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The Essential Role of Proteoglycans and Glycosaminoglycans in Odontogenesis. 蛋白聚糖和糖胺聚糖在牙齿生成过程中的重要作用
Pub Date : 2024-04-01 Epub Date: 2024-02-26 DOI: 10.1177/00220345231224228
J Chen, T Sun, B Lin, B Wu, J Wu

Tooth development and regeneration are regulated through a complex signaling network. Previous studies have focused on the exploration of intracellular signaling regulatory networks, but the regulatory roles of extracellular networks have only been revealed recently. Proteoglycans, which are essential components of the extracellular matrix (ECM) and pivotal signaling molecules, are extensively involved in the process of odontogenesis. Proteoglycans are composed of core proteins and covalently attached glycosaminoglycan chains (GAGs). The core proteins exhibit spatiotemporal expression patterns during odontogenesis and are pivotal for dental tissue formation and periodontium development. Knockout of core protein genes Biglycan, Decorin, Perlecan, and Fibromodulin has been shown to result in structural defects in enamel and dentin mineralization. They are also closely involved in the development and homeostasis of periodontium by regulating signaling transduction. As the functional component of proteoglycans, GAGs are negatively charged unbranched polysaccharides that consist of repeating disaccharides with various sulfation groups; they provide binding sites for cytokines and growth factors in regulating various cellular processes. In mice, GAG deficiency in dental epithelium leads to the reinitiation of tooth germ development and the formation of supernumerary incisors. Furthermore, GAGs are critical for the differentiation of dental stem cells. Inhibition of GAGs assembly hinders the differentiation of ameloblasts and odontoblasts. In summary, core proteins and GAGs are expressed distinctly and exert different functions at various stages of odontogenesis. Given their unique contributions in odontogenesis, this review summarizes the roles of proteoglycans and GAGs throughout the process of odontogenesis to provide a comprehensive understanding of tooth development.

牙齿的发育和再生是通过复杂的信号网络调控的。以往的研究侧重于细胞内信号调控网络的探索,但细胞外网络的调控作用直到最近才被揭示出来。蛋白聚糖是细胞外基质(ECM)的重要组成部分,也是关键的信号分子,广泛参与牙体发生过程。蛋白多糖由核心蛋白和共价连接的糖胺聚糖链(GAGs)组成。核心蛋白在牙体发生过程中呈现时空表达模式,是牙组织形成和牙周发育的关键。研究表明,敲除核心蛋白基因 Biglycan、Decorin、Perlecan 和 Fibromodulin 会导致釉质和牙本质矿化的结构缺陷。它们还通过调节信号转导密切参与牙周的发育和平衡。作为蛋白多糖的功能成分,GAGs 是一种带负电荷的无支链多糖,由带有不同硫酸化基团的重复二糖组成;它们为细胞因子和生长因子提供结合位点,以调节各种细胞过程。在小鼠中,牙上皮细胞缺乏 GAG 会导致牙齿胚芽发育的重启和超常门齿的形成。此外,GAGs 对牙齿干细胞的分化至关重要。抑制 GAGs 的组装会阻碍成釉细胞和牙本质细胞的分化。总之,核心蛋白和GAGs在牙体发生的不同阶段表达不同,发挥不同的功能。鉴于它们在牙体发生过程中的独特贡献,本综述总结了蛋白多糖和 GAGs 在整个牙体发生过程中的作用,以提供对牙齿发育的全面认识。
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引用次数: 0
A Bilayer Method for Measuring Toughness and Strength of Dental Ceramics. 测量牙科陶瓷韧性和强度的双层法
Pub Date : 2024-04-01 Epub Date: 2024-02-27 DOI: 10.1177/00220345231225445
H Chai, J Russ, S Vardhaman, C H Lim, Y Zhang

The ever-increasing usage of ceramic materials in restorative dentistry necessitates a simple and effective method to evaluate flexural strength σF and fracture toughness KC. We propose a novel method to determine these quantities using a bilayer specimen composed of a brittle plate adhesively bonded onto a transparent polycarbonate substrate. When this bilayer structure is placed under spherical indentation, tunneling radial cracks initiate and propagate in the lower surface of the brittle layer. The failure analysis is based on previous theoretical relationships, which correlate σF with the indentation force P and layer thickness d, and KC with P and mean length of radial cracks. This work examines the accuracy and limitations of this approach using a wide range of contemporary dental ceramic materials. The effect of layer thickness, indenter radius, load level, and length and number of radial cracks are carefully examined. The accuracy of the predicted σF and KC is similar to those obtained with other concurrent test methods, such as biaxial flexure and 3-point bending (σF), and bending specimens with crack-initiation flaws (KC). The benefits of the present approach include treatment for small and thin plates, elimination of the need to introduce a precrack, and avoidance of dealing with local material nonlinearity effects for the KC measurements. Finally, the bilayer configuration resembles occlusal loading of a ceramic restoration (brittle layer) bonded to a posterior tooth (compliant substrate).

