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Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK 苯乙双胍通过 NIBAN1 和 DDIT4 激活 ER 应激,促进口腔鳞状细胞癌细胞自噬性死亡,而与 AMPK 无关
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-05-08 DOI: 10.1038/s41368-024-00297-w
Dexuan Zhuang, Shuangshuang Wang, Huiting Deng, Yuxin Shi, Chang Liu, Xue Leng, Qun Zhang, Fuxiang Bai, Bin Zheng, Jing Guo, Xunwei Wu

The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors, however, not much is known about the influence of phenformin on OSCC cells. We found that phenformin suppresses OSCC cell proliferation, and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro. RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4 (DNA damage inducible transcript 4) and NIBAN1 (niban apoptosis regulator 1). We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy. Further, the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4 (activation transcription factor 4), which was induced by phenformin treatment in OSCC cells. Mechanistically, these results revealed that phenformin triggers endoplasmic reticulum (ER) stress to activate PERK (protein kinase R-like ER kinase), which phosphorylates the transitional initial factor eIF2, and the increased phosphorylation of eIF2 leads to the increased translation of ATF4. In summary, we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth. Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

口腔鳞状细胞癌(OSCC)的有效临床治疗仍然是一项挑战,需要开发有效的新药。与二甲双胍相比,苯乙双胍对不同肿瘤具有更强的抗肿瘤活性,但苯乙双胍对OSCC细胞的影响却鲜为人知。我们发现苯乙双胍可抑制OSCC细胞增殖,促进OSCC细胞自噬和凋亡,从而显著抑制OSCC细胞在体内和体外的生长。RNA-seq分析显示,自噬通路是苯福明的主要靶点,并发现了两个新靶点DDIT4(DNA损伤诱导转录本4)和NIBAN1(尼班凋亡调节因子1)。我们发现苯福明能明显诱导DDIT4和NIBAN1的表达,从而促进OSCC的自噬。此外,苯乙福明诱导的DDIT4和NIBAN1的表达增强并未被AMPK的敲除所阻断,但却被苯乙福明处理OSCC细胞时诱导的转录因子ATF4(活化转录因子4)的敲除所抑制。这些结果从机理上揭示了苯福明引发内质网(ER)应激激活PERK(蛋白激酶R样ER激酶),PERK使过渡初始因子eIF2磷酸化,eIF2磷酸化增加导致ATF4翻译增加。综上所述,我们发现苯乙双胍能诱导其新靶点DDIT4,尤其是NIBAN1,促进细胞自噬和凋亡,从而抑制OSCC细胞的生长。我们的研究为苯福明在未来治疗 OSCC 的潜在临床应用提供了支持。
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引用次数: 0
Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration 支架诱导缝合间充质再生的转录组和细胞解码
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-04-23 DOI: 10.1038/s41368-024-00295-y
Jiayi Wu, Feifei Li, Peng Yu, Changhao Yu, Chuyi Han, Yitian Wang, Fanyuan Yu, Ling Ye

Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.

精确协调细胞命运决定是基于支架的骨骼再生成功的基础。尽管对矿化实质组织重建进行了广泛研究,但再生和维持钙骨内未分化间充质仍极具挑战性,进展有限。现有知识证明,重建缝间充质干细胞龛对避免严重的脑损伤甚至系统性损伤是不可或缺的。但迄今为止,仍缺乏有前景的治疗生物材料/支架。究其原因,在于缺乏了解支架细胞命运调控的基础知识和方法证据。为了解决这些问题,在本研究中,我们系统地研究了不同类型的常用腓骨支架对细胞命运的决定作用和转录组机制。我们的数据阐明了无支架移植的自然过程,并展示了不同支架如何改变体内细胞反应。接下来,我们确定了一种可行的支架--聚乳酸电纺丝膜(PLA),它能精确控制间充质的生长和自我更新,在缺损中心重建非骨质生成的缝合线样组织,同时支持与缺损骨边缘的适当骨整合。特别是,该研究通过转录组分析,破译了 PLA 精心策划的细胞命运决定的细胞机制。这项研究首次从细胞角度解读了缝合骨复合体缺损愈合过程中支架的命运调控,为临床医生再生此类复杂损伤提供了可能的选择。
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引用次数: 0
Single cell analysis unveils B cell-dominated immune subtypes in HNSCC for enhanced prognostic and therapeutic stratification 单细胞分析揭示了 HNSCC 中以 B 细胞为主的免疫亚型,有助于加强预后和治疗分层
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-04-16 DOI: 10.1038/s41368-024-00292-1
Kang Li, Caihua Zhang, Ruoxing Zhou, Maosheng Cheng, Rongsong Ling, Gan Xiong, Jieyi Ma, Yan Zhu, Shuang Chen, Jie Chen, Demeng Chen, Liang Peng

