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Extracellular matrix remodelling in dental pulp tissue of carious human teeth through the prism of single-cell RNA sequencing. 单细胞RNA测序技术在龋齿牙髓组织细胞外基质重构中的应用。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-08-02 DOI: 10.1038/s41368-023-00238-z
Anamaria Balic, Dilara Perver, Pierfrancesco Pagella, Hubert Rehrauer, Bernd Stadlinger, Andreas E Moor, Viola Vogel, Thimios A Mitsiadis

Carious lesions are bacteria-caused destructions of the mineralised dental tissues, marked by the simultaneous activation of immune responses and regenerative events within the soft dental pulp tissue. While major molecular players in tooth decay have been uncovered during the past years, a detailed map of the molecular and cellular landscape of the diseased pulp is still missing. In this study we used single-cell RNA sequencing analysis, supplemented with immunostaining, to generate a comprehensive single-cell atlas of the pulp of carious human teeth. Our data demonstrated modifications in the various cell clusters within the pulp of carious teeth, such as immune cells, mesenchymal stem cells (MSC) and fibroblasts, when compared to the pulp of healthy human teeth. Active immune response in the carious pulp tissue is accompanied by specific changes in the fibroblast and MSC clusters. These changes include the upregulation of genes encoding extracellular matrix (ECM) components, including COL1A1 and Fibronectin (FN1), and the enrichment of the fibroblast cluster with myofibroblasts. The incremental changes in the ECM composition of carious pulp tissues were further confirmed by immunostaining analyses. Assessment of the Fibronectin fibres under mechanical strain conditions showed a significant tension reduction in carious pulp tissues, compared to the healthy ones. The present data demonstrate molecular, cellular and biomechanical alterations in the pulp of human carious teeth, indicative of extensive ECM remodelling, reminiscent of fibrosis observed in other organs. This comprehensive atlas of carious human teeth can facilitate future studies of dental pathologies and enable comparative analyses across diseased organs.

龋齿病变是细菌引起的矿化牙组织的破坏,其特征是同时激活免疫反应和软牙髓组织内的再生事件。虽然在过去的几年中发现了蛀牙的主要分子作用,但患病牙髓的分子和细胞景观的详细地图仍然缺失。在这项研究中,我们使用单细胞RNA测序分析,辅以免疫染色,生成了一个全面的单细胞牙髓图谱。我们的数据表明,与健康的人牙髓相比,龋齿牙髓内的各种细胞团(如免疫细胞、间充质干细胞(MSC)和成纤维细胞)发生了变化。龋齿牙髓组织中的主动免疫反应伴随着成纤维细胞和间充质干细胞簇的特异性变化。这些变化包括编码细胞外基质(ECM)成分的基因上调,包括COL1A1和纤维连接蛋白(FN1),以及肌成纤维细胞簇的富集。免疫染色分析进一步证实了龋牙髓组织ECM组成的增量变化。在机械应变条件下对纤维连接蛋白纤维的评估显示,与健康牙髓组织相比,龋齿牙髓组织的张力显著降低。目前的数据表明,人类龋齿牙髓中的分子、细胞和生物力学改变,表明广泛的ECM重塑,使人想起在其他器官中观察到的纤维化。这个全面的人类龋齿图谱可以促进未来牙齿病理学的研究,并使跨患病器官的比较分析成为可能。
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引用次数: 0
Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials. 树突状细胞在myd88介导的免疫识别和生物材料植入引发的骨诱导中的作用。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-08-02 DOI: 10.1038/s41368-023-00234-3
Zifan Zhao, Qin Zhao, Hu Chen, Fanfan Chen, Feifei Wang, Hua Tang, Haibin Xia, Yongsheng Zhou, Yuchun Sun

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.