随着陶瓷材料在牙科修复中的应用日益广泛,需要一种简单有效的方法来评估抗弯强度 σF 和断裂韧性 KC。我们提出了一种新颖的方法,利用由粘接在透明聚碳酸酯基底上的脆性板组成的双层试样来确定这些量。当这种双层结构被置于球形压痕下时,隧道径向裂纹在脆性层的下表面开始并扩展。失效分析基于之前的理论关系,即 σF 与压入力 P 和层厚度 d 相关,KC 与 P 和径向裂纹平均长度相关。这项研究使用了多种当代牙科陶瓷材料,检验了这种方法的准确性和局限性。仔细研究了层厚、压头半径、载荷水平以及径向裂纹长度和数量的影响。预测的 σF 和 KC 的准确性与其他同时进行的测试方法相似,如双轴弯曲和三点弯曲 (σF),以及带有裂纹引发缺陷的弯曲试样 (KC)。本方法的优点包括:可处理小而薄的板材,无需引入预裂纹,以及在 KC 测量中避免处理局部材料非线性效应。最后,双层结构类似于将陶瓷修复体(脆性层)粘结到后牙(顺应性基底)上的咬合加载。
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引用次数: 0
IL-36 Regulates Neutrophil Chemotaxis and Bone Loss at the Oral Barrier. IL-36 在口腔屏障调节中性粒细胞趋化和骨质流失
Pub Date : 2024-04-01 Epub Date: 2024-02-27 DOI: 10.1177/00220345231225413
J Liu, H Meng, Y Mao, L Zhong, W Pan, Q Chen

Tissue-specific mechanisms regulate neutrophil immunity at the oral barrier, which plays a key role in periodontitis. Although it has been proposed that fibroblasts emit a powerful neutrophil chemotactic signal, how this chemotactic signal is driven has not been clear. The objective of this study was to investigate the site-specific regulatory mechanisms by which fibroblasts drive powerful neutrophil chemotactic signals within the oral barrier, with particular emphasis on the role of the IL-36 family. The present study found that IL-36γ, agonist of IL-36R, could promote neutrophil chemotaxis via fibroblast. Single-cell RNA sequencing data disclosed that IL36G is primarily expressed in human and mouse gingival epithelial cells and mouse neutrophils. Notably, there was a substantial increase in IL-36γ levels during periodontitis. In vitro experiments demonstrated that IL-36γ specifically activates gingival fibroblasts, leading to chemotaxis of neutrophils. In vivo experiments revealed that IL-36Ra inhibited the infiltration of neutrophils and bone resorption, while IL-36γ promoted their progression in the ligature-induced periodontitis mouse model. In summary, these data elucidate the function of the site-enriched IL-36γ in regulating neutrophil immunity and bone resorption at the oral barrier. These findings provide new insights into the tissue-specific pathophysiology of periodontitis and offer a promising avenue for prevention and treatment through targeted intervention of the IL-36 family.