Head and neck squamous cell carcinoma (HNSCC) is characterized by high recurrence or distant metastases rate and the prognosis is challenging. There is mounting evidence that tumor-infiltrating B cells (TIL-Bs) have a crucial, synergistic role in tumor control. However, little is known about the role TIL-Bs play in immune microenvironment and the way TIL-Bs affect the outcome of immune checkpoint blockade. Using single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, the study identified distinct gene expression patterns in TIL-Bs. HNSCC samples were categorized into TIL-Bs inhibition and TIL-Bs activation groups using unsupervised clustering. This classification was further validated with TCGA HNSCC data, correlating with patient prognosis, immune cell infiltration, and response to immunotherapy. We found that the B cells activation group exhibited a better prognosis, higher immune cell infiltration, and distinct immune checkpoint levels, including elevated PD-L1. A prognostic model was also developed and validated, highlighting four genes as potential biomarkers for predicting survival outcomes in HNSCC patients. Overall, this study provides a foundational approach for B cells-based tumor classification in HNSCC, offering insights into targeted treatment and immunotherapy strategies.

头颈部鳞状细胞癌(HNSCC)的特点是高复发率或远处转移率,预后极具挑战性。越来越多的证据表明,肿瘤浸润B细胞(TIL-Bs)在肿瘤控制中发挥着至关重要的协同作用。然而,人们对TIL-Bs在免疫微环境中的作用以及TIL-Bs如何影响免疫检查点阻断的结果知之甚少。该研究利用基因表达总库(GEO)数据库中的单细胞RNA测序(scRNA-seq)数据,确定了TIL-Bs中不同的基因表达模式。利用无监督聚类将HNSCC样本分为TIL-Bs抑制组和TIL-Bs激活组。我们利用 TCGA HNSCC 数据进一步验证了这种分类方法,它与患者的预后、免疫细胞浸润和对免疫疗法的反应相关。我们发现,B 细胞激活组的预后较好,免疫细胞浸润较高,免疫检查点水平明显,包括 PD-L1 升高。我们还建立并验证了一个预后模型,其中强调了四个基因作为预测 HNSCC 患者生存结果的潜在生物标志物。总之,这项研究为基于 B 细胞的 HNSCC 肿瘤分类提供了一种基础方法,为靶向治疗和免疫疗法策略提供了启示。
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引用次数: 0
Tetrahedral framework nucleic acids/hyaluronic acid-methacrylic anhydride hybrid hydrogel with antimicrobial and anti-inflammatory properties for infected wound healing 具有抗菌消炎特性的四面体框架核酸/透明质酸-甲基丙烯酸酐杂化水凝胶,用于感染伤口愈合
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-04-16 DOI: 10.1038/s41368-024-00290-3
Cai Qi, Qiang Sun, Dexuan Xiao, Mei Zhang, Shaojingya Gao, Bin Guo, Yunfeng Lin