骨替代物植入术已成为修复口腔颌面骨缺损的重要治疗策略。近年来的研究表明,适当的炎症细胞和免疫细胞是骨替代材料成骨过程中必不可少的因素。以往的研究主要集中在巨噬细胞等先天免疫细胞上。在我们之前的工作中,我们发现T淋巴细胞,作为适应性免疫细胞,在骨诱导过程中也是必不可少的。树突状细胞作为最重要的抗原呈递细胞,其能否识别非抗原生物材料并参与骨诱导尚不清楚。在本研究中,我们发现与材料植入相关的手术创伤会引起细胞坏死,从而导致高迁移率基团蛋白-1 (HMGB1)的释放,该蛋白被吸附在骨替代材料表面。随后,hmgb1吸附的物质被树突状细胞的TLR4-MYD88-NFκB信号轴识别,炎症反应被激活。最后,活化的dc释放再生相关的趋化因子,招募间充质干细胞,并启动骨诱导过程。本研究揭示了骨替代材料植入后的免疫再生过程,为骨替代材料的发展指明了潜在的方向,为临床手术方法的发展提供指导。
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引用次数: 0
Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling. 癌相关成纤维细胞衍生的赖氨酸氧化酶丰富的细胞外囊泡介导胶原交联,并通过p-FAK/p-paxillin/YAP信号通路促进上皮-间质转化。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-08-02 DOI: 10.1038/s41368-023-00236-1
Xue Liu, Jiao Li, Xuesong Yang, Xiaojie Li, Jing Kong, Dongyuan Qi, Fuyin Zhang, Bo Sun, Yuehua Liu, Tingjiao Liu

Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.

癌相关成纤维细胞(CAFs)是肿瘤微环境的主要细胞成分,通过修饰细胞外基质(ECM)促进癌症进展。肿瘤相关的ECM以赖氨酸氧化酶(LOX)催化的胶原交联为特征。小细胞外囊泡(sEVs)介导细胞间的通讯。然而,sev与ECM之间的相互作用仍不清楚。在这里,我们证明了从口腔鳞状细胞癌(OSCC)衍生的CAFs释放的sev诱导胶原交联,从而促进上皮-间质转化(EMT)。CAF sev最好与ECM结合,而不是被成纤维细胞吸收和诱导的胶原交联,LOX抑制剂或阻断抗体抑制了这种作用。活性LOX (αLOX)在CAF sev中富集,而不是LOX前体,并与sev表面的骨膜蛋白、纤维连接蛋白和骨形态发生蛋白-1相互作用。CAF sEV相关整合素α2β1介导CAF sEV与I型胶原的结合,阻断整合素α2β1通过干扰CAF sEV与I型胶原的结合抑制胶原交联。CAF sEV诱导的胶原交联通过FAK/paxillin/YAP通路促进OSCC的EMT。综上所述,这些发现揭示了CAF sev在肿瘤ECM重塑中的新作用,提示了CAF诱导癌细胞EMT的关键机制。
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引用次数: 1
ChatGPT for shaping the future of dentistry: the potential of multi-modal large language model. 打造牙科未来的 ChatGPT:多模态大语言模型的潜力。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-07-28 DOI: 10.1038/s41368-023-00239-y
Hanyao Huang, Ou Zheng, Dongdong Wang, Jiayi Yin, Zijin Wang, Shengxuan Ding, Heng Yin, Chuan Xu, Renjie Yang, Qian Zheng, Bing Shi

The ChatGPT, a lite and conversational variant of Generative Pretrained Transformer 4 (GPT-4) developed by OpenAI, is one of the milestone Large Language Models (LLMs) with billions of parameters. LLMs have stirred up much interest among researchers and practitioners in their impressive skills in natural language processing tasks, which profoundly impact various fields. This paper mainly discusses the future applications of LLMs in dentistry. We introduce two primary LLM deployment methods in dentistry, including automated dental diagnosis and cross-modal dental diagnosis, and examine their potential applications. Especially, equipped with a cross-modal encoder, a single LLM can manage multi-source data and conduct advanced natural language reasoning to perform complex clinical operations. We also present cases to demonstrate the potential of a fully automatic Multi-Modal LLM AI system for dentistry clinical application. While LLMs offer significant potential benefits, the challenges, such as data privacy, data quality, and model bias, need further study. Overall, LLMs have the potential to revolutionize dental diagnosis and treatment, which indicates a promising avenue for clinical application and research in dentistry.

