Pub Date : 2024-03-01DOI: 10.1177/00220345231219987
A L Altrieth, J Kenney, D A Nelson, E G Suarez, V Gellatly, S Gabunia, M Larsen
Vascular endothelial cells have important tissue-specific functions in fibrosis and regeneration. In the salivary gland, endothelial cells are required for proper development, but their roles within adult glands are largely unknown. To identify ligand-receptor interactions between endothelial cells and other cell types that may be important during fibrosis and regeneration, we used a reversible ductal ligation injury. To induce injury, a clip was applied to the primary ducts for 14 d, and to induce a regenerative response, the clip was subsequently removed for 5 d. To identify endothelial cell-produced factors, we used single-cell RNA sequencing of stromal-enriched cells from adult female submandibular and sublingual salivary glands. Transcriptional profiles of homeostatic salivary gland endothelial cells were compared to endothelial cells of other organs. Salivary gland endothelial cells expressed many unique genes and displayed the highest overlap in gene expression with other fenestrated endothelial cells from the colon, small intestine, and kidney. Comparison of the 14-d ligated, mock-ligated, and 5-d deligated stromal-enriched transcripts and lineage tracing revealed that endothelial cells retain their identity following ligation and recovery from injury. CellChat and NATMI were used to predict changes in ligand-receptor interactions from endothelial cells to other cells in response to ligation and deligation. CellChat and NATMI predicted that after ligation, interactions with fibroblasts, epithelial cells, and glial cells were increased, and following deligation, interactions with pericyte, glia, fibroblasts, and immune cells were increased. Some of the highest-ranked interactions predicted in ligated compared to mock endothelial cells were between glial cells via Col4a2-Cd93 and Jag2-Notch1, as well as epithelial cells via Pecam1-Cd38, while in deligated compared to ligated endothelial cells, the top interactions were between fibroblasts via Ntf3-Ntrk2, glial cells via Hspg2-Itgb1, and pericytes via Jam2-F11r. Understanding salivary gland endothelial cell signaling will inform future endothelial cell-based regenerative therapies.
{"title":"Single-Cell Transcriptomic Analysis of Salivary Gland Endothelial Cells.","authors":"A L Altrieth, J Kenney, D A Nelson, E G Suarez, V Gellatly, S Gabunia, M Larsen","doi":"10.1177/00220345231219987","DOIUrl":"10.1177/00220345231219987","url":null,"abstract":"<p><p>Vascular endothelial cells have important tissue-specific functions in fibrosis and regeneration. In the salivary gland, endothelial cells are required for proper development, but their roles within adult glands are largely unknown. To identify ligand-receptor interactions between endothelial cells and other cell types that may be important during fibrosis and regeneration, we used a reversible ductal ligation injury. To induce injury, a clip was applied to the primary ducts for 14 d, and to induce a regenerative response, the clip was subsequently removed for 5 d. To identify endothelial cell-produced factors, we used single-cell RNA sequencing of stromal-enriched cells from adult female submandibular and sublingual salivary glands. Transcriptional profiles of homeostatic salivary gland endothelial cells were compared to endothelial cells of other organs. Salivary gland endothelial cells expressed many unique genes and displayed the highest overlap in gene expression with other fenestrated endothelial cells from the colon, small intestine, and kidney. Comparison of the 14-d ligated, mock-ligated, and 5-d deligated stromal-enriched transcripts and lineage tracing revealed that endothelial cells retain their identity following ligation and recovery from injury. CellChat and NATMI were used to predict changes in ligand-receptor interactions from endothelial cells to other cells in response to ligation and deligation. CellChat and NATMI predicted that after ligation, interactions with fibroblasts, epithelial cells, and glial cells were increased, and following deligation, interactions with pericyte, glia, fibroblasts, and immune cells were increased. Some of the highest-ranked interactions predicted in ligated compared to mock endothelial cells were between glial cells via <i>Col4a2-Cd93</i> and <i>Jag2-Notch1</i>, as well as epithelial cells via <i>Pecam1-Cd38</i>, while in deligated compared to ligated endothelial cells, the top interactions were between fibroblasts via <i>Ntf3-Ntrk2</i>, glial cells via <i>Hspg2-Itgb1</i>, and pericytes via <i>Jam2-F11r</i>. Understanding salivary gland endothelial cell signaling will inform future endothelial cell-based regenerative therapies.