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Age-related alveolar bone maladaptation in adult orthodontics: finding new ways out. 成人正畸中与年龄相关的牙槽骨适应不良:寻找新出路。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-08-01 DOI: 10.1038/s41368-024-00319-7
Yunfan Zhang, Jiale Yan, Yuning Zhang, Hao Liu, Bing Han, Weiran Li

Compared with teenage patients, adult patients generally show a slower rate of tooth movement and more pronounced alveolar bone loss during orthodontic treatment, indicating the maladaptation of alveolar bone homeostasis under orthodontic force. However, this phenomenon is not well-elucidated to date, leading to increased treatment difficulties and unsatisfactory treatment outcomes in adult orthodontics. Aiming to provide a comprehensive knowledge and further inspire insightful understanding towards this issue, this review summarizes the current evidence and underlying mechanisms. The age-related abatements in mechanosensing and mechanotransduction in adult cells and periodontal tissue may contribute to retarded and unbalanced bone metabolism, thus hindering alveolar bone reconstruction during orthodontic treatment. To this end, periodontal surgery, physical and chemical cues are being developed to reactivate or rejuvenate the aging periodontium and restore the dynamic equilibrium of orthodontic-mediated alveolar bone metabolism. We anticipate that this review will present a general overview of the role that aging plays in orthodontic alveolar bone metabolism and shed new light on the prospective ways out of the impasse.

与青少年患者相比,成年患者在正畸治疗过程中通常表现出牙齿移动速度较慢,牙槽骨流失更明显,这表明在正畸力的作用下牙槽骨平衡失调。然而,这一现象至今尚未得到很好的阐明,导致成人正畸治疗难度增加,治疗效果不尽人意。为了提供全面的知识并进一步启发对这一问题的深刻理解,本综述总结了当前的证据和内在机制。成人细胞和牙周组织中与年龄相关的机械感应和机械传导功能减退可能会导致骨代谢迟缓和不平衡,从而阻碍正畸治疗期间的牙槽骨重建。为此,人们正在开发牙周手术、物理和化学线索,以重新激活或恢复老化牙周,恢复正畸介导的牙槽骨新陈代谢的动态平衡。我们希望这篇综述能够概述老化在正畸牙槽骨代谢中所起的作用,并为走出僵局提供新的思路。
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引用次数: 0
Evaluation of a newly developed oral and maxillofacial surgical robotic platform (KD-SR-01) in head and neck surgery: a preclinical trial in porcine models 在头颈外科手术中评估新开发的口腔颌面外科机器人平台(KD-SR-01):猪模型临床前试验
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-07-10 DOI: 10.1038/s41368-024-00318-8
Zhongkai Ma, Zhiyong Guo, Zhangfan Ding, Chang Cao, Jialu He, Heyi Tang, Yufei Hua, Jiawei Hong, Qiang Shen, Grace Paka Lubamba, Xiaoyi Wang, Zheng Yang, Guiquan Zhu, Chunjie Li

Traditional open head and neck surgery often leaves permanent scars, significantly affecting appearance. The emergence of surgical robots has introduced a new era for minimally invasive surgery. However, the complex anatomy of the head and neck region, particularly the oral and maxillofacial areas, combined with the high costs associated with established systems such as the da Vinci, has limited the widespread adoption of surgical robots in this field. Recently, surgical robotic platform in China has developed rapidly, exemplified by the promise shown by the KangDuo Surgical Robot (KD-SR). Although the KD-SR has achieved some results comparable to the da Vinci surgical robot in urology and colorectal surgery, its performance in complex head and neck regions remains untested. This study evaluated the feasibility, effectiveness, and safety of the newly developed KD-SR-01, comparing it with standard endoscopic systems in head and neck procedures on porcine models. We performed parotidectomy, submandibular gland resection, and neck dissection, collected baseline characteristics, perioperative data, and specifically assessed cognitive workload using the NASA-TLX. None of the robotic procedures were converted to endoscopic or open surgery. The results showed no significant difference in operation time between the two groups (P = 0.126), better intraoperative bleeding control (P = 0.001), and a significant reduction in cognitive workload (P < 0.001) in the robotic group. In conclusion, the KD-SR-01 is feasible, effective, and safe for head and neck surgery. Further investigation through well-designed clinical trials with long-term follow-up is necessary to establish the full potential of this emerging robotic platform.

