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Partial-EMT in oral squamous cell carcinoma: molecular circuitry and clinical translation. 口腔鳞状细胞癌的部分emt:分子电路和临床翻译。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-30 DOI: 10.1038/s41368-025-00417-0
Chunhua Wang,Motoharu Sarubo,Siqi Chen,Yasusei Kudo
Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with high morbidity and mortality. Globally, about 400 000 people are affected, often with a poor quality of life. Its high mortality is mainly due to its aggressive growth and tendency to spread. Epithelial-mesenchymal transition (EMT) is a central regulatory hub driving tumor cell migration and invasion by enabling changes in cell characteristics. During EMT, epithelial cells gradually take on mesenchymal traits, gaining mobility and spreading more easily. Recent multi-omics studies show that many cancer cells exist in a hybrid or partial-EMT state, which lies between the full epithelial and mesenchymal forms. Cells in this state are especially invasive and metastatic, with high plasticity that promotes tumor progression. This review summarizes the role of partial-EMT in OSCC, with a focus on how it alters the tumor microenvironment (TME), promotes invasion and metastasis, and influences cancer stem cells (CSCs). We also highlight the link between partial-EMT and treatment resistance in OSCC. Based on these insights, we discuss therapeutic strategies targeting partial-EMT to improve outcomes. Targeting partial-EMT may offer promising strategies to enhance treatment effectiveness and improve patient survival and quality of life.
口腔鳞状细胞癌(OSCC)是一种发病率和死亡率高的常见恶性肿瘤。在全球范围内,约有40万人受到影响,他们的生活质量往往很差。它的高死亡率主要是由于它的侵略性生长和扩散趋势。上皮-间质转化(Epithelial-mesenchymal transition, EMT)是一个通过改变细胞特性来驱动肿瘤细胞迁移和侵袭的中央调控枢纽。在EMT过程中,上皮细胞逐渐呈现出间充质特性,更容易移动和扩散。最近的多组学研究表明,许多癌细胞处于混合或部分emt状态,介于完全上皮和间充质形态之间。这种状态下的细胞特别具有侵袭性和转移性,具有促进肿瘤进展的高可塑性。本文综述了部分emt在OSCC中的作用,重点介绍了它如何改变肿瘤微环境(TME)、促进侵袭和转移以及影响肿瘤干细胞(CSCs)。我们还强调了部分emt与OSCC治疗耐药性之间的联系。基于这些见解,我们讨论了针对部分emt的治疗策略以改善结果。靶向部分emt可能提供有希望的策略来提高治疗效果,改善患者的生存和生活质量。
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引用次数: 0
Periodontitis-associated salivary microbiota exacerbates systemic osteoclastogenesis via gut modulation and tryptophan metabolism suppression in ovariectomized mice. 在去卵巢小鼠中,牙周炎相关的唾液微生物群通过肠道调节和色氨酸代谢抑制加剧了系统性破骨细胞的形成。
IF 12.2 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-27 DOI: 10.1038/s41368-025-00415-2
Nannan Wang, Jun Qian, Min Wang, Lili Li, Wenzheng Liao, Rixin Chen, Hua Nie, Ruiyang Ge, Fangfang Sun, Fuhua Yan

Epidemiological studies have highlighted an association between periodontitis and osteoporosis. However, the mechanism underlining this association remains unclear. Here, we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients, with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria. Using an ovariectomized (OVX) mouse model, we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota. Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism. The tryptophan metabolite indole-3-lactic acid (ILA) directly inhibited osteoclast formation and differentiation. In OVX mice treated with periodontitis salivary microbiota, supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones. In summary, our data demonstrate that periodontitis can affect systemic bone metabolism via the oral-gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.