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":"103 3","pages":"269-278"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975062","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 : 2024-03-01Epub Date: 2024-01-07DOI: 10.1177/00220345231216660
N Zayed, H Munjaković, M K Aktan, K Simoens, K Bernaerts, N Boon, A Braem, F Pamuk, M Saghi, W Van Holm, A Fidler, R Gašperšič, W Teughels
Preventing the development and recurrence of periodontal diseases often includes antimicrobial mouthrinses to control the growth of the periodontal pathogens. Most antimicrobials are nonselective, targeting the symbiotic oral species as well as the dysbiosis-inducing ones. This affects the overall microbial composition and metabolic activity and consequently the host-microbe interactions, which can be detrimental (associated with inflammation) or beneficial (health-associated). Consequently, guiding the antimicrobial effect for modulating the microbial composition to a health-associated one should be considered. For such an approach, this study investigated electrolyzed saline as a novel rinse. Electrolyzed saline was prepared from sterile saline using a portable electrolysis device. Multispecies oral homeostatic and dysbiotic biofilms were grown on hydroxyapatite discs and rinsed daily with electrolyzed saline (EOS). Corresponding positive (NaOCl) and negative (phosphate-buffered saline) controls were included. After 3 rinses, biofilms were analyzed with viability quantitative polymerase chain reaction and scanning electron microscopy. Supernatants of rinsed biofilms were used for metabolic activity analysis (high-performance liquid chromatography) through measuring organic acid content. In addition, human oral keratinocytes (HOKs) were exposed to EOS to test biocompatibility (cytotoxicity and inflammation induction) and also to rinsed biofilms to assess their immunogenicity after rinsing. Rinsing the dysbiotic biofilms with EOS could reduce the counts of the pathobionts (>3 log10 Geq/mm2 reduction) and avert biofilm dysbiosis (≤1% pathobiont abundance), leading to the dominance of commensal species (≥99%), which altered both biofilm metabolism and interleukin 8 (IL-8) induction in HOKs. EOS had no harmful effects on homeostatic biofilms. The scanning electron micrographs confirmed the same. In addition, tested concentrations of EOS did not have any cytotoxic effects and did not induce IL-8 production in HOKs. EOS showed promising results for diverting dysbiosis in in vitro rinsed biofilms and controlling key periopathogens, with no toxic effects on commensal species or human cells. This novel rinsing should be considered for clinical applications.
预防牙周疾病的发生和复发通常包括使用抗菌漱口水来控制牙周病原体的生长。大多数抗菌剂都是非选择性的,既针对口腔共生菌种,也针对引起菌群失调的菌种。这会影响整体微生物组成和代谢活动,进而影响宿主与微生物之间的相互作用,这种相互作用可能是有害的(与炎症有关),也可能是有益的(与健康有关)。因此,应考虑引导抗菌效果,将微生物组成调整为有益健康。为此,本研究将电解生理盐水作为一种新型冲洗剂进行了研究。电解生理盐水是使用便携式电解装置从无菌生理盐水中制备出来的。在羟基磷灰石圆片上培养多菌种口腔同源生物膜和菌群失调生物膜,每天用电解生理盐水(EOS)冲洗。同时还包括相应的阳性(NaOCl)和阴性(磷酸盐缓冲盐水)对照组。冲洗 3 次后,用活力定量聚合酶链反应和扫描电子显微镜分析生物膜。冲洗后的生物膜上清液用于代谢活性分析(高效液相色谱法),测量有机酸含量。此外,还将人类口腔角质细胞(HOKs)暴露于 EOS,以测试其生物相容性(细胞毒性和炎症诱导),并将其暴露于冲洗后的生物膜,以评估其冲洗后的免疫原性。用 EOS 冲洗菌群失调的生物膜可减少病原菌的数量(减少量大于 3 log10 Geq/mm2),并避免生物膜菌群失调(病原菌丰度≤1%),从而使共生菌占优势(≥99%),这改变了 HOK 的生物膜代谢和白细胞介素 8(IL-8)诱导。EOS 对同源生物膜没有有害影响。扫描电子显微照也证实了这一点。此外,测试浓度的 EOS 没有任何细胞毒性作用,也不会诱导 HOK 产生 IL-8。EOS 在转移体外冲洗生物膜中的菌群失调和控制主要围病原体方面显示出良好的效果,而且对共生物种或人类细胞无毒性影响。应考虑将这种新型冲洗方法应用于临床。