Bacterial resistance and excessive inflammation are common issues that hinder wound healing. Antimicrobial peptides (AMPs) offer a promising and versatile antibacterial option compared to traditional antibiotics, with additional anti-inflammatory properties. However, the applications of AMPs are limited by their antimicrobial effects and stability against bacterial degradation. TFNAs are regarded as a promising drug delivery platform that could enhance the antibacterial properties and stability of nanodrugs. Therefore, in this study, a composite hydrogel (HAMA/t-GL13K) was prepared via the photocross-linking method, in which tFNAs carry GL13K. The hydrogel was injectable, biocompatible, and could be instantly photocured. It exhibited broad-spectrum antibacterial and anti-inflammatory properties by inhibiting the expression of inflammatory factors and scavenging ROS. Thereby, the hydrogel inhibited bacterial infection, shortened the wound healing time of skin defects in infected skin full-thickness defect wound models and reduced scarring. The constructed HAMA/tFNA-AMPs hydrogels exhibit the potential for clinical use in treating microbial infections and promoting wound healing.

细菌耐药性和过度炎症是阻碍伤口愈合的常见问题。与传统抗生素相比,抗菌肽(AMPs)提供了一种前景广阔的多功能抗菌选择,并具有额外的抗炎特性。然而,AMPs 的应用受到其抗菌效果和抗细菌降解稳定性的限制。TFNA 被认为是一种很有前景的给药平台,可以增强纳米药物的抗菌性能和稳定性。因此,本研究通过光交联法制备了一种复合水凝胶(HAMA/t-GL13K),其中 tFNAs 带有 GL13K。该水凝胶可注射,生物相容性好,可瞬间光固化。它通过抑制炎症因子的表达和清除 ROS,表现出广谱抗菌和抗炎特性。因此,该水凝胶可抑制细菌感染,缩短感染性皮肤全厚缺损伤口模型的伤口愈合时间,并减少瘢痕形成。所构建的 HAMA/tFNA-AMPs 水凝胶具有治疗微生物感染和促进伤口愈合的临床应用潜力。
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引用次数: 0
Tailored apoptotic vesicles promote bone regeneration by releasing the osteoinductive brake 定制的凋亡囊泡通过释放骨诱导制动器促进骨再生
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-04-16 DOI: 10.1038/s41368-024-00293-0
Yawen Cheng, Yuan Zhu, Yaoshan Liu, Xuenan Liu, Yanan Ding, Deli Li, Xiao Zhang, Yunsong Liu

Accumulating evidence has demonstrated that apoptotic vesicles (apoVs) derived from mesenchymal stem cells (MSCs; MSC-apoVs) are vital for bone regeneration, and possess superior capabilities compared to MSCs and other extracellular vesicles derived from MSCs (such as exosomes). The osteoinductive effect of MSC-apoVs is attributed to their diverse contents, especially enriched proteins or microRNAs (miRNAs). To optimize their osteoinduction activity, it is necessary to determine the unique cargo profiles of MSC-apoVs. We previously established the protein landscape and identified proteins specific to MSC-apoVs. However, the features and functions of miRNAs enriched in MSC-apoVs are unclear. In this study, we compared MSCs, MSC-apoVs, and MSC-exosomes from two types of MSC. We generated a map of miRNAs specific to MSC-apoVs and identified seven miRNAs specifically enriched in MSC-apoVs compared to MSCs and MSC-exosomes, which we classified as apoV-specific miRNAs. Among these seven specific miRNAs, hsa-miR-4485-3p was the most abundant and stable. Next, we explored its function in apoV-mediated osteoinduction. Unexpectedly, hsa-miR-4485-3p enriched in MSC-apoVs inhibited osteogenesis and promoted adipogenesis by targeting the AKT pathway. Tailored apoVs with downregulated hsa-miR-4485-3p exhibited a greater effect on bone regeneration than control apoVs. Like releasing the brake, we acquired more powerful osteoinductive apoVs. In summary, we identified the miRNA cargos, including miRNAs specific to MSC-apoVs, and generated tailored apoVs with high osteoinduction activity, which is promising in apoV-based therapies for bone regeneration.