ChatGPT 是 OpenAI 开发的生成预训练转换器 4(GPT-4)的精简版和会话变体,是具有数十亿参数的里程碑式大型语言模型(LLM)之一。LLMs 在自然语言处理任务中的出色技能引起了研究人员和从业人员的极大兴趣,并对各个领域产生了深远影响。本文主要讨论 LLM 在牙科领域的未来应用。我们介绍了在牙科领域应用 LLM 的两种主要方法,包括自动牙科诊断和跨模态牙科诊断,并探讨了它们的潜在应用。特别是,配备了跨模态编码器后,单个 LLM 就能管理多源数据,并进行高级自然语言推理,从而执行复杂的临床操作。我们还通过案例展示了全自动多模态 LLM 人工智能系统在牙科临床应用中的潜力。虽然 LLM 具有巨大的潜在优势,但其面临的挑战,如数据隐私、数据质量和模型偏差等,还需要进一步研究。总之,LLM 有可能彻底改变牙科诊断和治疗,这为牙科的临床应用和研究提供了一个前景广阔的途径。
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引用次数: 0
Minimally invasive techniques for lateral maxillary sinus floor elevation: small lateral window and one-stage surgery-a 2-5-year retrospective study. 上颌外侧窦底抬高的微创技术:小外侧窗口和一期手术-一项2-5年回顾性研究。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-07-11 DOI: 10.1038/s41368-023-00233-4
Shaojingya Gao, Yao Jiang, Yangxue Yao, Songhang Li, Xiaoxiao Cai

This study aimed to introduce a minimally invasive technique for maxillary sinus floor elevation using the lateral approach (lSFE) and to determine the factors that influence the stability of the grafted area in the sinus cavity. Thirty patients (30 implants) treated with lSFE using minimally invasive techniques from 2015 to 2019 were included in the study. Five aspects of the implant (central, mesial, distal, buccal, and palatal bone heights [BHs]) were measured using cone-beam computed tomography (CBCT) before implant surgery, immediately after surgery (T0), 6 months after surgery (T1), and at the last follow-up visit (T2). Patients' characteristics were collected. A small bone window (height, (4.40 ± 0.74) mm; length, (6.26 ± 1.03) mm) was prepared. No implant failed during the follow-up period (3.67 ± 1.75) years. Three of the 30 implants exhibited perforations. Changes in BH of the five aspects of implants showed strong correlations with each other and BH decreased dramatically before second-stage surgery. Residual bone height (RBH) did not significantly influence BH changes, whereas smoking status and type of bone graft materials were the potentially influential factors. During the approximate three-year observation period, lSFE with a minimally invasive technique demonstrated high implant survival rate and limited bone reduction in grafted area. In conclusion, lSFE using minimally invasive techniques was a viable treatment option. Patients who were nonsmokers and whose sinus cavity was filled with deproteinized bovine bone mineral (DBBM) had significantly limited bone resorption in grafted area.

本研究旨在介绍一种采用外侧入路(lSFE)进行上颌窦底提升的微创技术,并确定影响移植物区在窦腔内稳定性的因素。本研究纳入2015 - 2019年采用微创技术进行lSFE治疗的30例患者(30颗种植体)。在种植术前、术后即刻(T0)、术后6个月(T1)和最后一次随访时(T2),采用锥形束计算机断层扫描(CBCT)测量种植体的五个方面(中央、中、远端、颊和腭骨高度[BHs])。收集患者的特征。小骨窗(高度,(4.40±0.74)mm;长度为(6.26±1.03)mm。随访(3.67±1.75)年,无种植体失败。30个种植体中有3个出现穿孔。种植体五个方面的BH变化具有很强的相关性,二期手术前BH明显下降。残余骨高度(RBH)对骨高度变化无显著影响,而吸烟状况和植骨材料类型是潜在的影响因素。在大约三年的观察期间,微创技术的lSFE显示出高的种植体存活率和有限的移植区域骨复位。总之,采用微创技术的lSFE是一种可行的治疗选择。不吸烟且窦腔内填充脱蛋白牛骨矿物质(DBBM)的患者移植区骨吸收明显受限。
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引用次数: 0
Salivary biomarkers: novel noninvasive tools to diagnose chronic inflammation. 唾液生物标志物:诊断慢性炎症的新型无创工具。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-06-29 DOI: 10.1038/s41368-023-00231-6
Paola Dongiovanni, Marica Meroni, Sara Casati, Riccardo Goldoni, Douglas Vieira Thomaz, Nermin Seda Kehr, Daniela Galimberti, Massimo Del Fabbro, Gianluca M Tartaglia