流行病学研究强调了牙周炎和骨质疏松症之间的联系。然而,这种关联的机制仍不清楚。在这里,我们发现牙周健康个体和牙周炎患者的唾液微生物群存在显著差异,牙周炎患者的唾液微生物群多样性增加,致病菌丰度升高。使用卵巢切除(OVX)小鼠模型,我们证明牙周炎患者的唾液微生物群通过调节肠道微生物群加剧骨破坏。代谢组学分析显示,牙周炎相关的唾液微生物群抑制色氨酸代谢。色氨酸代谢物吲哚-3-乳酸(ILA)直接抑制破骨细胞的形成和分化。在用牙周炎唾液微生物群治疗的OVX小鼠中,补充ILA有效地抑制了破骨细胞的生成,减轻了牙周炎相关唾液微生物群对全身骨骼的有害影响。总之,我们的数据表明,牙周炎可以通过口腔-肠道轴影响全身骨代谢,而补充ILA可以作为一种潜在的治疗选择来减轻这些不良反应。
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引用次数: 0
Expert consensus on the diagnosis and management of tooth developmental anomalies. 专家对牙齿发育异常的诊断和处理的共识。
IF 12.2 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-20 DOI: 10.1038/s41368-025-00401-8
Jingxian Zhu, Mian Wan, Xiaohong Duan, Zhipeng Fan, Yao Sun, Xudong Wang, Shuguo Zheng, Liwei Zheng, Qinglin Zhu, Dong Chen, Jiewen Dai, Dong Han, Miao He, Cui Huang, Yuegui Jiang, Zhonglin Jia, Yihuai Pan, Yongchu Pan, Tiemei Wang, Wenmei Wang, Baoshan Xu, Wei Yin, Tingting Zhang, Yanli Zhang, Zhenjin Zhao, Zhuan Bian, Yaling Song

Tooth developmental anomalies are a group of disorders caused by unfavorable factors affecting the tooth development process, resulting in abnormalities in tooth number, structure, and morphology. These anomalies typically manifest during childhood, impairing dental function, maxillofacial development, and facial aesthetics, while also potentially impacting overall physical and mental health. The complex etiology and diverse clinical phenotypes of these anomalies pose significant challenges for prevention, early diagnosis, and treatment. As they usually emerge early in life, long-term management and multidisciplinary collaboration in dental care are essential. However, there is currently a lack of systematic clinical guidelines for the diagnosis and treatment of these conditions, adding to the difficulties in clinical practice. In response to this need, this expert consensus summarizes the classifications, etiology, typical clinical manifestations, and diagnostic criteria of tooth developmental anomalies based on current clinical evidence. It also provides prevention strategies and stage-specific clinical management recommendations to guide clinicians in diagnosis and treatment, promoting early intervention and standardized care for these anomalies.

牙齿发育异常是由于影响牙齿发育过程的不利因素而引起的一组疾病,导致牙齿数量、结构、形态等方面的异常。这些异常通常在儿童时期表现出来,损害牙齿功能、颌面发育和面部美观,同时也潜在地影响整体身心健康。这些异常的复杂病因和多样的临床表型对预防、早期诊断和治疗提出了重大挑战。由于它们通常出现在生命早期,长期管理和多学科合作在牙科保健是必不可少的。然而,目前缺乏系统的诊断和治疗这些疾病的临床指南,增加了临床实践的困难。针对这一需求,本专家共识根据目前的临床证据,总结了牙齿发育异常的分类、病因、典型临床表现和诊断标准。它还提供了预防策略和针对不同阶段的临床管理建议,以指导临床医生进行诊断和治疗,促进对这些异常的早期干预和标准化护理。
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引用次数: 0
Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux. 靶向TARDBP-EGFR剪接轴的反义寡核苷酸通过abca1调节的胆固醇外排抑制口腔鳞状细胞癌的进展。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-16 DOI: 10.1038/s41368-025-00402-7
Nan Ni,Moxu Wang,Zhiran Yuan,Leqi Zhang,Jilin Cai,Qingqing Du,Pengcheng Li,Chang Gao,Hanwen Zhang,Yuancheng Li,Hua Yuan
Splice quantitative trait loci (sQTL) serve as another critical link between genetic variations and human diseases, besides expression quantitative trait loci (eQTL). Their role in oral squamous cell carcinoma (OSCC) development remains unexplored. We collected surgically resected cancer and adjacent normal epithelial tissue samples from 67 OSCC cases, and extracted RNA for sequencing after quality control. A genome-wide sQTL analysis was performed using the RNA sequencing data from 67 normal oral epithelial tissue samples. We included peripheral blood DNA samples from 1044 patients with OSCC and 3199 healthy controls to conduct a genome-wide association study. Systematic screening of sQTLs associated with OSCC risk identified a sQTL variant-the rs737540-T allele-independent of eQTLs, significantly associated with an increased risk of OSCC (OR = 1.2, P = 6.84 × 10-4). The rs737540-T allele reduced skipping of EGFR alternative exon 4 by enhancing TAR DNA binding protein (TARDBP) binding to the RNA sequence, leading to increased expression of the longer isoform (EGFR-001) and reduced expression of the truncated isoform (EGFR-004). Compared with EGFR-004, EGFR-001 promoted OSCC cell proliferation by reducing ATP-binding cassette subfamily A member 1 (ABCA1) ubiquitination through lower EGFR phosphorylation. ABCA1 was demonstrated to increase the cholesterol content of the plasma membrane via cholesterol efflux, thus affecting membrane fluidity and vimentin-mediated epithelial-mesenchymal transition. An antisense oligonucleotide targeting rs737540 significantly inhibited OSCC proliferation and reversed membrane cholesterol-induced resistance. This study provides novel insights into how genetic variants regulating alternative splicing contribute to OSCC risk and identifies potential therapeutic targets.
