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Organoids in the oral and maxillofacial region: present and future. 口腔颌面部的器官组织:现状与未来。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-11-01 DOI: 10.1038/s41368-024-00324-w
Yufei Wu, Xiang Li, Hanzhe Liu, Xiao Yang, Rui Li, Hui Zhao, Zhengjun Shang

The oral and maxillofacial region comprises a variety of organs made up of multiple soft and hard tissue, which are anatomically vulnerable to the pathogenic factors of trauma, inflammation, and cancer. The studies of this intricate entity have been long-termly challenged by a lack of versatile preclinical models. Recently, the advancements in the organoid industry have provided novel strategies to break through this dilemma. Here, we summarize the existing biological and engineering approaches that were employed to generate oral and maxillofacial organoids. Then, we detail the use of modified co-culture methods, such as cell cluster co-inoculation and air-liquid interface culture technology to reconstitute the vascular network and immune microenvironment in assembled organoids. We further retrospect the existing oral and maxillofacial assembled organoids and their potential to recapitulate the homeostasis in parental tissues such as tooth, salivary gland, and mucosa. Finally, we discuss how the next-generation organoids may benefit to regenerative and precision medicine for treatment of oral-maxillofacial illness.

口腔颌面部由多种软硬组织组成,在解剖学上容易受到创伤、炎症和癌症等致病因素的影响。由于缺乏多功能临床前模型,对这一复杂实体的研究长期面临挑战。最近,类器官产业的发展为突破这一困境提供了新的策略。在此,我们总结了生成口腔颌面部类器官的现有生物学和工程学方法。然后,我们详细介绍了如何使用改良的共培养方法,如细胞簇共接种和气液界面培养技术,在组装的类器官中重建血管网络和免疫微环境。我们进一步回顾了现有的口腔颌面部组装型有机体及其重现牙齿、唾液腺和粘膜等亲体组织平衡的潜力。最后,我们讨论了下一代类器官如何有利于再生医学和精准医学治疗口腔颌面疾病。
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引用次数: 0
Personalized bioceramic grafts for craniomaxillofacial bone regeneration 用于颅颌面骨再生的个性化生物陶瓷移植物
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-10-31 DOI: 10.1038/s41368-024-00327-7
Ana Beatriz G. de Carvalho, Maedeh Rahimnejad, Rodrigo L. M. S. Oliveira, Prabaha Sikder, Guilherme S. F. A. Saavedra, Sarit B. Bhaduri, Debby Gawlitta, Jos Malda, Darnell Kaigler, Eliandra S. Trichês, Marco C. Bottino

The reconstruction of craniomaxillofacial bone defects remains clinically challenging. To date, autogenous grafts are considered the gold standard but present critical drawbacks. These shortcomings have driven recent research on craniomaxillofacial bone reconstruction to focus on synthetic grafts with distinct materials and fabrication techniques. Among the various fabrication methods, additive manufacturing (AM) has shown significant clinical potential. AM technologies build three-dimensional (3D) objects with personalized geometry customizable from a computer-aided design. These layer-by-layer 3D biomaterial structures can support bone formation by guiding cell migration/proliferation, osteogenesis, and angiogenesis. Additionally, these structures can be engineered to degrade concomitantly with the new bone tissue formation, making them ideal as synthetic grafts. This review delves into the key advances of bioceramic grafts/scaffolds obtained by 3D printing for personalized craniomaxillofacial bone reconstruction. In this regard, clinically relevant topics such as ceramic-based biomaterials, graft/scaffold characteristics (macro/micro-features), material extrusion-based 3D printing, and the step-by-step workflow to engineer personalized bioceramic grafts are discussed. Importantly, in vitro models are highlighted in conjunction with a thorough examination of the signaling pathways reported when investigating these bioceramics and their effect on cellular response/behavior. Lastly, we summarize the clinical potential and translation opportunities of personalized bioceramics for craniomaxillofacial bone regeneration.