{"title":"Electrolyzed Saline Targets Biofilm Periodontal Pathogens In Vitro.","authors":"N Zayed, H Munjaković, M K Aktan, K Simoens, K Bernaerts, N Boon, A Braem, F Pamuk, M Saghi, W Van Holm, A Fidler, R Gašperšič, W Teughels","doi":"10.1177/00220345231216660","DOIUrl":"10.1177/00220345231216660","url":null,"abstract":"<p><p>Preventing the development and recurrence of periodontal diseases often includes antimicrobial mouthrinses to control the growth of the periodontal pathogens. Most antimicrobials are nonselective, targeting the symbiotic oral species as well as the dysbiosis-inducing ones. This affects the overall microbial composition and metabolic activity and consequently the host-microbe interactions, which can be detrimental (associated with inflammation) or beneficial (health-associated). Consequently, guiding the antimicrobial effect for modulating the microbial composition to a health-associated one should be considered. For such an approach, this study investigated electrolyzed saline as a novel rinse. Electrolyzed saline was prepared from sterile saline using a portable electrolysis device. Multispecies oral homeostatic and dysbiotic biofilms were grown on hydroxyapatite discs and rinsed daily with electrolyzed saline (EOS). Corresponding positive (NaOCl) and negative (phosphate-buffered saline) controls were included. After 3 rinses, biofilms were analyzed with viability quantitative polymerase chain reaction and scanning electron microscopy. Supernatants of rinsed biofilms were used for metabolic activity analysis (high-performance liquid chromatography) through measuring organic acid content. In addition, human oral keratinocytes (HOKs) were exposed to EOS to test biocompatibility (cytotoxicity and inflammation induction) and also to rinsed biofilms to assess their immunogenicity after rinsing. Rinsing the dysbiotic biofilms with EOS could reduce the counts of the pathobionts (>3 log<sub>10</sub> Geq/mm<sup>2</sup> reduction) and avert biofilm dysbiosis (≤1% pathobiont abundance), leading to the dominance of commensal species (≥99%), which altered both biofilm metabolism and interleukin 8 (IL-8) induction in HOKs. EOS had no harmful effects on homeostatic biofilms. The scanning electron micrographs confirmed the same. In addition, tested concentrations of EOS did not have any cytotoxic effects and did not induce IL-8 production in HOKs. EOS showed promising results for diverting dysbiosis in in vitro rinsed biofilms and controlling key periopathogens, with no toxic effects on commensal species or human cells. This novel rinsing should be considered for clinical applications.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"243-252"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139379043","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 : 2024-03-01Epub Date: 2024-02-12DOI: 10.1177/00220345231222181
K Pandi, S Angabo, H Makkawi, H Benyamini, S Elgavish, G Nussbaum
Porphyromonas gingivalis is a Gram-negative anaerobic bacterium strongly associated with periodontal disease. Toll-like receptor 2 (TLR2) is indispensable for the host response to P. gingivalis, but P. gingivalis escapes from immune clearance via TLR2-dependent activation of phosphoinositide-3-kinase (PI3K). To probe the TLR2-dependent escape pathway of P. gingivalis, we analyzed the TLR2 interactome induced following P. gingivalis infection or activation by a synthetic lipopeptide TLR2/1 agonist on human macrophages overexpressing TLR2. Interacting proteins were stabilized by cross-linking and then immunoprecipitated and analyzed by mass spectrometry. In total, 792 proteins were recovered and network analysis enabled mapping of the TLR2 interactome at baseline and in response to infection. The P. gingivalis infection-induced TLR2 interactome included the poly (ADP-ribose) polymerase family member mono-ADP-ribosyltransferase protein 9 (PARP9) and additional members of the PARP9 complex (DTX3L and NMI). PARP9 and its complex members are highly upregulated in macrophages exposed to P. gingivalis or to the synthetic TLR2/1 ligand Pam3Cys-Ser-(Lys)4 (PAM). Consistent with its known role in virally induced interferon production, PARP9 knockdown blocked type I interferon (IFN-I) production in response to P. gingivalis and reduced inflammatory cytokine production. We found that P. gingivalis drives signal transducer and activation of transcription (STAT) 1 (S727) phosphorylation through TLR2-PARP9, explaining PARP9's role in the induction of IFN-I downstream of TLR2. Furthermore, PARP9 knockdown reduced PI3K activation by P. gingivalis, leading to improved macrophage bactericidal activity. In summary, PARP9 is a novel TLR2 interacting partner that enables IFN-I induction and P. gingivalis immune escape in macrophages downstream of TLR2 sensing.