剪接数量性状位点(Splice quantitative trait loci, sQTL)是除表达数量性状位点(expression quantitative trait loci, eQTL)外,遗传变异与人类疾病之间的又一重要联系。它们在口腔鳞状细胞癌(OSCC)发展中的作用尚不清楚。我们收集了67例OSCC手术切除的癌和邻近正常上皮组织样本,并在质量控制后提取RNA进行测序。利用67个正常口腔上皮组织样本的RNA测序数据进行全基因组sQTL分析。我们纳入了1044名OSCC患者和3199名健康对照者的外周血DNA样本,进行全基因组关联研究。系统筛选与OSCC风险相关的sQTL,发现一个独立于eqtl的sQTL变异——rs737540-T等位基因,与OSCC风险增加显著相关(OR = 1.2, P = 6.84 × 10-4)。rs737540-T等位基因通过增强TAR DNA结合蛋白(TARDBP)与RNA序列的结合,减少了EGFR备选外显子4的跳跃,导致较长亚型(EGFR-001)的表达增加,截断亚型(EGFR-004)的表达减少。与EGFR-004相比,EGFR-001通过降低EGFR磷酸化,减少atp结合盒亚家族A成员1 (ABCA1)的泛素化,从而促进OSCC细胞增殖。ABCA1通过胆固醇外溢增加质膜胆固醇含量,从而影响膜流动性和vimentin介导的上皮-间质转化。靶向rs737540的反义寡核苷酸显著抑制OSCC增殖,逆转膜胆固醇诱导的耐药。这项研究提供了关于基因变异如何调节选择性剪接导致OSCC风险的新见解,并确定了潜在的治疗靶点。
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引用次数: 0
Wnt3a promotes in situ dentin formation through NKD1-MSX1 axis-mediated odontogenic differentiation of dental pulp stem cells. Wnt3a通过NKD1-MSX1轴介导的牙髓干细胞成牙分化促进原位牙本质形成。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-13 DOI: 10.1038/s41368-025-00406-3
Haoran Du,Qiong Li,Chenchen Zhou,Junji Xu,Kang Gao,Zixiao Li,Yifan Xu,Ousheng Liu,Bing Li,Jianguang Xu,Jingsong Wang,Hideaki Kagami,Xianqi Li,Su Chen,Jian Zhou
The functional regeneration of the dentin-pulp complex is pivotal for tooth preservation, yet the molecular mechanisms governing odontoblast differentiation remain poorly understood. In the current study, we revealed a distinct NKD1+ subpopulation exhibiting secretory odontoblast characteristics, which was specifically induced in dental pulp stem cells (DPSCs) by Wnt3a, but not by Wnt5a or Wnt10a through single-cell transcriptomic profiling. We then found that the NKD1+ subpopulation was functional conservation, which were consistently identified in the odontoblast layers of developing tooth germs in both murine and miniature pig models, as well as within the apical open area in human molars. This conserved spatial distribution and co-localization with DSPP strongly indicates that NKD1+ cells were active dentin-secreting odontoblasts. Analysis of gene regulatory networks using SCENIC identified MSX1 as a key transcription factor regulating the specification of NKD1+ lineage. Mechanistically, Wnt3a orchestrates a tripartite cascade: upregulating NKD1/MSX1 expression, triggering NKD1 membrane detachment, and facilitating direct NKD1-MSX1 interaction to promote MSX1 nuclear translocation. CUT&Tag analysis demonstrated MSX1 occupancy at promoters of odontogenic regulators, establishing its necessity for odontogenic gene activation. Murine pulp exposure models validated that Wnt3a-activated NKD1-MSX1 signaling significantly enhances reparative dentin formation. This study delineates an evolutionarily conserved Wnt3a-NKD1-MSX1 axis that resolves stem cell heterogeneity into functional odontoblast commitment, providing both mechanistic insights into dentin-pulp regeneration and a foundation for targeted regenerative therapies.