越来越多的证据表明,间充质干细胞(间充质干细胞;MSC-apoVs)产生的凋亡囊泡(apoVs)对骨再生至关重要,与间充质干细胞和间充质干细胞产生的其他细胞外囊泡(如外泌体)相比,间充质干细胞-apoVs具有更强的能力。间充质干细胞无泡囊泡的骨诱导作用归因于其丰富的内容物,尤其是富含蛋白质或微量核糖核酸(miRNA)。为了优化它们的骨诱导活性,有必要确定间充质干细胞蛋白apoVs独特的载货特征。我们以前曾建立了间充质干细胞-apoVs的蛋白质图谱,并鉴定了间充质干细胞-apoVs的特异性蛋白质。然而,MSC-apoVs中富集的miRNA的特征和功能尚不清楚。在这项研究中,我们比较了来自两种间充质干细胞的间充质干细胞、间充质干细胞apoVs和间充质干细胞外泌体。我们绘制了一张MSC-apoVs特异性miRNA图谱,并发现了7种与间充质干细胞和间充质干细胞外小体相比在MSC-apoVs中特异性富集的miRNA,我们把它们归类为载脂蛋白V特异性miRNA。在这七种特异性 miRNA 中,hsa-miR-4485-3p 的含量最高且最稳定。接下来,我们探讨了它在载脂蛋白V介导的骨诱导中的功能。意想不到的是,在间充质干细胞-apoVs中富集的hsa-miR-4485-3p通过靶向AKT通路抑制骨生成并促进脂肪生成。与对照apoVs相比,下调了hsa-miR-4485-3p的定制apoVs对骨再生的影响更大。就像松开刹车一样,我们获得了更强大的骨诱导载脂蛋白。总之,我们鉴定了miRNA cargos,包括间充质干细胞载脂蛋白的特异性miRNA,并生成了具有高骨诱导活性的定制载脂蛋白,这在基于载脂蛋白的骨再生疗法中大有可为。
{"title":"Tailored apoptotic vesicles promote bone regeneration by releasing the osteoinductive brake","authors":"Yawen Cheng, Yuan Zhu, Yaoshan Liu, Xuenan Liu, Yanan Ding, Deli Li, Xiao Zhang, Yunsong Liu","doi":"10.1038/s41368-024-00293-0","DOIUrl":"https://doi.org/10.1038/s41368-024-00293-0","url":null,"abstract":"<p>Accumulating evidence has demonstrated that apoptotic vesicles (apoVs) derived from mesenchymal stem cells (MSCs; MSC-apoVs) are vital for bone regeneration, and possess superior capabilities compared to MSCs and other extracellular vesicles derived from MSCs (such as exosomes). The osteoinductive effect of MSC-apoVs is attributed to their diverse contents, especially enriched proteins or microRNAs (miRNAs). To optimize their osteoinduction activity, it is necessary to determine the unique cargo profiles of MSC-apoVs. We previously established the protein landscape and identified proteins specific to MSC-apoVs. However, the features and functions of miRNAs enriched in MSC-apoVs are unclear. In this study, we compared MSCs, MSC-apoVs, and MSC-exosomes from two types of MSC. We generated a map of miRNAs specific to MSC-apoVs and identified seven miRNAs specifically enriched in MSC-apoVs compared to MSCs and MSC-exosomes, which we classified as apoV-specific miRNAs. Among these seven specific miRNAs, hsa-miR-4485-3p was the most abundant and stable. Next, we explored its function in apoV-mediated osteoinduction. Unexpectedly, hsa-miR-4485-3p enriched in MSC-apoVs inhibited osteogenesis and promoted adipogenesis by targeting the AKT pathway. Tailored apoVs with downregulated hsa-miR-4485-3p exhibited a greater effect on bone regeneration than control apoVs. Like releasing the brake, we acquired more powerful osteoinductive apoVs. In summary, we identified the miRNA cargos, including miRNAs specific to MSC-apoVs, and generated tailored apoVs with high osteoinduction activity, which is promising in apoV-based therapies for bone regeneration.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"41 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expert consensus on pediatric orthodontic therapies of malocclusions in children 儿童牙齿畸形矫治专家共识
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-04-16 DOI: 10.1038/s41368-024-00299-8
Chenchen Zhou, Peipei Duan, Hong He, Jinlin Song, Min Hu, Yuehua Liu, Yan Liu, Jie Guo, Fang Jin, Yang Cao, Lingyong Jiang, Qingsong Ye, Min Zhu, Beizhan Jiang, Wenhua Ruan, Xiao Yuan, Huang Li, Rui Zou, Yulou Tian, Li Gao, Rui Shu, Jianwei Chen, Renkai Liu, Shujuan Zou, Xiaobing Li