{"title":"<i>P. gingivalis</i>-Induced TLR2 Interactome Analysis Reveals Association with PARP9.","authors":"K Pandi, S Angabo, H Makkawi, H Benyamini, S Elgavish, G Nussbaum","doi":"10.1177/00220345231222181","DOIUrl":"10.1177/00220345231222181","url":null,"abstract":"<p><p><i>Porphyromonas gingivalis</i> is a Gram-negative anaerobic bacterium strongly associated with periodontal disease. Toll-like receptor 2 (TLR2) is indispensable for the host response to <i>P. gingivalis</i>, but <i>P. gingivalis</i> escapes from immune clearance via TLR2-dependent activation of phosphoinositide-3-kinase (PI3K). To probe the TLR2-dependent escape pathway of <i>P. gingivalis</i>, we analyzed the TLR2 interactome induced following <i>P. gingivalis</i> infection or activation by a synthetic lipopeptide TLR2/1 agonist on human macrophages overexpressing TLR2. Interacting proteins were stabilized by cross-linking and then immunoprecipitated and analyzed by mass spectrometry. In total, 792 proteins were recovered and network analysis enabled mapping of the TLR2 interactome at baseline and in response to infection. The <i>P. gingivalis</i> infection-induced TLR2 interactome included the poly (ADP-ribose) polymerase family member mono-ADP-ribosyltransferase protein 9 (PARP9) and additional members of the PARP9 complex (DTX3L and NMI). PARP9 and its complex members are highly upregulated in macrophages exposed to <i>P. gingivalis</i> or to the synthetic TLR2/1 ligand Pam<sub>3</sub>Cys-Ser-(Lys)<sub>4</sub> (PAM). Consistent with its known role in virally induced interferon production, PARP9 knockdown blocked type I interferon (IFN-I) production in response to <i>P. gingivalis</i> and reduced inflammatory cytokine production. We found that <i>P. gingivalis</i> drives signal transducer and activation of transcription (STAT) 1 (S727) phosphorylation through TLR2-PARP9, explaining PARP9's role in the induction of IFN-I downstream of TLR2. Furthermore, PARP9 knockdown reduced PI3K activation by <i>P. gingivalis</i>, leading to improved macrophage bactericidal activity. In summary, PARP9 is a novel TLR2 interacting partner that enables IFN-I induction and <i>P. gingivalis</i> immune escape in macrophages downstream of TLR2 sensing.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"329-338"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139725480","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 : 2024-03-01Epub Date: 2024-01-29DOI: 10.1177/00220345231220915
Y Deng, Q Li, K K H Svoboda, L A Opperman, L B Ruest, X Liu
Periodontal mesenchymal stem cells (MSCs) play a crucial role in maintaining periodontium homeostasis and in tissue repair. However, little is known about how periodontal MSCs in vivo respond under periodontal disease conditions, posing a challenge for periodontium tissue regeneration. In this study, Gli1 was used as a periodontal MSC marker and combined with a Gli1-cre ERT2 mouse model for lineage tracing to investigate periodontal MSC fate in an induced periodontitis model. Our findings show significant changes in the number and contribution of Gli1+ MSCs within the inflamed periodontium. The number of Gli1+ MSCs that contributed to periodontal ligament homeostasis decreased in the periodontitis-induced teeth. While the proliferation of Gli1+ MSCs had no significant difference between the periodontitis and the control groups, more Gli1+ MSCs underwent apoptosis in diseased teeth. In addition, the number of Gli1+ MSCs for osteogenic differentiation decreased during the progression of periodontitis. Following tooth extraction, the contribution of Gli1+ MSCs to the tooth socket repair was significantly reduced in the periodontitis-induced teeth. Collectively, these findings indicate that the function of Gli1+ MSCs in periodontitis was compromised, including reduced contribution to periodontium homeostasis and impaired injury response.
{"title":"Gli1<sup>+</sup> Periodontal Mesenchymal Stem Cells in Periodontitis.","authors":"Y Deng, Q Li, K K H Svoboda, L A Opperman, L B Ruest, X Liu","doi":"10.1177/00220345231220915","DOIUrl":"10.1177/00220345231220915","url":null,"abstract":"<p><p>Periodontal mesenchymal stem cells (MSCs) play a crucial role in maintaining periodontium homeostasis and in tissue repair. However, little is known about how periodontal MSCs in vivo respond under periodontal disease conditions, posing a challenge for periodontium tissue regeneration. In this study, Gli1 was used as a periodontal MSC marker and combined with a Gli1-cre ERT2 mouse model for lineage tracing to investigate periodontal MSC fate in an induced periodontitis model. Our findings show significant changes in the number and contribution of Gli1<sup>+</sup> MSCs within the inflamed periodontium. The number of Gli1<sup>+</sup> MSCs that contributed to periodontal ligament homeostasis decreased in the periodontitis-induced teeth. While the proliferation of Gli1<sup>+</sup> MSCs had no significant difference between the periodontitis and the control groups, more Gli1<sup>+</sup> MSCs underwent apoptosis in diseased teeth. In addition, the number of Gli1<sup>+</sup> MSCs for osteogenic differentiation decreased during the progression of periodontitis. Following tooth extraction, the contribution of Gli1<sup>+</sup> MSCs to the tooth socket repair was significantly reduced in the periodontitis-induced teeth. Collectively, these findings indicate that the function of Gli1<sup>+</sup> MSCs in periodontitis was compromised, including reduced contribution to periodontium homeostasis and impaired injury response.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"279-288"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572352","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 : 2024-03-01Epub Date: 2024-01-10DOI: 10.1177/00220345231221712
S L Fu, Y Y Qian, A N Dai, H Y Li, X H Jin, W T He, S Kang, P H Ding
Periodontitis (PD) is the primary cause of tooth loss in adults. Porphyromonas gingivalis (P.g), a keystone pathogen, has been identified as a crucial contributor to this process. Pyroptosis activation in PD is acknowledged, with accumulating evidence underscoring the crucial role of Caspase-11 (described as Caspase-4/5 in humans)-mediated noncanonical pyroptosis. However, the mechanism behind its impact on PD remains unclear. In this study, we delved into the interplay between the Caspase-11-mediated noncanonical pyroptosis, subgingival microbiota alteration, and macrophage polarization. Clinical samples from PD patients revealed heightened expression of Caspase-4, gasdermin-D, and their active fragments, pointing to the activation of the noncanonical pyroptosis. Single-cell sequencing analysis linked Caspase-4 with gingival macrophages, emphasizing their involvement in PD. In vitro cell experiments confirmed that P.g-induced pyroptosis was activated in macrophages, with Casp11 deficiency attenuating these effects. In an experimental PD mouse model, Casp11 deficiency led to an alteration in subgingival microbiota composition and reduced alveolar bone resorption. Casp11-/- mice cohousing with wild-type mice confirmed the alteration of the subgingival microbiota and aggravated the alveolar bone resorption. Notably, Casp11 deficiency led to decreased M1-polarized macrophages, corresponding with reduced alveolar bone resorption, uncovering a connection between subgingival microbiota alteration, macrophage M1 polarization, and alveolar bone resorption. Taken together, we showed that Caspase-11 fulfilled a crucial role in the noncanonical pyroptosis in PD, potentially influencing the subgingival microbiota and linking to M1 polarization, which was associated with alveolar bone resorption. These findings underscored the pivotal role of the Caspase-11-mediated noncanonical pyroptosis in PD pathogenesis and may provide critical insights into potential therapeutic avenues for mitigating PD.