牙本质-牙髓复合体的功能再生是牙齿保存的关键,但控制成牙细胞分化的分子机制仍然知之甚少。在目前的研究中,我们通过单细胞转录组分析发现了一种独特的NKD1+亚群,它具有分泌性成牙细胞特征,这种特征是由Wnt3a在牙髓干细胞(DPSCs)中特异性诱导的,而不是由Wnt5a或Wnt10a诱导的。然后我们发现NKD1+亚群具有功能保守性,在小鼠和微型猪模型中发育中的牙胚的成牙层中以及在人磨牙的顶端开放区域中都一致地发现了NKD1+亚群。这种保守的空间分布和与DSPP的共定位强烈表明NKD1+细胞是活跃的分泌牙本质的成牙细胞。利用SCENIC对基因调控网络进行分析,发现MSX1是调控NKD1+谱系的关键转录因子。在机制上,Wnt3a协调了三方级联:上调NKD1/MSX1表达,触发NKD1膜脱离,促进NKD1-MSX1直接相互作用,促进MSX1核易位。CUT&Tag分析显示MSX1在牙源性调节因子的启动子上占有,从而确定了MSX1在牙源性基因激活中的必要性。小鼠牙髓暴露模型验证了wnt3a激活的NKD1-MSX1信号显著增强修复性牙本质的形成。该研究描述了一个进化上保守的Wnt3a-NKD1-MSX1轴,该轴将干细胞异质性分解为功能性成牙本质细胞,为牙本质-牙髓再生提供了机制见解,并为靶向再生治疗奠定了基础。
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引用次数: 0
MARCH2 suppresses odontoblast differentiation by polyubiquitinating PTPRD. MARCH2通过泛素化PTPRD抑制成牙细胞分化。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-10 DOI: 10.1038/s41368-025-00407-2
Hao Feng,Jiaxin Niu,Zhi Chen,Guobin Yang,Guohua Yuan
Dentin, the main component of dental hard tissues, is produced by differentiated odontoblasts. How odontoblast differentiation is regulated remains understudied. Here, we screen that the expression of membrane-associated RING finger protein 2 (March2) is the highest among all March family members, with an increasing trend during odontoblast differentiation. In mouse incisors and molars, MARCH2 is moderately expressed in the undifferentiated dental papilla cells and strongly expressed in the odontoblasts. Knockdown and overexpression experiments demonstrate that MARCH2 inhibits odontoblastic differentiation of mouse dental papilla cells (mDPCs). Additionally, both March2 deficient mice and mice with odontoblast specific knockdown of March2 exhibit the phenotype of increased dentin thickness, accelerated dentin deposition as well as elevated expression levels of odontoblast markers compared with control littermates. Therefore, MARCH2 plays an inhibitory role in odontoblast differentiation. Mechanistically, MARCH2 interacts with protein tyrosine phosphatase receptor delta (PTPRD) and facilitates its K27-linked polyubiquitination and subsequent degradation, which is dependent on the ligase activity of MARCH2. The presence of MARCH2 promotes the translocation of PTPRD from the cell membrane to the lysosome, thereby enhancing its degradation via the lysosomal pathway. Further experiments show that knockdown of endogenous Ptprd impairs odontoblastic differentiation of mDPCs. Ptprd and March2 double knockdown in mDPCs apparently reversed the enhanced odontoblastic differentiation by knockdown of March2 alone, indicating that MARCH2 inhibits odontoblastic differentiation by promoting PTPRD degradation. This study unveils a novel mechanism where an E3 ubiquitin ligase regulates odontoblast differentiation through post-translational modification of a membrane protein, highlighting a promising direction for future exploration.