Malocclusion, identified by the World Health Organization (WHO) as one of three major oral diseases, profoundly impacts the dental-maxillofacial functions, facial esthetics, and long-term development of ~260 million children in China. Beyond its physical manifestations, malocclusion also significantly influences the psycho-social well-being of these children. Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition, by mitigating the negative impact of abnormal environmental influences on the growth. Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development, ranging from fetal stages to the early permanent dentition phase. From an economic and societal standpoint, the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated, underlining its profound practical and social importance. This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children, emphasizing critical need for early treatment. It elaborates on corresponding core principles and fundamental approaches in early orthodontics, proposing comprehensive guidance for preventive and interceptive orthodontic treatment, serving as a reference for clinicians engaged in early orthodontic treatment.

错颌畸形被世界卫生组织(WHO)确定为三大口腔疾病之一,对中国约 2.6 亿儿童的牙颌面功能、面部美观和长期发展造成了深远影响。除了身体上的表现,错颌畸形还严重影响着这些儿童的社会心理健康。对错颌畸形的及时干预可以营造一个有利于牙颌面发育的环境,通过减轻异常环境对生长发育的负面影响,大大降低错颌畸形的发生率或降低恒牙列错颌畸形的严重性和复杂性。早期正畸治疗包括准确识别和治疗牙颌面发育各个阶段的牙颌面形态和功能异常,从胎儿阶段到恒牙早期阶段。从经济和社会的角度来看,对儿童期错颌畸形进行有效的早期正畸治疗的紧迫性怎么强调都不为过,这凸显了其深远的现实意义和社会重要性。本共识文件讨论了儿童错颌畸形的特点和有害影响,强调了早期治疗的关键必要性。它阐述了早期正畸的相应核心原则和基本方法,为预防性和阻断性正畸治疗提出了全面的指导,可供从事早期正畸治疗的临床医生参考。
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引用次数: 0
The evolution of robotics: research and application progress of dental implant robotic systems 机器人技术的发展:牙科植入机器人系统的研究与应用进展
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-04-08 DOI: 10.1038/s41368-024-00296-x
Chen Liu, Yuchen Liu, Rui Xie, Zhiwen Li, Shizhu Bai, Yimin Zhao

The use of robots to augment human capabilities and assist in work has long been an aspiration. Robotics has been developing since the 1960s when the first industrial robot was introduced. As technology has advanced, robotic-assisted surgery has shown numerous advantages, including more precision, efficiency, minimal invasiveness, and safety than is possible with conventional techniques, which are research hotspots and cutting-edge trends. This article reviewed the history of medical robot development and seminal research papers about current research progress. Taking the autonomous dental implant robotic system as an example, the advantages and prospects of medical robotic systems would be discussed which would provide a reference for future research.

长期以来,人们一直希望使用机器人来增强人类的能力并协助工作。自 20 世纪 60 年代第一台工业机器人问世以来,机器人技术一直在不断发展。随着技术的发展,机器人辅助外科手术已显示出诸多优势,包括比传统技术更精确、更高效、微创和更安全,这些都是研究热点和前沿趋势。本文回顾了医疗机器人的发展历史和开创性研究论文,介绍了当前的研究进展。以自主牙科种植机器人系统为例,探讨了医疗机器人系统的优势和前景,为今后的研究提供参考。
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引用次数: 0
Periodontitis exacerbates pulmonary hypertension by promoting IFNγ+ T cell infiltration in mice 牙周炎通过促进小鼠 IFNγ+ T 细胞浸润加剧肺动脉高压
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-03-28 DOI: 10.1038/s41368-024-00291-2
Xiaoqian Meng, Linjuan Du, Shuo Xu, Lujun Zhou, Boyan Chen, Yulin Li, Chumao Chen, Huilin Ye, Jun Zhang, Guocai Tian, Xuebing Bai, Ting Dong, Wenzhen Lin, Mengjun Sun, Kecong Zhou, Yan Liu, Wuchang Zhang, Shengzhong Duan