{"title":"<i>Casp11</i> Deficiency Alters Subgingival Microbiota and Attenuates Periodontitis.","authors":"S L Fu, Y Y Qian, A N Dai, H Y Li, X H Jin, W T He, S Kang, P H Ding","doi":"10.1177/00220345231221712","DOIUrl":"10.1177/00220345231221712","url":null,"abstract":"<p><p>Periodontitis (PD) is the primary cause of tooth loss in adults. <i>Porphyromonas gingivalis</i> (<i>P.g</i>), a keystone pathogen, has been identified as a crucial contributor to this process. Pyroptosis activation in PD is acknowledged, with accumulating evidence underscoring the crucial role of Caspase-11 (described as Caspase-4/5 in humans)-mediated noncanonical pyroptosis. However, the mechanism behind its impact on PD remains unclear. In this study, we delved into the interplay between the Caspase-11-mediated noncanonical pyroptosis, subgingival microbiota alteration, and macrophage polarization. Clinical samples from PD patients revealed heightened expression of Caspase-4, gasdermin-D, and their active fragments, pointing to the activation of the noncanonical pyroptosis. Single-cell sequencing analysis linked Caspase-4 with gingival macrophages, emphasizing their involvement in PD. In vitro cell experiments confirmed that <i>P.g</i>-induced pyroptosis was activated in macrophages, with <i>Casp11</i> deficiency attenuating these effects. In an experimental PD mouse model, <i>Casp11</i> deficiency led to an alteration in subgingival microbiota composition and reduced alveolar bone resorption. <i>Casp11</i><sup><i>-/-</i></sup> mice cohousing with wild-type mice confirmed the alteration of the subgingival microbiota and aggravated the alveolar bone resorption. Notably, <i>Casp11</i> deficiency led to decreased M1-polarized macrophages, corresponding with reduced alveolar bone resorption, uncovering a connection between subgingival microbiota alteration, macrophage M1 polarization, and alveolar bone resorption. Taken together, we showed that Caspase-11 fulfilled a crucial role in the noncanonical pyroptosis in PD, potentially influencing the subgingival microbiota and linking to M1 polarization, which was associated with alveolar bone resorption. These findings underscored the pivotal role of the Caspase-11-mediated noncanonical pyroptosis in PD pathogenesis and may provide critical insights into potential therapeutic avenues for mitigating PD.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"298-307"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139405726","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 : 2024-03-01Epub Date: 2023-11-01DOI: 10.1177/00220345231200814
V Chrepa, S Villasenor, A Mauney, G Kotsakis, L Macpherson
Odontogenic pain can be debilitating, and nonopioid analgesic options are limited. This randomized placebo-controlled clinical trial aimed to assess the effectiveness and safety of cannabidiol (CBD) as an analgesic for patients with emergency acute dental pain. Sixty-one patients with moderate to severe toothache were randomized into 3 groups: CBD10 (CBD 10 mg/kg), CBD20 (CBD 20 mg/kg), and placebo. We administered a single dose of respective oral solution and monitored the subjects for 3 h. The primary outcome measure was the numerical pain differences using a visual analog scale (VAS) from baseline within and among the groups. Secondary outcome measures included ordinal pain intensity differences, the onset of significant pain relief, maximum pain relief, changes in bite force within and among the groups, psychoactive effects, mood changes, and other adverse events. Both CBD groups resulted in significant VAS pain reduction compared to their baseline and the placebo group, with a maximum median VAS pain reduction of 73% from baseline pain at the 180-min time point (P < 0.05). CBD20 experienced a faster onset of significant pain relief than CBD10 (15 versus 30 min after drug administration), and both groups reached maximum pain relief at 180-min. Number needed to treat was 3.1 for CBD10 and 2.4 for CBD20. Intragroup comparisons showed a significant increase in bite forces in both CBD groups (P < 0.05) but not in the placebo group (P > 0.05). CBD20 resulted in a significant difference in mean percent bite force change in the 90- and 180-min time points compared to the placebo group (P < 0.05). Compared to placebo, sedation, diarrhea, and abdominal pain were significantly associated with the CBD groups (P < 0.05). There were no other significant psychoactive or mood change effects. This randomized trial provides the first clinical evidence that oral CBD can be an effective and safe analgesic for dental pain.