牙本质是牙硬组织的主要组成部分,由分化的成牙细胞产生。成牙细胞分化是如何被调控的仍有待研究。本研究通过筛选发现,膜相关环指蛋白2 (March2)在March家族成员中表达最高,并在成牙细胞分化过程中呈上升趋势。在小鼠门牙和磨牙中,MARCH2在未分化的牙乳头细胞中中等表达,在成牙细胞中强烈表达。敲低和过表达实验表明,MARCH2抑制小鼠牙乳头细胞(mDPCs)的成牙细胞分化。此外,与对照组相比,March2缺陷小鼠和成牙本质特异性敲除March2的小鼠均表现出牙本质厚度增加、牙本质沉积加速以及成牙本质标志物表达水平升高的表型。因此,MARCH2在成牙细胞分化中起抑制作用。从机制上讲,MARCH2与蛋白酪氨酸磷酸酶受体(PTPRD)相互作用,促进其k27连接的多泛素化和随后的降解,这取决于MARCH2的连接酶活性。MARCH2的存在促进PTPRD从细胞膜向溶酶体的易位,从而通过溶酶体途径增强其降解。进一步的实验表明,内源性Ptprd的下调会损害mDPCs的成牙细胞分化。mDPCs中Ptprd和March2双敲低明显逆转了仅敲低March2增强的成牙细胞分化,表明March2通过促进Ptprd降解抑制成牙细胞分化。本研究揭示了E3泛素连接酶通过翻译后修饰膜蛋白调控成牙细胞分化的新机制,为未来的探索指明了一个有希望的方向。
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引用次数: 0
Periodontitis pathogen Porphyromonas gingivalis promotes chronic obstructive pulmonary disease via affecting neutrophils chemotaxis and function. 牙周炎病原体牙龈卟啉单胞菌通过影响中性粒细胞趋化性和功能促进慢性阻塞性肺疾病。
IF 12.2 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-09 DOI: 10.1038/s41368-025-00397-1
Luyao Zhang, Huan Tian, Yuanyuan Ma, Jing Xu, Chang Guo, Zuomin Wang, Jie Ma

Chronic obstructive pulmonary disease (COPD), a disease responsible for early mortality worldwide, is well accepted to be associated with periodontitis epidemiologically. Although both of the diseases are the multi-microbial inflammatory disease, the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown. Here, we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology, characterized by poorer respiratory function, thickened bronchial walls, and increased neutrophils infiltration in lung tissue. Mechanistically, periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) relocated in the lung through the respiratory tract and LPS from P. gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils. Furthermore, exposure to P. gingivalis of infiltrated neutrophils released matrix metallopeptidase-8 (MMP-8) and neutrophil elastase (NE), which aggravated airway inflammation and tissue damage. These findings indicated that periodontitis could exacerbate COPD via its pathogen P. gingivalis, which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.

慢性阻塞性肺疾病(COPD)是导致全球早期死亡的一种疾病,在流行病学上被普遍认为与牙周炎有关。虽然这两种疾病都是多微生物炎症性疾病,但牙周炎影响慢性阻塞性肺病进展的确切潜在机制在很大程度上仍然未知。在这里,我们建立了慢性阻塞性肺病伴牙周炎小鼠模型,观察到肺部症状和组织病理学的明显进展,其特征是呼吸功能变差,支气管壁增厚,肺组织中中性粒细胞浸润增加。机制上,牙周炎病原体牙龈卟啉单胞菌(P. gingivalis)通过呼吸道重新定位到肺部,牙龈卟啉单胞菌的LPS通过NF-κB和p38 MAPK途径促进肺泡上皮细胞分泌趋化因子CXCL2和G-CSF募集中性粒细胞。此外,浸润的中性粒细胞暴露于牙龈假单胞菌,释放基质金属肽酶-8 (MMP-8)和中性粒细胞弹性蛋白酶(NE),加重气道炎症和组织损伤。这些结果表明,牙周炎可通过其病原菌牙龈卟啉单胞菌(P. gingivalis)在肺中易位并刺激肺中性粒细胞趋化和活化而加重COPD。
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引用次数: 0
SMAD7 regulates the canonical Wnt signaling through TGF-β cascade crosstalk and SMAD7/β-CATENIN transcription factor complex formation during tooth regeneration. SMAD7在牙齿再生过程中通过TGF-β级联串和SMAD7/β-CATENIN转录因子复合物的形成调控典型Wnt信号。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-06 DOI: 10.1038/s41368-025-00393-5
Qiuyu Chen,Zhi Liu,Bohuai Zhou,Cheng Liang,Yiping Chen,Weidong Tian,Tian Chen
Tooth morphogenesis is orchestrated by a complex interplay of signaling pathways and transcription factors that control cell proliferation, apoptosis, and differentiation, with the Wnt/β-catenin signaling pathway playing a pivotal role. However, the comprehensive regulatory mechanisms of Wnt/β-catenin signaling remain largely unclear. Smad7, a key antagonist of the TGF-β superfamily, is essential for maintaining tissue homeostasis and ensuring proper cellular function. Our previous study has demonstrated that Smad7 knockout in mice leads to impaired