have the lowest socioeconomic profiles (adjusted time-series rate 5.7 [95% CI 5.3; 6.1] and 5.2 [5.0; 5.4] percent points, respectively). Our findings support the positive impact of the Prevent Brazil policy on prenatal dental care in Brazil. The policy was associated with a countrywide improvement in prenatal dental care use, with a greater impact in socioeconomically disadvantaged regions.
{"title":"Changes in Use of Prenatal Dental Care After Brazil's Incentive Policy.","authors":"H S Schuch, M Furtado, A D P Chiavegatto Filho, H W Elani","doi":"10.1177/00220345241258459","DOIUrl":"10.1177/00220345241258459","url":null,"abstract":"<p><p>In 2020, the Brazilian federal government launched the \"Prevent Brazil\" program to incentivize cities to improve their performance across 7 health care indicators, including prenatal dental care. Our study examines the impact of this policy on the use of oral health care among pregnant women in Brazil. We used a series of cross-sectional data from the Brazilian Public Health System from 2018 to 2023. We linked publicly available data from the Brazilian Ministry of Health and the Brazilian Institute of Geography and Statistics. Our outcome was the proportion of pregnant women receiving prenatal care who had at least 1 dental visit during the past year. Covariates included city-level socioeconomic (income and literacy), demographic (gender, race, and urban areas), and workforce variables (number of dentists working in the public health system per city/year). We estimated the impact of the policy on prenatal dental visits nationwide and stratified by geographic region using interrupted time-series analysis. Our analyses included 99.9% of all Brazilian cities (<i>n</i> = 5,562). The use of oral health care among pregnant women increased from 15% in 2018 to 69% in 2023. Adjusted estimates show that, after initiation of the Prevent Brazil, dental care use among pregnant women increased nationally at a rate of 4.6 percentage points per 4-mo period (95% confidence interval [CI] 4.5; 4.7). The policy's largest impact was in the North and Northeast regions, which have the lowest socioeconomic profiles (adjusted time-series rate 5.7 [95% CI 5.3; 6.1] and 5.2 [5.0; 5.4] percent points, respectively). Our findings support the positive impact of the Prevent Brazil policy on prenatal dental care in Brazil. The policy was associated with a countrywide improvement in prenatal dental care use, with a greater impact in socioeconomically disadvantaged regions.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"863-869"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}