组织特异性机制调节口腔屏障的中性粒细胞免疫,这在牙周炎中起着关键作用。尽管有人提出成纤维细胞会发出强大的中性粒细胞趋化信号,但这种趋化信号是如何驱动的还不清楚。本研究旨在探讨成纤维细胞在口腔屏障内驱动强大的中性粒细胞趋化信号的特定位点调控机制,特别强调了 IL-36 家族的作用。本研究发现,IL-36R的激动剂IL-36γ可通过成纤维细胞促进中性粒细胞趋化。单细胞 RNA 测序数据显示,IL36G 主要在人和小鼠牙龈上皮细胞及小鼠中性粒细胞中表达。值得注意的是,在牙周炎期间,IL-36γ的水平大幅上升。体外实验表明,IL-36γ 能特异性地激活牙龈成纤维细胞,导致中性粒细胞趋化。体内实验表明,在结扎诱导的牙周炎小鼠模型中,IL-36Ra 抑制了中性粒细胞的浸润和骨吸收,而 IL-36γ 则促进了它们的发展。总之,这些数据阐明了富集位点的IL-36γ在口腔屏障调节中性粒细胞免疫和骨吸收的功能。这些发现为牙周炎的组织特异性病理生理学提供了新的见解,并为通过有针对性地干预 IL-36 家族来预防和治疗牙周炎提供了一条很有前景的途径。
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引用次数: 0
Injectable Tissue-Specific Hydrogel System for Pulp-Dentin Regeneration. 用于牙髓-牙本质再生的可注射组织特异性水凝胶系统
Pub Date : 2024-04-01 Epub Date: 2024-02-27 DOI: 10.1177/00220345241226649
Y Han, J Xu, H Chopra, Z Zhang, N Dubey, W L Dissanayaka, J E Nör, M C Bottino

The quest for finding a suitable scaffold system that supports cell survival and function and, ultimately, the regeneration of the pulp-dentin complex remains challenging. Herein, we hypothesized that dental pulp stem cells (DPSCs) encapsulated in a collagen-based hydrogel with varying stiffness would regenerate functional dental pulp and dentin when concentrically injected into the tooth slices. Collagen hydrogels with concentrations of 3 mg/mL (Col3) and 10 mg/mL (Col10) were prepared, and their stiffness and microstructure were assessed using a rheometer and scanning electron microscopy, respectively. DPSCs were then encapsulated in the hydrogels, and their viability and differentiation capacity toward endothelial and odontogenic lineages were evaluated using live/dead assay and quantitative real-time polymerase chain reaction. For in vivo experiments, DPSC-encapsulated collagen hydrogels with different stiffness, with or without growth factors, were injected into pulp chambers of dentin tooth slices and implanted subcutaneously in severe combined immunodeficient (SCID) mice. Specifically, vascular endothelial growth factor (VEGF [50 ng/mL]) was loaded into Col3 and bone morphogenetic protein (BMP2 [50 ng/mL]) into Col10. Pulp-dentin regeneration was evaluated by histological and immunofluorescence staining. Data were analyzed using 1-way or 2-way analysis of variance accordingly (α = 0.05). Rheology and microscopy data revealed that Col10 had a stiffness of 8,142 Pa with a more condensed and less porous structure, whereas Col3 had a stiffness of 735 Pa with a loose microstructure. Furthermore, both Col3 and Col10 supported DPSCs' survival. Quantitative polymerase chain reaction showed Col3 promoted significantly higher von Willebrand factor (VWF) and CD31 expression after 7 and 14 d under endothelial differentiation conditions (P < 0.05), whereas Col10 enhanced the expression of dentin sialophosphoprotein (DSPP), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and collagen 1 (Col1) after 7, 14, and 21 d of odontogenic differentiation (P < 0.05). Hematoxylin and eosin and immunofluorescence (CD31 and vWF) staining revealed Col10+Col3+DPSCs+GFs enhanced pulp-dentin tissue regeneration. In conclusion, the collagen-based concentric construct modified by growth factors guided the specific lineage differentiation of DPSCs and promoted pulp-dentin tissue regeneration in vivo.