proliferative property of tooth germ cells, resulting in small molars. Here, we identified SMAD7 expression in human dental papilla and dental pulp, colocalized with β-CATENIN and cell proliferation-related proteins. RNA sequencing analysis revealed a significant reduction in Wnt signaling activity in Smad7-deficient mouse tooth germs. Using lentivirus transfection, we established SMAD7-knockdown human dental papilla stem cells, which manifested remarkably blunt proliferation rate, along with diminished Wnt signaling activity. In vivo transplantation investigations further revealed the indispensable role of SMAD7 in dentin formation. Mechanistically, we revealed that β-CATENIN interacts with P-SMAD2/3 and SMAD7 through co-immunoprecipitation and yeast two-hybrid assays. Inhibition of TGF-β pathway or disruption of SMAD7/β-CATENIN transcription factor complex formation potently impacted Wnt/β-catenin activities, indicating both direct and indirect regulatory mechanisms. These findings highlight the critical role of SMAD7 in the proliferation and differentiation of human dental stem cells, which could contribute to dental tissue regeneration and engineering.
牙齿形态发生是由控制细胞增殖、凋亡和分化的信号通路和转录因子的复杂相互作用精心组织的,其中Wnt/β-catenin信号通路起着关键作用。然而,Wnt/β-catenin信号的综合调控机制在很大程度上仍不清楚。Smad7是TGF-β超家族的关键拮抗剂,对于维持组织稳态和确保适当的细胞功能至关重要。我们之前的研究表明,Smad7基因敲除会导致小鼠牙齿生殖细胞增殖能力受损,导致臼齿变小。在这里,我们发现SMAD7在人牙乳头和牙髓中表达,并与β-CATENIN和细胞增殖相关蛋白共定位。RNA测序分析显示,在smad7缺失的小鼠牙齿细菌中,Wnt信号活性显著降低。通过慢病毒转染,我们建立了smad7敲低的人牙乳头干细胞,其增殖速度明显减慢,Wnt信号活性降低。体内移植研究进一步揭示了SMAD7在牙本质形成中不可或缺的作用。在机制上,我们通过共免疫沉淀和酵母双杂交实验发现β-CATENIN与P-SMAD2/3和SMAD7相互作用。抑制TGF-β通路或破坏SMAD7/β-CATENIN转录因子复合物的形成可能会影响Wnt/ β-CATENIN活性,这表明了直接和间接的调节机制。这些发现强调了SMAD7在人牙干细胞增殖和分化中的关键作用,这可能有助于牙组织再生和工程。
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引用次数: 0
Structure insight into FtsZ function maintaining under acid stress of Streptococcus mutans. 变形链球菌酸胁迫下FtsZ功能维持的结构研究。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-04 DOI: 10.1038/s41368-025-00400-9
Yuxing Chen,Yongliang Li,Jiahao Niu,Liuchang Yang,Yaqi Chi,Xue Cai,Fengjiao Xin,Jie Zhang,Xianyang Fang,Yiqin Gao,Manas Mondal,Xiaoyan Wang
Understanding the acid resistance mechanism of S. mutans is crucial for preventing dental caries. FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis. Our previous study revealed that the FtsZ in S. mutans (SmFtsZ) has higher self-assembly and GTPase activity under acidic stress, which may be responsible for acid resistance and cariogenesis of S. mutans. However, the functional structure mechanism of SmFtsZ under low pH conditions is still unclear. Here, we further reported the crystal structure of S. mutans FtsZ, revealing a unique lateral interface. Through protein polymerization and GTPase activity assay, we experimentally demonstrated that the mutation of Arg68 on this lateral interface significantly reduced the functional activity of FtsZ in an acidic environment. The phenotype assay and rat caries model further showed that the mutation of Arg68 effectively inhibited the acid resistance of S. mutans and the occurrence and progress of dental caries in vivo. By employing a molecular dynamics simulation analysis, we conclude that the mutation of Arg68 disrupts the conformation change necessary for SmFtsZ polymerization under acidic conditions. Our study proposes a novel mechanism to maintain FtsZ function in bacteria and could be a potential target for antimicrobial drugs to inhibit the growth of S. mutans in acidic environments.