颅颌面骨缺损的重建在临床上仍具有挑战性。迄今为止,自体移植物被认为是黄金标准,但却存在严重缺陷。这些缺点促使最近的颅颌面骨重建研究将重点放在采用不同材料和制造技术的合成移植物上。在各种制造方法中,增材制造(AM)已显示出巨大的临床潜力。增材制造技术可根据计算机辅助设计构建具有个性化几何形状的三维(3D)物体。这些逐层叠加的三维生物材料结构可通过引导细胞迁移/增殖、成骨和血管生成来支持骨形成。此外,这些结构还可以在新骨组织形成的同时降解,使其成为理想的合成移植物。本综述将深入探讨通过三维打印技术获得的生物陶瓷移植物/支架在个性化颅颌面骨重建方面的主要进展。在这方面,将讨论与临床相关的主题,如陶瓷基生物材料、移植物/支架特性(宏观/微观特征)、基于材料挤压的三维打印,以及设计个性化生物陶瓷移植物的逐步工作流程。重要的是,我们强调了体外模型,并对研究这些生物陶瓷及其对细胞反应/行为的影响时所报道的信号通路进行了深入探讨。最后,我们总结了用于颅颌面骨再生的个性化生物陶瓷的临床潜力和转化机会。
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引用次数: 0
An unexpected role of neurite outgrowth inhibitor A as regulator of tooth enamel formation 神经细胞生长抑制剂 A 在牙釉质形成过程中发挥着意想不到的调节作用
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-10-20 DOI: 10.1038/s41368-024-00323-x
Pierfrancesco Pagella, Chai Foong Lai, Laurence Pirenne, Claudio Cantù, Martin E. Schwab, Thimios A. Mitsiadis

Neurite outgrowth inhibitor A (Nogo-A) is a major player in neural development and regeneration and the target of clinical trials aiming at promoting the regeneration of the central nervous system upon traumatic and ischemic injury. In this work, we investigated the functions of Nogo-A during tooth development to determine its role in dental physiology and pathology. Using immunohistochemistry and in situ hybridization techniques, we showed that Nogo-A is highly expressed in the developing mouse teeth and, most specifically, in the ameloblasts that are responsible for the formation of enamel. Using both Nogo-A knockout and K14-Cre;Nogo-A fl/fl transgenic mice, we showed that Nogo-A deletion in the dental epithelium leads to the formation of defective enamel. This phenotype is associated with overexpression of a set of specific genes involved in ameloblast differentiation and enamel matrix production, such as amelogenin, ameloblastin and enamelin. By characterising the interactome of Nogo-A in the dental epithelium of wild-type and mutant animals, we found that Nogo-A directly interacts with molecules important for regulating gene expression, and its deletion disturbs their cellular localisation. Furthermore, we demonstrated that inhibition of the intracellular, but not cell-surface, Nogo-A is responsible for gene expression modulation in ameloblasts. Taken together, these results reveal an unexpected function for Nogo-A in tooth enamel formation by regulating gene expression and cytodifferentiation events.