Uncovering the risk factors of pulmonary hypertension and its mechanisms is crucial for the prevention and treatment of the disease. In the current study, we showed that experimental periodontitis, which was established by ligation of molars followed by orally smearing subgingival plaques from patients with periodontitis, exacerbated hypoxia-induced pulmonary hypertension in mice. Mechanistically, periodontitis dysregulated the pulmonary microbiota by promoting ectopic colonization and enrichment of oral bacteria in the lungs, contributing to pulmonary infiltration of interferon gamma positive (IFNγ+) T cells and aggravating the progression of pulmonary hypertension. In addition, we identified Prevotella zoogleoformans as the critical periodontitis-associated bacterium driving the exacerbation of pulmonary hypertension by periodontitis, and the exacerbation was potently ameliorated by both cervical lymph node excision and IFNγ neutralizing antibodies. Our study suggests a proof of concept that the combined prevention and treatment of periodontitis and pulmonary hypertension are necessary.

揭示肺动脉高压的危险因素及其机制对于预防和治疗该疾病至关重要。在本研究中,我们发现实验性牙周炎(通过结扎磨牙,然后口服涂抹牙周炎患者的龈下斑块而建立)会加剧缺氧诱发的小鼠肺动脉高压。从机理上讲,牙周炎通过促进口腔细菌在肺部的异位定植和富集,使肺部微生物群失调,导致干扰素γ阳性(IFNγ+)T细胞的肺部浸润,加重了肺动脉高压的进展。此外,我们还发现了动物口腔普雷沃特氏菌(Prevotella zoogleoformans)是导致牙周炎加重肺动脉高压的关键牙周炎相关细菌,而颈淋巴结切除术和IFNγ中和抗体都能有效缓解肺动脉高压的加重。我们的研究证明,有必要对牙周炎和肺动脉高压进行联合预防和治疗。
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引用次数: 0
FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression FUT8介导的SEMA7A异常N-糖基化促进头颈部鳞状细胞癌的进展
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-03-28 DOI: 10.1038/s41368-024-00289-w
Zhonglong Liu, Xiaoyan Meng, Yuxin Zhang, Jingjing Sun, Xiao Tang, Zhiyuan Zhang, Liu Liu, Yue He

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

SEMA7A属于Semaphorin家族,参与了肿瘤的发生和发展。异常糖基化与免疫逃逸和肿瘤生长密切相关。SEMA7A 是一种高度糖基化的蛋白质,有五个糖基化位点。SEMA7A糖基化的潜在机制及其对免疫抑制和肿瘤发生的贡献尚不清楚。在这里,我们确定了 SEMA7A 在头颈部鳞状细胞癌中的过表达和异常 N-糖基化,并阐明了岩藻糖基转移酶 FUT8 通过蛋白质与蛋白质之间的直接相互作用,催化 SEMA7A 在 N-连接寡糖(Asn 105、157、258、330 和 602)上的异常核心岩藻糖基化。SEMA7A 的糖基化雕像是其从细胞质到细胞膜的细胞内运输所必需的。细胞因子 EGF 通过增加 SEMA7A 与 FUT8 的结合亲和力来触发 SEMA7A 的 N-糖基化,而 TGF-β1 则通过诱导上皮-间质转化来促进 SEMA7A 的异常糖基化。SEMA7A 的异常 N-糖基化会导致 CD8+ T 细胞沿着衰竭状态的轨迹分化,从而形成免疫抑制性微环境,并导致抗免疫原性细胞死亡。SEMA7A的去糖基化可显著改善表皮生长因子受体靶向和基于抗PD-L1的免疫疗法的临床疗效。最后,我们还发现剪接调节因子 RBM4 是糖基化 SEMA7A 的下游效应因子,也是 PD-L1 替代剪接的关键介质。这些发现表明,靶向 FUT8-SEMA7A 轴可能是改善头颈部鳞状细胞癌患者抗肿瘤反应的一种有前途的策略。
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引用次数: 0
A Wnt10a-Notch signaling axis controls Hertwig's epithelial root sheath cell behaviors during root furcation patterning. Wnt10a-Notch信号轴控制着赫氏上皮根鞘细胞在根皮毛形成过程中的行为。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-03-13 DOI: 10.1038/s41368-024-00288-x
Kai Sun, Miao Yu, Jiayu Wang, Hu Zhao, Haochen Liu, Hailan Feng, Yang Liu, Dong Han