{"title":"Cannabidiol as an Alternative Analgesic for Acute Dental Pain.","authors":"V Chrepa, S Villasenor, A Mauney, G Kotsakis, L Macpherson","doi":"10.1177/00220345231200814","DOIUrl":"10.1177/00220345231200814","url":null,"abstract":"<p><p>Odontogenic pain can be debilitating, and nonopioid analgesic options are limited. This randomized placebo-controlled clinical trial aimed to assess the effectiveness and safety of cannabidiol (CBD) as an analgesic for patients with emergency acute dental pain. Sixty-one patients with moderate to severe toothache were randomized into 3 groups: CBD10 (CBD 10 mg/kg), CBD20 (CBD 20 mg/kg), and placebo. We administered a single dose of respective oral solution and monitored the subjects for 3 h. The primary outcome measure was the numerical pain differences using a visual analog scale (VAS) from baseline within and among the groups. Secondary outcome measures included ordinal pain intensity differences, the onset of significant pain relief, maximum pain relief, changes in bite force within and among the groups, psychoactive effects, mood changes, and other adverse events. Both CBD groups resulted in significant VAS pain reduction compared to their baseline and the placebo group, with a maximum median VAS pain reduction of 73% from baseline pain at the 180-min time point (<i>P</i> < 0.05). CBD20 experienced a faster onset of significant pain relief than CBD10 (15 versus 30 min after drug administration), and both groups reached maximum pain relief at 180-min. Number needed to treat was 3.1 for CBD10 and 2.4 for CBD20. Intragroup comparisons showed a significant increase in bite forces in both CBD groups (<i>P</i> < 0.05) but not in the placebo group (<i>P</i> > 0.05). CBD20 resulted in a significant difference in mean percent bite force change in the 90- and 180-min time points compared to the placebo group (<i>P</i> < 0.05). Compared to placebo, sedation, diarrhea, and abdominal pain were significantly associated with the CBD groups (<i>P</i> < 0.05). There were no other significant psychoactive or mood change effects. This randomized trial provides the first clinical evidence that oral CBD can be an effective and safe analgesic for dental pain.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"235-242"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430538","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 : 2024-03-01Epub Date: 2024-02-12DOI: 10.1177/00220345231223691
K N Theken, E V Hersh
{"title":"Cannabidiol for Toothache: Ups, Downs, and Regulatory Considerations.","authors":"K N Theken, E V Hersh","doi":"10.1177/00220345231223691","DOIUrl":"10.1177/00220345231223691","url":null,"abstract":"","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"225-226"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139725481","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 : 2024-03-01Epub Date: 2024-01-09DOI: 10.1177/00220345231221709
E Buetas, M Jordán-López, A López-Roldán, A Mira, M Carda-Diéguez
Colorectal cancer (CRC) and periodontitis have recently been related due to the higher incidence of CRC in periodontal patients and the involvement of periodontal pathogens in carcinogenesis, suggesting that leakage from the oral cavity to the gut occurs. However, the magnitude of this pass-through in healthy individuals is controversial, and the effect that periodontitis could play in it is understudied. To evaluate the rate of bacterial leakage from the oral cavity to the gut, we analyzed the microbial composition of saliva, subgingival plaque, and fecal samples in healthy individuals without gastrointestinal disorders, including 20 periodontitis patients and 20 oral healthy controls, using PacBio full-length 16S rRNA gene sequencing. As expected, we observed a higher abundance of periodontal pathogens in the subgingival plaque and saliva of periodontal patients. In contrast, no significant differences were found between the fecal samples of both groups, implying that gut samples from periodontal patients were not enriched in periodontal pathogens. Fusobacterium nucleatum, a biomarker of CRC, was not found in the fecal samples of any participant. Our study does show a small leakage of some oral bacteria (mainly streptococci) to the gut, regardless of periodontal health status. Future studies should test whether other host factors and/or the preexistence of a gut disorder must be present in addition to periodontitis to promote the colonization of the gut by oral pathogens. The absence of periodontal pathogens in feces supports the idea that these bacteria could be used as biomarkers of intestinal disorders, including CRC.