神经元外生抑制剂 A(Nogo-A)是神经发育和再生过程中的一个重要角色,也是旨在促进中枢神经系统在创伤和缺血性损伤后再生的临床试验目标。在这项工作中,我们研究了 Nogo-A 在牙齿发育过程中的功能,以确定其在牙齿生理和病理中的作用。通过免疫组织化学和原位杂交技术,我们发现 Nogo-A 在小鼠牙齿发育过程中高度表达,尤其是在负责形成釉质的成釉细胞中。利用 Nogo-A 基因敲除和 K14-Cre;Nogo-A fl/fl 转基因小鼠,我们发现牙齿上皮细胞中的 Nogo-A 基因缺失会导致缺陷釉质的形成。这种表型与参与成釉细胞分化和釉质基质生成的一系列特定基因(如amelogenin、ameloblastin和enamelin)的过度表达有关。通过分析野生型和突变型动物牙齿上皮细胞中 Nogo-A 的相互作用组,我们发现 Nogo-A 直接与调控基因表达的重要分子相互作用,其缺失会扰乱这些分子的细胞定位。此外,我们还证明,抑制细胞内而不是细胞表面的 Nogo-A 是导致骨髓母细胞基因表达调节的原因。综上所述,这些结果揭示了 Nogo-A 在牙釉质形成过程中通过调节基因表达和细胞分化事件所发挥的意想不到的功能。
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引用次数: 0
Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches. 牙周炎对血栓性疾病的影响:从临床方面到未来的治疗方法。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-10-15 DOI: 10.1038/s41368-024-00325-9
Jinting Ge,Xuanzhi Zhu,Chengxin Weng,Ding Yuan,Jichun Zhao,Lei Zhao,Tiehao Wang,Yafei Wu
Periodontitis is a chronic inflammatory disease initiated by biofilm microorganisms and mediated by host immune imbalance. Uncontrolled periodontal infections are the leading cause of tooth loss in adults. Thrombotic diseases can lead to partial or complete obstruction of blood flow in the circulatory system, manifesting as organ or tissue ischemia and necrosis in patients with arterial thrombosis, and local edema, pain and circulatory instability in patients with venous thrombosis, which may lead to mortality or fatality in severe case. Recent studies found that periodontitis might enhance thrombosis through bacterial transmission or systemic inflammation by affecting platelet-immune cell interactions, as well as the coagulation, and periodontal therapy could have a prophylactic effect on patients with thrombotic diseases. In this review, we summarized clinical findings on the association between periodontitis and thrombotic diseases and discussed several novel prothrombotic periodontitis-related agents, and presented a perspective to emphasize the necessity of oral health management for people at high risk of thrombosis.
牙周炎是一种由生物膜微生物引发并由宿主免疫失衡介导的慢性炎症性疾病。不受控制的牙周感染是成年人牙齿脱落的主要原因。血栓性疾病可导致循环系统血流部分或完全受阻,动脉血栓患者表现为器官或组织缺血坏死,静脉血栓患者表现为局部水肿、疼痛和循环不稳定,严重者可导致死亡。最新研究发现,牙周炎可能通过细菌传播或全身炎症影响血小板与免疫细胞的相互作用以及凝血功能,从而促进血栓形成,牙周治疗对血栓性疾病患者有预防作用。在这篇综述中,我们总结了牙周炎与血栓性疾病相关的临床研究结果,讨论了几种新型促血栓形成的牙周炎相关药物,并从一个角度强调了血栓高危人群口腔健康管理的必要性。
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引用次数: 0
CREB3L1 deficiency impairs odontoblastic differentiation and molar dentin deposition partially through the TMEM30B. CREB3L1 缺乏会部分通过 TMEM30B 影响牙本质分化和磨牙牙本质沉积。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-10-10 DOI: 10.1038/s41368-024-00322-y
Yuanyuan Li, Yuxiu Lin, Jinqiang Guo, Delan Huang, Huanyan Zuo, Hanshu Zhang, Guohua Yuan, Huan Liu, Zhi Chen

Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins, which are crucial for dentinogenesis. Our previous single-cell profile and RNAscope for odontoblast lineage revealed that cyclic adenosine monophosphate responsive element-binding protein 3 like 1 (Creb3l1) was specifically enriched in the terminal differentiated odontoblasts. In this study, deletion of Creb3l1 in the Wnt1+ lineage led to insufficient root elongation and dentin deposition. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing were performed to revealed that in CREB3L1-deficient mouse dental papilla cells (mDPCs), the genes near the closed chromatin regions were mainly associated with mesenchymal development and the downregulated genes were primarily related to biological processes including cell differentiation, protein biosynthesis and transport, all of which were evidenced by a diminished ability of odontoblastic differentiation, a significant reduction in intracellular proteins, and an even greater decline in extracellular supernatant proteins. Dentin matrix protein 1 (Dmp1), dentin sialophosphoprotein (Dspp), and transmembrane protein 30B (Tmem30b) were identified as direct transcriptional regulatory targets. TMEM30B was intensively expressed in the differentiated odontoblasts, and exhibited a significant decline in both CREB3L1-deficient odontoblasts in vivo and in vitro. Deletion of Tmem30b impaired the ability of odontoblastic differentiation, protein synthesis, and protein secretion in mDPCs. Moreover, overexpressing TMEM30B in CREB3L1-deficient mDPCs partially rescued the extracellular proteins secretion. Collectively, our findings suggest that CREB3L1 participates in dentinogenesis and facilitates odontoblastic differentiation by directly enhancing the transcription of Dmp1, Dspp, and other differentiation-related genes and indirectly promoting protein secretion partially via TMEM30B.