Human with bi-allelic WNT10A mutations and epithelial Wnt10a knockout mice present enlarged pulp chamber and apical displacement of the root furcation of multi-rooted teeth, known as taurodontism; thus, indicating the critical role of Wnt10a in tooth root morphogenesis. However, the endogenous mechanism by which epithelial Wnt10a regulates Hertwig's epithelial root sheath (HERS) cellular behaviors and contributes to root furcation patterning remains unclear. In this study, we found that HERS in the presumptive root furcating region failed to elongate at an appropriate horizontal level in K14-Cre;Wnt10afl/fl mice from post-natal day 0.5 (PN0.5) to PN4.5. EdU assays and immunofluorescent staining of cyclin D1 revealed significantly decreased proliferation activity of inner enamel epithelial (IEE) cells of HERS in K14-Cre;Wnt10afl/fl mice at PN2.5 and PN3.5. Immunofluorescent staining of E-Cadherin and acetyl-α-Tubulin demonstrated that the IEE cells of HERS tended to divide perpendicularly to the horizontal plane, which impaired the horizontal extension of HERS in the presumptive root furcating region of K14-Cre;Wnt10afl/fl mice. RNA-seq and immunofluorescence showed that the expressions of Jag1 and Notch2 were downregulated in IEE cells of HERS in K14-Cre;Wnt10afl/fl mice. Furthermore, after activation of Notch signaling in K14-Cre;Wnt10afl/fl molars by Notch2 adenovirus and kidney capsule grafts, the root furcation defect was partially rescued. Taken together, our study demonstrates that an epithelial Wnt10a-Notch signaling axis is crucial for modulating HERS cell proper proliferation and horizontal-oriented division during tooth root furcation morphogenesis.

WNT10A双等位突变的人类和上皮Wnt10a基因敲除的小鼠表现出牙髓腔扩大和多生根牙齿根嵴顶端移位,即所谓的 "陶牙症",从而表明Wnt10a在牙根形态发生中的关键作用。然而,上皮Wnt10a调控赫氏上皮根鞘(HERS)细胞行为并促进牙根沟形态形成的内源机制仍不清楚。在这项研究中,我们发现从出生后第 0.5 天(PN0.5)到出生后第 4.5 天,K14-Cre;Wnt10afl/fl 小鼠推定根皮毛区的 HERS 未能以适当的水平伸长。EdU测定和细胞周期蛋白D1免疫荧光染色显示,K14-Cre;Wnt10afl/fl小鼠HERS内釉上皮(IEE)细胞的增殖活性在PN2.5和PN3.5时明显下降。E-Cadherin和乙酰基-α-微管蛋白的免疫荧光染色表明,HERS的IEE细胞倾向于垂直于水平面分裂,这阻碍了HERS在K14-Cre;Wnt10afl/fl小鼠的假定根皮脂区的水平延伸。RNA-seq和免疫荧光显示,K14-Cre;Wnt10afl/fl小鼠HERS的IEE细胞中Jag1和Notch2的表达下调。此外,通过Notch2腺病毒和肾囊移植激活K14-Cre;Wnt10afl/fl小鼠磨牙中的Notch信号后,牙根沟缺陷得到了部分修复。综上所述,我们的研究表明,上皮 Wnt10a-Notch 信号轴在牙根犁沟形态发生过程中对于调节 HERS 细胞的正常增殖和水平定向分裂至关重要。
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International Journal of Oral Science
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