{"title":"Impact of Periodontitis on the Leakage of Oral Bacteria to the Gut.","authors":"E Buetas, M Jordán-López, A López-Roldán, A Mira, M Carda-Diéguez","doi":"10.1177/00220345231221709","DOIUrl":"10.1177/00220345231221709","url":null,"abstract":"<p><p>Colorectal cancer (CRC) and periodontitis have recently been related due to the higher incidence of CRC in periodontal patients and the involvement of periodontal pathogens in carcinogenesis, suggesting that leakage from the oral cavity to the gut occurs. However, the magnitude of this pass-through in healthy individuals is controversial, and the effect that periodontitis could play in it is understudied. To evaluate the rate of bacterial leakage from the oral cavity to the gut, we analyzed the microbial composition of saliva, subgingival plaque, and fecal samples in healthy individuals without gastrointestinal disorders, including 20 periodontitis patients and 20 oral healthy controls, using PacBio full-length 16S rRNA gene sequencing. As expected, we observed a higher abundance of periodontal pathogens in the subgingival plaque and saliva of periodontal patients. In contrast, no significant differences were found between the fecal samples of both groups, implying that gut samples from periodontal patients were not enriched in periodontal pathogens. <i>Fusobacterium nucleatum</i>, a biomarker of CRC, was not found in the fecal samples of any participant. Our study does show a small leakage of some oral bacteria (mainly streptococci) to the gut, regardless of periodontal health status. Future studies should test whether other host factors and/or the preexistence of a gut disorder must be present in addition to periodontitis to promote the colonization of the gut by oral pathogens. The absence of periodontal pathogens in feces supports the idea that these bacteria could be used as biomarkers of intestinal disorders, including CRC.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"289-297"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139405728","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 : 2024-03-01Epub Date: 2024-01-10DOI: 10.1177/00220345231217402
Y Huang, R Ge, J Qian, J Lu, D Qiao, R Chen, H Jiang, D Cui, T Zhang, N Wang, S He, M Wang, F Yan
Periodontal bone regeneration remains a clinical challenge, and hyperlipidemia can aggravate alveolar bone resorption. Probiotics have recently been reported to improve bone mass. We aimed to determine the role of Lacticaseibacillus rhamnosus GG (LGG) in periodontal bone regeneration improvement within the context of periodontitis with hyperlipidemia. A Sprague Dawley rat model for periodontitis, hyperlipidemia, and periodontal fenestration defect was constructed (n = 36) and administered LGG gavage for 6 wk (the rats were subsequently sacrificed). Fecal microbiota from donor rats 3 wk after LGG gavage was transplanted into recipient rats to evaluate the role of LGG-modulated gut microbiota in periodontal bone regeneration. Regenerated bone mass was detected using micro-computerized tomography and hematoxylin and eosin stain. Gut microbiota was analyzed using 16S ribosomal RNA sequencing. Serum metabolites were detected by liquid chromatography-mass spectrometry (6 wk after LGG gavage). The pro-osteogenic effects of screened serum metabolite were verified in vitro on bone marrow mesenchymal stem cells (BMMSCs). We found that the bone mineral density, bone volume (BV), trabecular bone volume fraction (BV/TV), and trabecular thickness of the regenerated periodontal bone increased after LGG gavage (P < 0.05) but had little effect on oral flora. After LGG gavage, Staphylococcus, Corynebacterium, and Collinsella in the gut of donors were significantly changed, and these differences were maintained in recipients, who also showed increased trabecular thickness of the regenerated periodontal bone (P < 0.05). These key genera were correlated with BV/TV and BV (P < 0.05). In addition, LGG gavage significantly regulated bone-related blood metabolites, of which selenomethionine promoted BMMSC osteogenesis. Notably, selenomethionine was associated with key gut genera (P < 0.05). Collectively, LGG improved periodontal bone regeneration in the context of periodontitis with hyperlipidemia by modulating gut microbiota and increasing pro-osteogenic metabolites in the blood. These results reveal new insights into the use of probiotics to promote periodontal bone regeneration via the gut-blood-bone axis.