牙本质母细胞主要负责合成和分泌细胞外基质蛋白,这对牙本质的形成至关重要。我们之前对骨母细胞系的单细胞图谱和 RNAscope 发现,环腺苷酸单磷酸反应元件结合蛋白 3 like 1(Creb3l1)特异性地富集在末端分化的骨母细胞中。在这项研究中,在 Wnt1+ 系中缺失 Creb3l1 会导致牙根伸长和牙本质沉积不足。通过高通量测序(ATAC-seq)和RNA测序对转座酶可进入染色质进行检测,发现在CREB3L1缺失的小鼠牙乳头细胞(mDPCs)中,封闭染色质区域附近的基因主要与间质发育有关,而下调的基因主要与细胞分化等生物过程有关、蛋白质的生物合成和运输,所有这些都表现为牙本质分化能力的减弱、细胞内蛋白质的显著减少以及细胞外上清液蛋白质的更大幅度下降。牙本质基质蛋白 1(Dmp1)、牙本质糖磷蛋白(Dspp)和跨膜蛋白 30B(Tmem30b)被确定为直接转录调控靶标。TMEM30B在分化的颌骨细胞中大量表达,在体内和体外CREB3L1缺陷的颌骨细胞中均表现出显著下降。缺失 Tmem30b 会损害 mDPCs 中骨母细胞的分化能力、蛋白质合成能力和蛋白质分泌能力。此外,在 CREB3L1 缺失的 mDPCs 中过表达 TMEM30B 可部分修复细胞外蛋白的分泌。总之,我们的研究结果表明,CREB3L1 通过直接增强 Dmp1、Dspp 和其他分化相关基因的转录,并部分通过 TMEM30B 间接促进蛋白质分泌,从而参与牙本质生成并促进牙本质分化。
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引用次数: 0
Experts consensus on management of tooth luxation and avulsion 专家就牙齿松动和脱落的处理达成共识
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-09-26 DOI: 10.1038/s41368-024-00321-z
Ruijie Huang, Chenchen Zhou, Ling Zhan, Yuan Liu, Xian Liu, Qin Du, Jun Wang, Wei Zhao, Guangtai Song, Li-an Wu, Beizhan Jiang, Yanhong Li, Hongmei Zhang, Jing Zou

Traumatic dental injuries (TDIs) of teeth occur frequently in children and adolescents. TDIs that impact the periodontal tissues and alveolar tissue can be classified into concussion, subluxation, extrusive luxation, intrusive luxation, lateral luxation, and avulsion. In these TDIs, management of injured soft tissue, mainly periodontal ligament, and dental pulp, is crucial in maintaining the function and longevity of the injured teeth. Factors that need to be considered for management in laxation injuries include the maturation stage of the traumatic teeth, mobility, direction of displacement, distance of displacement, and whether there are alveolar fractures. In avulsion, the maturation stage of the permanent tooth, the out-socket time, storage media/condition of the avulsed tooth, and management of the PDL should also be considered. Especially, in this review, we have subdivided the immature tooth into the adolescent tooth (Nolla stage 9) and the very young tooth (Nolla stage 8 and below). This consensus paper aimed to discuss the impacts of those factors on the trauma management and prognosis of TDI to provide a streamlined guide for clinicians from clinical evaluation, diagnostic process, management plan decision, follow-up, and orthodontic treatment for tooth luxation and avulsion injuries.