Several chronic disorders including type 2 diabetes (T2D), obesity, heart disease and cancer are preceded by a state of chronic low-grade inflammation. Biomarkers for the early assessment of chronic disorders encompass acute phase proteins (APP), cytokines and chemokines, pro-inflammatory enzymes, lipids and oxidative stress mediators. These substances enter saliva through the blood flow and, in some cases, there is a close relation between their salivary and serum concentration. Saliva can be easily collected and stored with non-invasive and cost-saving procedures, and it is emerging the concept to use it for the detection of inflammatory biomarkers. To this purpose, the present review aims to discuss the advantages and challenges of using standard and cutting-edge techniques to discover salivary biomarkers which may be used in diagnosis/therapy of several chronic diseases with inflammatory consequences with the pursuit to possibly replace conventional paths with detectable soluble mediators in saliva. Specifically, the review describes the procedures used for saliva collection, the standard approaches for the measurement of salivary biomarkers and the novel methodological strategies such as biosensors to improve the quality of care for chronically affected patients.

包括2型糖尿病(T2D)、肥胖、心脏病和癌症在内的一些慢性疾病在发生前都有慢性低度炎症状态。用于慢性疾病早期评估的生物标志物包括急性期蛋白(APP)、细胞因子和趋化因子、促炎酶、脂质和氧化应激介质。这些物质通过血流进入唾液,在某些情况下,它们的唾液浓度和血清浓度密切相关。唾液可以通过非侵入性和节省成本的方法轻松收集和储存,并且正在出现将其用于检测炎症生物标志物的概念。为此,本综述旨在讨论使用标准和尖端技术发现唾液生物标志物的优势和挑战,这些生物标志物可能用于诊断/治疗几种具有炎症后果的慢性疾病,并追求用唾液中可检测的可溶性介质可能取代传统途径。具体来说,这篇综述描述了用于唾液收集的程序,唾液生物标志物测量的标准方法和新的方法策略,如生物传感器,以提高慢性感染患者的护理质量。
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引用次数: 5
Oral pathogen aggravates atherosclerosis by inducing smooth muscle cell apoptosis and repressing macrophage efferocytosis. 口腔病原体通过诱导平滑肌细胞凋亡和抑制巨噬细胞efferocysis而加重动脉粥样硬化。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-06-28 DOI: 10.1038/s41368-023-00232-5
Hanyu Xie, Ziyue Qin, Ziji Ling, Xiao Ge, Hang Zhang, Shuyu Guo, Laikui Liu, Kai Zheng, Hongbing Jiang, Rongyao Xu

Periodontitis imparting the increased risk of atherosclerotic cardiovascular diseases is partially due to the immune subversion of the oral pathogen, particularly the Porphyromonas gingivalis (P. gingivalis), by inducing apoptosis. However, it remains obscure whether accumulated apoptotic cells in P. gingivalis-accelerated plaque formation are associated with impaired macrophage clearance. Here, we show that smooth muscle cells (SMCs) have a greater susceptibility to P. gingivalis-induced apoptosis than endothelial cells through TLR2 pathway activation. Meanwhile, large amounts of miR-143/145 in P.gingivalis-infected SMCs are extracellularly released and captured by macrophages. Then, these miR-143/145 are translocated into the nucleus to promote Siglec-G transcription, which represses macrophage efferocytosis. By constructing three genetic mouse models, we further confirm the in vivo roles of TLR2 and miR-143/145 in P. gingivalis-accelerated atherosclerosis. Therapeutically, we develop P.gingivalis-pretreated macrophage membranes to coat metronidazole and anti-Siglec-G antibodies for treating atherosclerosis and periodontitis simultaneously. Our findings extend the knowledge of the mechanism and therapeutic strategy in oral pathogen-associated systemic diseases.