了解变形链球菌的耐酸机制对预防龋齿至关重要。FtsZ是细菌细胞分裂的核心蛋白,可以聚合成z环并驱动细胞分裂。我们前期的研究发现,突变链球菌中的FtsZ (SmFtsZ)在酸性胁迫下具有较高的自组装和GTPase活性,这可能是突变链球菌耐酸性和龋齿发生的原因。然而,SmFtsZ在低pH条件下的功能结构机制尚不清楚。在这里,我们进一步报道了S. mutans FtsZ的晶体结构,揭示了一个独特的侧向界面。通过蛋白聚合和GTPase活性测定,我们实验证明了Arg68在该侧界面上的突变显著降低了FtsZ在酸性环境中的功能活性。表型实验和大鼠龋模型进一步表明,Arg68突变有效抑制变形链球菌的耐酸能力和体内龋的发生发展。通过分子动力学模拟分析,我们得出结论,Arg68的突变破坏了酸性条件下SmFtsZ聚合所需的构象变化。我们的研究提出了一种维持细菌中FtsZ功能的新机制,可能成为抗菌药物抑制变形链球菌在酸性环境中生长的潜在靶点。
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引用次数: 0
Next-generation craniomaxillofacial implants for reconstructive surgery: balancing biomechanics, biocompatibility, and bioactivity. 用于重建手术的下一代颅颌面植入物:平衡生物力学、生物相容性和生物活性。
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2026-01-04 DOI: 10.1038/s41368-025-00410-7
Bozhi Hou,Yuehua Li,Raymond Chung Wen Wong
Next-generation craniomaxillofacial implants (CMFIs) are redefining personalized bone reconstruction by balancing and optimizing biomechanics, biocompatibility, and bioactivity-the "3Bs". This review highlights recent progress in implant design, material development, additive manufacturing, and preclinical evaluation. Emerging biomaterials, including bioresorbable polymers, magnesium alloys, and composites with bioactive ceramics, enable patient-specific solutions with improved safety and functionality. Triply periodic minimal surface (TPMS) architectures exemplify how structural design can enhance both mechanical performance and biological integration. Additive manufacturing technologies further allow the fabrication of geometrically complex, customized implants that meet individual anatomical and pathological needs. In parallel, multiscale evaluation techniques-from mechanical testing to in vitro and in vivo models-provide comprehensive insights into implant performance and safety. Looking ahead, the field is poised to benefit from several transformative trends: the development of smart and multifunctional biomaterials; AI-driven design frameworks that leverage patient-specific data and computational modeling; predictive additive manufacturing with real-time quality control; and advanced biological testing platforms for preclinical evaluation. Together, these advances form the foundation of a data-informed, translational pipeline from bench to bedside. Realizing the full potential of next-generation CMFIs will require close interdisciplinary collaboration across materials science, computational engineering, and clinical medicine.
下一代颅颌面植入物(cmfi)通过平衡和优化生物力学、生物相容性和生物活性(“3b”)来重新定义个性化骨重建。本文综述了种植体设计、材料开发、增材制造和临床前评估方面的最新进展。新兴的生物材料,包括生物可吸收聚合物、镁合金和具有生物活性陶瓷的复合材料,使患者特定的解决方案具有更高的安全性和功能性。三周期最小表面(TPMS)结构说明了结构设计如何提高机械性能和生物集成。增材制造技术进一步允许制造几何复杂的定制植入物,以满足个人解剖和病理需求。同时,多尺度评估技术——从机械测试到体外和体内模型——为植入物的性能和安全性提供了全面的见解。展望未来,该领域有望从以下几个变革趋势中受益:智能多功能生物材料的发展;利用特定患者数据和计算建模的人工智能驱动设计框架;具有实时质量控制的预测增材制造;先进的临床前评估生物检测平台。总之,这些进步构成了从实验到临床的数据信息型转化管道的基础。实现下一代cmfi的全部潜力需要材料科学、计算工程和临床医学之间的密切跨学科合作。
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International Journal of Oral Science
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