牙齿外伤(TDI)经常发生在儿童和青少年身上。影响牙周组织和牙槽组织的牙外伤可分为震荡、半脱位、挤压性脱位、侵入性脱位、侧向脱位和撕脱。在这些 TDI 中,处理受伤的软组织(主要是牙周韧带和牙髓)对于保持受伤牙齿的功能和寿命至关重要。处理松动伤时需要考虑的因素包括创伤牙齿的成熟阶段、活动度、移位方向、移位距离以及是否存在牙槽骨骨折。在撕脱伤中,还应该考虑恒牙的成熟阶段、脱出牙槽窝的时间、撕脱牙的保存介质/条件以及 PDL 的管理。特别是在本综述中,我们将未成熟牙细分为青少年牙(Nolla 9 期)和非常年轻的牙(Nolla 8 期及以下)。本共识文件旨在讨论这些因素对 TDI 的创伤管理和预后的影响,从而为临床医生提供从临床评估、诊断过程、管理计划决策、随访到牙齿脱落和撕脱伤矫治的简化指南。
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引用次数: 0
The circadian clock in enamel development 珐琅质发育过程中的昼夜节律时钟
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-09-06 DOI: 10.1038/s41368-024-00317-9
Ke Wu, Xiaochan Li, Yunyang Bai, Boon Chin Heng, Xuehui Zhang, Xuliang Deng

Circadian rhythms are self-sustaining oscillations within biological systems that play key roles in a diverse multitude of physiological processes. The circadian clock mechanisms in brain and peripheral tissues can oscillate independently or be synchronized/disrupted by external stimuli. Dental enamel is a type of mineralized tissue that forms the exterior surface of the tooth crown. Incremental Retzius lines are readily observable microstructures of mature tooth enamel that indicate the regulation of amelogenesis by circadian rhythms. Teeth enamel is formed by enamel-forming cells known as ameloblasts, which are regulated and orchestrated by the circadian clock during amelogenesis. This review will first examine the key roles of the circadian clock in regulating ameloblasts and amelogenesis. Several physiological processes are involved, including gene expression, cell morphology, metabolic changes, matrix deposition, ion transportation, and mineralization. Next, the potential detrimental effects of circadian rhythm disruption on enamel formation are discussed. Circadian rhythm disruption can directly lead to Enamel Hypoplasia, which might also be a potential causative mechanism of amelogenesis imperfecta. Finally, future research trajectory in this field is extrapolated. It is hoped that this review will inspire more intensive research efforts and provide relevant cues in formulating novel therapeutic strategies for preventing tooth enamel developmental abnormalities.

昼夜节律是生物系统内自我维持的振荡,在多种生理过程中发挥着关键作用。大脑和外周组织中的昼夜节律机制可以独立振荡,也可以在外部刺激下同步/中断。牙釉质是一种形成牙冠外表面的矿化组织。增量雷齐乌斯线是成熟牙釉质易于观察到的微观结构,表明釉质的生成受昼夜节律的调节。牙釉质是由称为釉母细胞的釉质形成细胞形成的,在釉质形成过程中,这些细胞受到昼夜节律的调控和协调。本综述将首先探讨昼夜节律钟在调节釉母细胞和釉质形成过程中的关键作用。其中涉及多个生理过程,包括基因表达、细胞形态、新陈代谢变化、基质沉积、离子运输和矿化。接下来,将讨论昼夜节律紊乱对釉质形成的潜在不利影响。昼夜节律紊乱可直接导致釉质发育不全,这也可能是釉质发育不全症的潜在致病机制。最后,对这一领域未来的研究轨迹进行了推断。希望这篇综述能激发更深入的研究工作,并为制定预防牙釉质发育异常的新型治疗策略提供相关线索。
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引用次数: 0
Expert consensus on the diagnosis and therapy of endo-periodontal lesions 牙周病内病变诊断与治疗专家共识
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-09-01 DOI: 10.1038/s41368-024-00320-0
Bin Chen, Yanan Zhu, Minkui Lin, Yangheng Zhang, Yanfen Li, Xiangying Ouyang, Song Ge, Jiang Lin, Yaping Pan, Yan Xu, Yi Ding, Shaohua Ge, Faming Chen, Zhongchen Song, Shaoyun Jiang, Jiang Sun, Lijun Luo, Junqi Ling, Zhi Chen, Lin Yue, Xuedong Zhou, Fuhua Yan