牙周炎增加动脉粥样硬化性心血管疾病的风险部分是由于口腔病原体,特别是牙龈卟啉单胞菌(P. gingivalis),通过诱导细胞凋亡的免疫颠覆。然而,目前尚不清楚牙龈假单胞菌加速斑块形成中积累的凋亡细胞是否与巨噬细胞清除受损有关。在这里,我们发现通过TLR2通路激活,平滑肌细胞(SMCs)比内皮细胞更容易受到牙龈假单胞菌诱导的凋亡。同时,大量的miR-143/145在牙龈假单胞菌感染的SMCs中被细胞外释放并被巨噬细胞捕获。然后,这些miR-143/145被易位到细胞核中,促进siglecg转录,从而抑制巨噬细胞的efferocytosis。通过构建三种小鼠遗传模型,我们进一步证实了TLR2和miR-143/145在牙龈卟卟酸加速动脉粥样硬化中的体内作用。在治疗方面,我们开发了牙龈卟啉预处理的巨噬细胞膜,以包裹甲硝唑和抗siglecg抗体,同时治疗动脉粥样硬化和牙周炎。我们的发现扩展了对口腔病原体相关全身性疾病的机制和治疗策略的认识。
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引用次数: 0
Periodontitis as a promoting factor of T2D: current evidence and mechanisms. 牙周炎作为T2D的促进因素:目前的证据和机制。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-06-15 DOI: 10.1038/s41368-023-00227-2
Yuan Su, Leilei Ye, Chen Hu, Yanli Zhang, Jia Liu, Longquan Shao

Periodontitis is an infectious disease caused by an imbalance between the local microbiota and host immune response. Epidemiologically, periodontitis is closely related to the occurrence, development, and poor prognosis of T2D and is recognized as a potential risk factor for T2D. In recent years, increasing attention has been given to the role of the virulence factors produced by disorders of the subgingival microbiota in the pathological mechanism of T2D, including islet β-cell dysfunction and insulin resistance (IR). However, the related mechanisms have not been well summarized. This review highlights periodontitis-derived virulence factors, reviews how these stimuli directly or indirectly regulate islet β-cell dysfunction. The mechanisms by which IR is induced in insulin-targeting tissues (the liver, visceral adipose tissue, and skeletal muscle) are explained, clarifying the influence of periodontitis on the occurrence and development of T2D. In addition, the positive effects of periodontal therapy on T2D are overviewed. Finally, the limitations and prospects of the current research are discussed. In summary, periodontitis is worthy of attention as a promoting factor of T2D. Understanding on the effect of disseminated periodontitis-derived virulence factors on the T2D-related tissues and cells may provide new treatment options for reducing the risk of T2D associated with periodontitis.

牙周炎是一种由局部微生物群与宿主免疫反应不平衡引起的传染病。在流行病学上,牙周炎与T2D的发生、发展和预后不良密切相关,被认为是T2D的潜在危险因素。近年来,牙龈下微生物群紊乱产生的毒力因子在T2D病理机制中的作用越来越受到关注,包括胰岛β细胞功能障碍和胰岛素抵抗(insulin resistance, IR)。然而,相关机制尚未得到很好的总结。这篇综述强调了牙周炎衍生的毒力因子,综述了这些刺激如何直接或间接调节胰岛β细胞功能障碍。本文解释了胰岛素靶向组织(肝脏、内脏脂肪组织和骨骼肌)诱导IR的机制,阐明了牙周炎对T2D发生和发展的影响。此外,还概述了牙周治疗对T2D的积极作用。最后,对目前研究的局限性和前景进行了讨论。综上所述,牙周炎作为T2D的促进因素值得关注。了解播散性牙周炎源性毒力因子对T2D相关组织和细胞的影响,可能为降低与牙周炎相关的T2D风险提供新的治疗选择。
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引用次数: 3
LIMP-2 enhances cancer stem-like cell properties by promoting autophagy-induced GSK3β degradation in head and neck squamous cell carcinoma. 在头颈部鳞状细胞癌中,LIMP-2通过促进自噬诱导的GSK3β降解增强癌症干样细胞特性。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-06-08 DOI: 10.1038/s41368-023-00229-0
Yuantong Liu, Shujin Li, Shuo Wang, Qichao Yang, Zhizhong Wu, Mengjie Zhang, Lei Chen, Zhijun Sun

Cancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.