寻找一种合适的支架系统,以支持细胞的存活和功能,并最终支持牙髓-牙本质复合体的再生,仍然具有挑战性。在此,我们假设将牙髓干细胞(DPSCs)包裹在不同硬度的胶原蛋白水凝胶中,集中注射到牙片中,可再生出功能性牙髓和牙本质。制备了浓度为 3 毫克/毫升(Col3)和 10 毫克/毫升(Col10)的胶原水凝胶,并分别使用流变仪和扫描电子显微镜评估了它们的硬度和微观结构。然后将 DPSCs 包囊在水凝胶中,使用活/死检测法和定量实时聚合酶链反应评估它们的存活率以及向内皮细胞和牙本质细胞系分化的能力。在体内实验中,将含有或不含生长因子的不同硬度胶原水凝胶包裹的 DPSC 注入牙本质牙齿切片的牙髓腔,并植入严重联合免疫缺陷(SCID)小鼠的皮下。具体来说,在 Col3 中注入血管内皮生长因子(VEGF [50 ng/mL]),在 Col10 中注入骨形态发生蛋白(BMP2 [50 ng/mL])。通过组织学和免疫荧光染色对牙髓-牙本质再生进行评估。数据采用单因子或双因子方差分析(α = 0.05)进行分析。流变学和显微镜数据显示,Col10 的硬度为 8,142 Pa,结构更加凝结,孔隙较少;而 Col3 的硬度为 735 Pa,微观结构疏松。此外,Col3 和 Col10 都支持 DPSC 的存活。定量聚合酶链反应显示,在内皮分化条件下,Col3能在7天和14天后显著提高von Willebrand因子(VWF)和CD31的表达量(P < 0.05),而Col10则能在牙本质分化7天、14天和21天后提高牙本质磷蛋白(DSPP)、碱性磷酸酶(ALP)、runt相关转录因子2(Runx2)和胶原蛋白1(Col1)的表达量(P < 0.05)。血红素和伊红以及免疫荧光(CD31 和 vWF)染色显示 Col10+Col3+DPSCs+GFs 增强了牙髓-牙本质组织再生。总之,生长因子修饰的胶原同心构建物引导了 DPSCs 的特异性系分化,促进了体内牙髓-牙本质组织的再生。
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引用次数: 0
Salivary Glands and Viral Pathogenesis. 唾液腺与病毒发病机制
Pub Date : 2024-03-01 Epub Date: 2024-02-12 DOI: 10.1177/00220345231222871
N Atyeo, J O Maldonado, B M Warner, J A Chiorini

The oral cavity is an epidemiologically relevant route of viral transmission due to the shedding of viruses in saliva. With advancements in salivary diagnostics, an increasing number of viruses have been detected. However, the anatomic source of virus in saliva is still largely unknown. Some viruses have a well-established tropism for the salivary glands (SGs), and recent studies have emphasized the importance of the glands as potential reservoirs for infectious viruses. Viral infections of the SGs have been linked to acute and chronic SG pathology and may be associated with SG dysfunction, with phenotypes similar to those seen in SjÖgren's disease (SjD), an autoimmune condition that affects the salivary and lacrimal glands. Understanding the breadth of viruses that infect the SG and the conserved or distinct host responses to these infections may provide insights into the pathogenesis of virus-mediated SG diseases. There is a need for further research to fully understand the molecular mechanisms by which viruses enter and replicate in the glands, their physiologic impact on SG function, and whether the SGs can serve as a long-term reservoir for infectious viral particles. The purpose of this review is to highlight a group of viruses that infect the salivary gland: hepatitis C virus, hepatitis D virus, severe acute respiratory syndrome coronavirus 2, enteric viruses, human T-cell leukemia virus type I, human immunodeficiency virus, human cytomegalovirus, and BK polyomavirus. We focus on the effects of viral infection on salivary gland (SG) inflammation, function, and its association with SjD.

由于病毒会在唾液中脱落,因此口腔是一个与流行病学相关的病毒传播途径。随着唾液诊断技术的进步,越来越多的病毒被检测出来。然而,唾液中病毒的解剖学来源在很大程度上仍然是未知的。有些病毒对唾液腺(SG)有明显的滋养作用,最近的研究强调了唾液腺作为潜在的传染性病毒库的重要性。唾液腺的病毒感染与唾液腺的急性和慢性病变有关,并可能与唾液腺功能障碍有关,其表型与影响唾液腺和泪腺的自身免疫性疾病--斯约格伦病(SjÖgren's disease,SjD)相似。了解感染唾液腺的病毒的种类以及宿主对这些感染的反应是一致的还是不同的,有助于深入了解病毒介导的唾液腺疾病的发病机制。我们需要进一步研究,以充分了解病毒进入睑板腺并在睑板腺中复制的分子机制、病毒对睑板腺功能的生理影响以及睑板腺是否可作为传染性病毒颗粒的长期储存库。本综述的目的是重点介绍感染唾液腺的一组病毒:丙型肝炎病毒、丁型肝炎病毒、严重急性呼吸系统综合征冠状病毒 2、肠道病毒、人类 T 细胞白血病病毒 I 型、人类免疫缺陷病毒、人类巨细胞病毒和 BK 多瘤病毒。我们重点研究病毒感染对唾液腺(SG)炎症、功能的影响及其与 SjD 的关联。
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引用次数: 0
Single-Cell Transcriptomic Analysis of Salivary Gland Endothelial Cells. 唾液腺内皮细胞的单细胞转录组分析
Pub Date : 2024-03-01 DOI: 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.