Endo-periodontal lesions (EPLs) involve both the periodontium and pulp tissue and have complicated etiologies and pathogenic mechanisms, including unique anatomical and microbiological characteristics and multiple contributing factors. This etiological complexity leads to difficulties in determining patient prognosis, posing great challenges in clinical practice. Furthermore, EPL-affected teeth require multidisciplinary therapy, including periodontal therapy, endodontic therapy and others, but there is still much debate about the appropriate timing of periodontal therapy and root canal therapy. By compiling the most recent findings on the etiology, pathogenesis, clinical characteristics, diagnosis, therapy, and prognosis of EPL-affected teeth, this consensus sought to support clinicians in making the best possible treatment decisions based on both biological and clinical evidence.

牙周内病变(EPL)涉及牙周和牙髓组织,病因和致病机制复杂,包括独特的解剖学和微生物学特征以及多种致病因素。病因的复杂性导致难以确定患者的预后,给临床实践带来了巨大挑战。此外,受 EPL 影响的牙齿需要多学科治疗,包括牙周治疗、根管治疗和其他治疗,但关于牙周治疗和根管治疗的适当时机仍存在很多争议。本共识汇编了有关 EPL 受影响牙齿的病因、发病机制、临床特征、诊断、治疗和预后的最新研究成果,旨在支持临床医生根据生物学和临床证据做出最佳治疗决策。
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引用次数: 0
Caspase-11 mediated inflammasome activation in macrophages by systemic infection of A. actinomycetemcomitans exacerbates arthritis. 放线菌全身感染导致巨噬细胞中的 Caspase-11 介导的炎性体激活会加重关节炎。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-08-15 DOI: 10.1038/s41368-024-00315-x
Tokuju Okano, Hiroshi Ashida, Noriko Komatsu, Masayuki Tsukasaki, Tamako Iida, Marie Iwasawa, Yuto Takahashi, Yasuo Takeuchi, Takanori Iwata, Miwa Sasai, Masahiro Yamamoto, Hiroshi Takayanagi, Toshihiko Suzuki

Clinical studies have shown that Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is associated with aggressive periodontitis and can potentially trigger or exacerbate rheumatoid arthritis (RA). However, the mechanism is poorly understood. Here, we show that systemic infection with A. actinomycetemcomitans triggers the progression of arthritis in mice anti-collagen antibody-induced arthritis (CAIA) model following IL-1β secretion and cell infiltration in paws in a manner that is dependent on caspase-11-mediated inflammasome activation in macrophages. The administration of polymyxin B (PMB), chloroquine, and anti-CD11b antibody suppressed inflammasome activation in macrophages and arthritis in mice, suggesting that the recognition of lipopolysaccharide (LPS) in the cytosol after bacterial degradation by lysosomes and invasion via CD11b are needed to trigger arthritis following inflammasome activation in macrophages. These data reveal that the inhibition of caspase-11-mediated inflammasome activation potentiates aggravation of RA induced by infection with A. actinomycetemcomitans. This work highlights how RA can be progressed by inflammasome activation as a result of periodontitis-associated bacterial infection and discusses the mechanism of inflammasome activation in response to infection with A. actinomycetemcomitans.