癌症干细胞样细胞(CSCs)具有很强的肿瘤诱发能力和可塑性,在头颈部鳞状细胞癌(HNSCC)的异质性、转移和耐药性中扮演着不可或缺的角色。在这里,我们发现了一个名为 LIMP-2 的候选基因,它是调控 HNSCC 进展和 CSC 特性的新型治疗靶点。LIMP-2 在 HNSCC 患者中的高表达提示其预后较差,并可能对免疫疗法产生抗药性。在功能上,LIMP-2可促进自溶体的形成,从而促进自噬通量。敲除 LIMP-2 可抑制自噬通量,降低 HNSCC 的致瘤能力。进一步的机理研究表明,自噬的增强有助于HNSCC维持干性,促进GSK3β的降解,进而促进β-catenin的核转位和下游靶基因的转录。总之,这项研究揭示了LIMP-2是HNSCC的一个新的前瞻性治疗靶点,并为自噬、CSC和免疫疗法耐药性之间的联系提供了证据。
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引用次数: 1
Promotion effect of TGF-β-Zfp423-ApoD pathway on lip sensory recovery after nerve sacrifice caused by nerve collateral compensation. TGF-β-Zfp423-ApoD通路对神经侧支代偿所致神经牺牲后唇部感觉恢复的促进作用。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2023-06-08 DOI: 10.1038/s41368-023-00230-7
Pingchuan Ma, Gaowei Zhang, Su Chen, Cheng Miao, Yubin Cao, Meng Wang, Wenwen Liu, Jiefei Shen, Patrick Ming-Kuen Tang, Yi Men, Li Ye, Chunjie Li

Resection of oral and maxillofacial tumors is often accompanied by the inferior alveolar nerve neurectomy, resulting in abnormal sensation in lower lip. It is generally believed that spontaneous sensory recovery in this nerve injury is difficult. However, during our follow-up, patients with inferior alveolar nerve sacrifice showed different degrees of lower lip sensory recovery. In this study, a prospective cohort study was conducted to demonstrate this phenomenon and analyze the factors influencing sensory recovery. A mental nerve transection model of Thy1-YFP mice and tissue clearing technique were used to explore possible mechanisms in this process. Gene silencing and overexpression experiments were then conducted to detect the changes in cell morphology and molecular markers. In our follow-up, 75% of patients with unilateral inferior alveolar nerve neurectomy had complete sensory recovery of the lower lip 12 months postoperatively. Patients with younger age, malignant tumors, and preservation of ipsilateral buccal and lingual nerves had a shorter recovery time. The buccal nerve collateral sprouting compensation was observed in the lower lip tissue of Thy1-YFP mice. ApoD was demonstrated to be involved in axon growth and peripheral nerve sensory recovery in the animal model. TGF-β inhibited the expression of STAT3 and the transcription of ApoD in Schwann cells through Zfp423. Overall, after sacrificing the inferior alveolar nerve, the collateral compensation of the ipsilateral buccal nerve could innervate the sensation. And this process was regulated by TGF-β-Zfp423-ApoD pathway.

口腔颌面部肿瘤切除术常伴有下肺泡神经切除术,造成下唇感觉异常。一般认为,这种神经损伤的自发性感觉恢复是困难的。然而,在我们的随访中,下肺泡神经牺牲的患者表现出不同程度的下唇感觉恢复。本研究通过前瞻性队列研究证实了这一现象,并分析了影响感觉恢复的因素。采用Thy1-YFP小鼠心神经横断模型和组织清除技术探讨其可能的机制。然后进行基因沉默和过表达实验,检测细胞形态和分子标记的变化。在我们的随访中,75%的单侧下肺泡神经切除术患者术后12个月下唇感觉功能完全恢复。年龄较小、肿瘤恶性、保留同侧颊、舌神经的患者恢复时间较短。在Thy1-YFP小鼠下唇组织中观察到颊神经侧枝发芽代偿。在动物模型中证实ApoD参与轴突生长和周围神经感觉恢复。TGF-β通过Zfp423抑制雪旺细胞STAT3的表达和ApoD的转录。综上所述,牺牲下牙槽神经后,同侧颊神经的侧支代偿可以支配感觉。该过程受TGF-β-Zfp423-ApoD通路调控。
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International Journal of Oral Science
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