血管内皮细胞在纤维化和再生过程中具有重要的组织特异性功能。在唾液腺中,内皮细胞是正常发育所必需的,但它们在成人唾液腺中的作用却大多不为人知。为了确定内皮细胞与其他细胞类型之间的配体-受体相互作用在纤维化和再生过程中的重要作用,我们使用了可逆性导管结扎损伤。为了诱导损伤,在原发性导管上放置夹子 14 天,为了诱导再生反应,随后移除夹子 5 天。为了确定内皮细胞产生的因子,我们对成年女性颌下腺和舌下腺的基质富集细胞进行了单细胞 RNA 测序。我们将唾液腺内皮细胞的转录谱与其他器官内皮细胞的转录谱进行了比较。唾液腺内皮细胞表达了许多独特的基因,并与结肠、小肠和肾脏的其他栅栏状内皮细胞在基因表达上有最大的重叠。对 14 天结扎、模拟结扎和 5 天脱落的基质富集转录本进行比较和系谱追踪发现,内皮细胞在结扎和损伤恢复后仍能保持其特性。CellChat 和 NATMI 被用来预测结扎和脱落后内皮细胞与其他细胞之间配体-受体相互作用的变化。根据 CellChat 和 NATMI 预测,在结扎后,与成纤维细胞、上皮细胞和神经胶质细胞的相互作用增加,而在去除结扎后,与包膜细胞、神经胶质细胞、成纤维细胞和免疫细胞的相互作用增加。与模拟内皮细胞相比,在已连接内皮细胞中预测的最高级相互作用是神经胶质细胞之间通过 Col4a2-Cd93 和 Jag2-Notch1 以及上皮细胞之间通过 Pecam1-Cd38 进行的相互作用,而与已连接内皮细胞相比,在已脱连接内皮细胞中预测的最高级相互作用是成纤维细胞之间通过 Ntf3-Ntrk2 进行的相互作用、神经胶质细胞之间通过 Hspg2-Itgb1 进行的相互作用以及周细胞之间通过 Jam2-F11r 进行的相互作用。了解涎腺内皮细胞信号转导将为未来基于内皮细胞的再生疗法提供信息。
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引用次数: 0
Electrolyzed Saline Targets Biofilm Periodontal Pathogens In Vitro. 电解生理盐水体外靶向生物膜牙周病原体
Pub Date : 2024-03-01 Epub Date: 2024-01-07 DOI: 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。
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引用次数: 0
P. gingivalis-Induced TLR2 Interactome Analysis Reveals Association with PARP9. 牙龈脓疱病诱导的 TLR2 相互作用组分析显示与 PARP9 有关。
Pub Date : 2024-03-01 Epub Date: 2024-02-12 DOI: 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.

牙龈卟啉单胞菌是一种与牙周病密切相关的革兰氏阴性厌氧菌。Toll样受体2(TLR2)是宿主对牙龈卟啉单胞菌做出反应所不可或缺的,但牙龈卟啉单胞菌通过TLR2依赖性激活磷酸肌醇-3-激酶(PI3K)逃避免疫清除。为了探究牙龈脓毒性噬菌体依赖 TLR2 的逃逸途径,我们分析了牙龈脓毒性噬菌体感染或在过表达 TLR2 的人巨噬细胞上被合成脂肽 TLR2/1 激动剂激活后诱导的 TLR2 相互作用组。通过交联稳定相互作用蛋白,然后进行免疫沉淀和质谱分析。共回收了 792 个蛋白质,并通过网络分析绘制出了基线和感染时 TLR2 相互作用组的图谱。牙龈球菌感染诱导的 TLR2 相互作用组包括聚(ADP-核糖)聚合酶家族成员单-ADP-核糖基转移酶蛋白 9(PARP9)和 PARP9 复合物的其他成员(DTX3L 和 NMI)。PARP9 及其复合体成员在暴露于牙龈脓疱病菌或合成 TLR2/1 配体 Pam3Cys-Ser-(Lys)4 (PAM) 的巨噬细胞中高度上调。与已知的 PARP9 在病毒诱导的干扰素产生中的作用相一致,PARP9 基因敲除会阻止 I 型干扰素(IFN-I)在牙龈脓疱病中的产生,并减少炎性细胞因子的产生。我们发现牙龈脓疱疮通过 TLR2-PARP9 驱动信号转导和激活转录(STAT)1 (S727) 磷酸化,这解释了 PARP9 在 TLR2 下游诱导 IFN-I 中的作用。此外,PARP9 的敲除减少了牙龈脓毒性杆菌对 PI3K 的激活,从而提高了巨噬细胞的杀菌活性。总之,PARP9 是一种新型的 TLR2 相互作用伙伴,它能在 TLR2 传感下游诱导 IFN-I 并使牙龈脓疱噬菌体免疫逃逸。
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引用次数: 0
Gli1+ Periodontal Mesenchymal Stem Cells in Periodontitis. 牙周炎中的 Gli1+ 牙周间充质干细胞
Pub Date : 2024-03-01 Epub Date: 2024-01-29 DOI: 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.