临床研究表明,放线杆菌(A. actinomycetemcomitans)与侵袭性牙周炎有关,并可能诱发或加重类风湿性关节炎(RA)。然而,人们对其机制知之甚少。在此,我们发现,在小鼠抗胶原抗体诱导的关节炎(CAIA)模型中,放线菌全身感染会诱发关节炎的恶化,而这种恶化是在IL-1β分泌和细胞浸润爪子之后发生的,其方式依赖于巨噬细胞中caspase-11介导的炎性体激活。服用多粘菌素 B(PMB)、氯喹和抗 CD11b 抗体可抑制巨噬细胞中的炎性体活化和小鼠的关节炎,这表明巨噬细胞中的炎性体活化后,需要溶酶体降解细菌后识别细胞膜中的脂多糖(LPS)并通过 CD11b 侵袭才能引发关节炎。这些数据揭示,抑制 caspase-11 介导的炎症小体活化会加剧放线菌感染诱发的 RA。这项研究强调了牙周炎相关细菌感染导致的炎性体活化可导致 RA 的恶化,并探讨了放线菌感染导致炎性体活化的机制。
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引用次数: 0
Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects. 牙龈卟啉单胞菌中的 Gingipain 通过直接蛋白水解作用降解胰岛素受体,从而导致胰岛素抵抗。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-08-01 DOI: 10.1038/s41368-024-00313-z
Fen Liu, Bofeng Zhu, Ying An, Zhifei Zhou, Peiying Xiong, Xuan Li, Yang Mi, Tongqiang He, Faming Chen, Buling Wu

Periodontitis is a critical risk factor for the occurrence and development of diabetes. Porphyromonas gingivalis may participate in insulin resistance (IR) caused by periodontal inflammation, but the functional role and specific mechanisms of P. gingivalis in IR remain unclear. In the present study, clinical samples were analysed to determine the statistical correlation between P. gingivalis and IR occurrence. Through culturing of hepatocytes, myocytes, and adipocytes, and feeding mice P. gingivalis orally, the functional correlation between P. gingivalis and IR occurrence was further studied both in vitro and in vivo. Clinical data suggested that the amount of P. gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score. In vitro studies suggested that coculture with P. gingivalis decreased glucose uptake and insulin receptor (INSR) protein expression in hepatocytes, myocytes, and adipocytes. Mice fed P. gingivalis tended to undergo IR. P. gingivalis was detectable in the liver, skeletal muscle, and adipose tissue of experimental mice. The distribution sites of gingipain coincided with the downregulation of INSR. Gingipain proteolysed the functional insulin-binding region of INSR. Coculture with P. gingivalis significantly decreased the INSR-insulin binding ability. Knocking out gingipain from P. gingivalis alleviated the negative effects of P. gingivalis on IR in vivo. Taken together, these findings indicate that distantly migrated P. gingivalis may directly proteolytically degrade INSR through gingipain, thereby leading to IR. The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

牙周炎是糖尿病发生和发展的一个重要风险因素。牙龈卟啉单胞菌可能参与牙周炎症引起的胰岛素抵抗(IR),但牙龈卟啉单胞菌在IR中的功能作用和具体机制仍不清楚。本研究对临床样本进行了分析,以确定牙龈卟啉菌与 IR 发生之间的统计学相关性。通过培养肝细胞、肌细胞和脂肪细胞,以及给小鼠口服牙龈脓毒性菌,进一步研究了牙龈脓毒性菌与 IR 发生之间在体外和体内的功能相关性。临床数据表明,分离出的牙龈脓胞的数量与 IR 的平衡模型评估得分相关。体外研究表明,与牙龈脓疱共培养可降低肝细胞、肌细胞和脂肪细胞的葡萄糖摄取量和胰岛素受体(INSR)蛋白表达。喂食了牙龈脓疱病菌的小鼠往往会出现 IR。在实验小鼠的肝脏、骨骼肌和脂肪组织中都能检测到牙龈脓疱噬菌体。Gingipain的分布位置与INSR的下调相吻合。Gingipain蛋白水解了INSR的胰岛素结合功能区。与牙龈脓胞共培养可显著降低 INSR 与胰岛素的结合能力。敲除牙龈脓胞中的gingipain可减轻牙龈脓胞对体内IR的负面影响。综上所述,这些研究结果表明,远距离迁移的牙龈脓胞可能通过gingipain直接蛋白水解INSR,从而导致IR。这些结果为通过靶向牙周病原体预防糖尿病提供了新策略,并为探索牙周炎症影响全身代谢状态的新机制提供了新思路。
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引用次数: 0
期刊
International Journal of Oral Science
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