{"title":"Lacticaseibacillus rhamnosus GG Improves Periodontal Bone Repair via Gut-Blood Axis in Hyperlipidemia.","authors":"Y Huang, R Ge, J Qian, J Lu, D Qiao, R Chen, H Jiang, D Cui, T Zhang, N Wang, S He, M Wang, F Yan","doi":"10.1177/00220345231217402","DOIUrl":"10.1177/00220345231217402","url":null,"abstract":"<p><p>Periodontal bone regeneration remains a clinical challenge, and hyperlipidemia can aggravate alveolar bone resorption. Probiotics have recently been reported to improve bone mass. We aimed to determine the role of <i>Lacticaseibacillus rhamnosus</i> GG (LGG) in periodontal bone regeneration improvement within the context of periodontitis with hyperlipidemia. A Sprague Dawley rat model for periodontitis, hyperlipidemia, and periodontal fenestration defect was constructed (<i>n</i> = 36) and administered LGG gavage for 6 wk (the rats were subsequently sacrificed). Fecal microbiota from donor rats 3 wk after LGG gavage was transplanted into recipient rats to evaluate the role of LGG-modulated gut microbiota in periodontal bone regeneration. Regenerated bone mass was detected using micro-computerized tomography and hematoxylin and eosin stain. Gut microbiota was analyzed using 16S ribosomal RNA sequencing. Serum metabolites were detected by liquid chromatography-mass spectrometry (6 wk after LGG gavage). The pro-osteogenic effects of screened serum metabolite were verified in vitro on bone marrow mesenchymal stem cells (BMMSCs). We found that the bone mineral density, bone volume (BV), trabecular bone volume fraction (BV/TV), and trabecular thickness of the regenerated periodontal bone increased after LGG gavage (<i>P</i> < 0.05) but had little effect on oral flora. After LGG gavage, <i>Staphylococcus</i>, <i>Corynebacterium</i>, and <i>Collinsella</i> in the gut of donors were significantly changed, and these differences were maintained in recipients, who also showed increased trabecular thickness of the regenerated periodontal bone (<i>P</i> < 0.05). These key genera were correlated with BV/TV and BV (<i>P</i> < 0.05). In addition, LGG gavage significantly regulated bone-related blood metabolites, of which selenomethionine promoted BMMSC osteogenesis. Notably, selenomethionine was associated with key gut genera (<i>P</i> < 0.05). Collectively, LGG improved periodontal bone regeneration in the context of periodontitis with hyperlipidemia by modulating gut microbiota and increasing pro-osteogenic metabolites in the blood. These results reveal new insights into the use of probiotics to promote periodontal bone regeneration via the gut-blood-bone axis.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"253-262"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139405729","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 : 2024-03-01Epub Date: 2024-01-29DOI: 10.1177/00220345231218903
S L Reckelkamm, Z Alayash, B Holtfreter, M Nolde, S E Baumeister
Epidemiological studies have consistently shown that Sjögren's disease (SjD) increases the risk of dental caries. Despite similar evidence indicating an elevated risk of periodontitis, SjD remains a disputed risk factor for this disease. The risk of bias in observational research is a major impediment to confirming this link. Within an instrumental variable framework, genetic variants associated with a risk factor can be used to proxy its effect on an outcome while avoiding common sources of observational study bias. In this study, we leveraged an instrumental variable approach to investigate whether SjD affects the risk of caries and periodontitis. A total of 57 genetic variants strongly associated with SjD were identified from a genome-wide association study of 2,247 European descent cases and 332,115 controls. We tested for associations of these genetic instruments with caries (measured as the number of decayed, missing, and filled surfaces in 26,792 individuals) and periodontitis (17,353 clinical periodontitis cases and 28,210 European controls). Several sensitivity analyses were used to further validate the primary inverse variance weighted (IVW) estimate. IVW analysis revealed an adverse effect of SjD on caries (β = 0.039, P = 6.3e-16) and periodontitis (odds ratio = 1.033, P = 2.3e-05). Sensitivity analyses, conducted to assess the robustness to potential violations of instrumental variable assumptions, further support these findings. Our results showed that SjD has a detrimental effect on caries and also suggest that SjD promotes periodontitis.
{"title":"Sjögren's Disease and Oral Health: A Genetic Instrumental Variable Analysis.","authors":"S L Reckelkamm, Z Alayash, B Holtfreter, M Nolde, S E Baumeister","doi":"10.1177/00220345231218903","DOIUrl":"10.1177/00220345231218903","url":null,"abstract":"<p><p>Epidemiological studies have consistently shown that Sjögren's disease (SjD) increases the risk of dental caries. Despite similar evidence indicating an elevated risk of periodontitis, SjD remains a disputed risk factor for this disease. The risk of bias in observational research is a major impediment to confirming this link. Within an instrumental variable framework, genetic variants associated with a risk factor can be used to proxy its effect on an outcome while avoiding common sources of observational study bias. In this study, we leveraged an instrumental variable approach to investigate whether SjD affects the risk of caries and periodontitis. A total of 57 genetic variants strongly associated with SjD were identified from a genome-wide association study of 2,247 European descent cases and 332,115 controls. We tested for associations of these genetic instruments with caries (measured as the number of decayed, missing, and filled surfaces in 26,792 individuals) and periodontitis (17,353 clinical periodontitis cases and 28,210 European controls). Several sensitivity analyses were used to further validate the primary inverse variance weighted (IVW) estimate. IVW analysis revealed an adverse effect of SjD on caries (β = 0.039, <i>P</i> = 6.3e-16) and periodontitis (odds ratio = 1.033, <i>P</i> = 2.3e-05). Sensitivity analyses, conducted to assess the robustness to potential violations of instrumental variable assumptions, further support these findings. Our results showed that SjD has a detrimental effect on caries and also suggest that SjD promotes periodontitis.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"263-268"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572356","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}