牙周间充质干细胞(MSCs)在维持牙周稳态和组织修复方面发挥着至关重要的作用。然而,人们对牙周间充质干细胞在牙周疾病条件下的体内反应知之甚少,这给牙周组织再生带来了挑战。在这项研究中,Gli1被用作牙周间充质干细胞的标记物,并结合Gli1-cre ERT2小鼠模型进行系谱追踪,以研究诱导性牙周炎模型中牙周间充质干细胞的命运。我们的研究结果表明,在发炎的牙周中,Gli1+间充质干细胞的数量和贡献率发生了重大变化。在牙周炎诱导的牙齿中,促进牙周韧带平衡的 Gli1+ 间充质干细胞数量减少。虽然 Gli1+ 间充质干细胞的增殖在牙周炎组和对照组之间没有显著差异,但在病变牙中有更多的 Gli1+ 间充质干细胞发生凋亡。此外,随着牙周炎的发展,用于成骨分化的 Gli1+ 间充质干细胞数量减少。拔牙后,Gli1+间充质干细胞对牙周炎引起的牙槽骨修复的贡献明显减少。总之,这些研究结果表明,Gli1+间充质干细胞在牙周炎中的功能受到损害,包括对牙周稳态的贡献减少和损伤反应受损。
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引用次数: 0
Casp11 Deficiency Alters Subgingival Microbiota and Attenuates Periodontitis. Casp11 缺乏会改变龈下微生物群并减轻牙周炎。
Pub Date : 2024-03-01 Epub Date: 2024-01-10 DOI: 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.

牙周炎(PD)是成年人牙齿脱落的主要原因。牙龈卟啉单胞菌(P.g)是一种关键的病原体,已被确定为这一过程的关键因素。人们已认识到牙周病中的裂解酶活化,不断积累的证据强调了 Caspase-11(在人类中被描述为 Caspase-4/5)介导的非典型裂解酶的关键作用。然而,其对帕金森病的影响机制仍不清楚。在本研究中,我们深入研究了 Caspase-11 介导的非典型性热脓毒症、龈下微生物群改变和巨噬细胞极化之间的相互作用。PD患者的临床样本显示,Caspase-4、gasdermin-D及其活性片段的表达增高,这表明非典型脓毒症被激活。单细胞测序分析将Caspase-4与牙龈巨噬细胞联系在一起,强调了它们在白血病中的参与。体外细胞实验证实,P.g诱导的热噬在巨噬细胞中被激活,而Casp11的缺乏会减弱这些效应。在实验性骨髓增生性疾病小鼠模型中,缺乏 Casp11 会导致龈下微生物群组成的改变,并减少牙槽骨的吸收。Casp11-/-小鼠与野生型小鼠同群饲养证实了龈下微生物群的改变,并加剧了牙槽骨的吸收。值得注意的是,Casp11缺陷导致M1极化巨噬细胞减少,与牙槽骨吸收减少相对应,揭示了龈下微生物群改变、巨噬细胞M1极化和牙槽骨吸收之间的联系。总之,我们的研究表明,Caspase-11在肺结核非典型性热蛋白沉积中起着关键作用,可能影响龈下微生物群,并与M1极化有关,而M1极化与牙槽骨吸收有关。这些发现强调了Caspase-11介导的非典型热脓毒症在脓疱病发病机制中的关键作用,并可能为缓解脓疱病的潜在治疗途径提供重要见解。
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引用次数: 0
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Journal of dental research
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