传统的开放式头颈部手术往往会留下永久性疤痕,严重影响外观。手术机器人的出现开创了微创手术的新时代。然而,由于头颈部尤其是口腔颌面部的解剖结构复杂,再加上达芬奇等成熟系统的高昂成本,限制了手术机器人在这一领域的广泛应用。近来,中国的手术机器人平台发展迅速,康多手术机器人(KD-SR)就是其中的佼佼者。虽然 KD-SR 在泌尿外科和结直肠外科取得了一些可与达芬奇手术机器人媲美的成果,但其在复杂头颈部手术中的表现仍有待检验。本研究评估了新开发的 KD-SR-01 的可行性、有效性和安全性,并在猪模型上将其与头颈部手术中的标准内窥镜系统进行了比较。我们进行了腮腺切除术、颌下腺切除术和颈部解剖,收集了基线特征和围手术期数据,并使用 NASA-TLX 专门评估了认知工作量。所有机器人手术均未转为内窥镜或开放手术。结果显示,两组手术时间无明显差异(P = 0.126),机器人组术中出血控制更好(P = 0.001),认知工作量明显减少(P < 0.001)。总之,KD-SR-01 在头颈部手术中是可行、有效和安全的。有必要通过精心设计的临床试验和长期随访进行进一步调查,以确定这一新兴机器人平台的全部潜力。
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引用次数: 0
Synthetic high-density lipoprotein (sHDL): a bioinspired nanotherapeutics for managing periapical bone inflammation 合成高密度脂蛋白(sHDL):一种用于控制根尖周骨炎的生物启发纳米疗法
IF 14.9 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-07-02 DOI: 10.1038/s41368-024-00316-w
Renan Dal-Fabbro, Minzhi Yu, Ling Mei, Hajime Sasaki, Anna Schwendeman, Marco C. Bottino

Apical periodontitis (AP) is a dental-driven condition caused by pathogens and their toxins infecting the inner portion of the tooth (i.e., dental pulp tissue), resulting in inflammation and apical bone resorption affecting 50% of the worldwide population, with more than 15 million root canals performed annually in the United States. Current treatment involves cleaning and decontaminating the infected tissue with chemo-mechanical approaches and materials introduced years ago, such as calcium hydroxide, zinc oxide–eugenol, or even formalin products. Here, we present, for the first time, a nanotherapeutics based on using synthetic high-density lipoprotein (sHDL) as an innovative and safe strategy to manage dental bone inflammation. sHDL application in concentrations ranging from 25 µg to 100 µg/mL decreases nuclear factor Kappa B (NF-κB) activation promoted by an inflammatory stimulus (lipopolysaccharide, LPS). Moreover, sHDL at 500 µg/mL concentration markedly decreases in vitro osteoclastogenesis (P < 0.001), and inhibits IL-1α (P = 0.027), TNF-α (P = 0.004), and IL-6 (P < 0.001) production in an inflammatory state. Notably, sHDL strongly dampens the Toll-Like Receptor signaling pathway facing LPS stimulation, mainly by downregulating at least 3-fold the pro-inflammatory genes, such as Il1b, Il1a, Il6, Ptgs2, and Tnf. In vivo, the lipoprotein nanoparticle applied after NaOCl reduced bone resorption volume to (1.3 ± 0.05) mm3 and attenuated the inflammatory reaction after treatment to (1 090 ± 184) cells compared to non-treated animals that had (2.9 ± 0.6) mm3 (P = 0.012 3) and (2 443 ± 931) cells (P = 0.004), thus highlighting its promising clinical potential as an alternative therapeutic for managing dental bone inflammation.

牙根尖牙周炎(AP)是一种由病原体及其毒素感染牙齿内部(即牙髓组织)引起的牙科疾病,会导致炎症和牙根尖骨吸收,影响全球50%的人口,美国每年进行的根管治疗超过1500万例。目前的治疗方法包括使用多年前引入的化学机械方法和材料(如氢氧化钙、氧化锌-丁香酚,甚至福尔马林产品)清洁和净化受感染的组织。在这里,我们首次提出了一种基于合成高密度脂蛋白(sHDL)的纳米疗法,作为一种创新而安全的策略来控制牙槽骨炎症。sHDL 的应用浓度从 25 微克到 100 微克/毫升不等,可降低炎症刺激(脂多糖,LPS)引起的核因子卡巴 B(NF-κB)活化。此外,浓度为 500 µg/mL 的 sHDL 能显著降低体外破骨细胞生成(P < 0.001),并抑制炎症状态下 IL-1α (P = 0.027)、TNF-α (P = 0.004) 和 IL-6 (P < 0.001) 的产生。值得注意的是,sHDL 能强烈抑制 LPS 刺激下的 Toll-Like 受体信号通路,主要是通过下调至少 3 倍的促炎基因,如 Il1b、Il1a、Il6、Ptgs2 和 Tnf。在体内,与未处理动物的(2.9 ± 0.6)立方毫米(P = 0.012 3)和(2 443 ± 931)个细胞(P = 0.004)相比,NaOCl 处理后使用的脂蛋白纳米粒子可将骨吸收体积减少到(1.3 ± 0.05)立方毫米,并将处理后的炎症反应减弱到(1 090 ± 184)个细胞,从而凸显了其作为牙科骨炎替代疗法的巨大临床潜力。
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引用次数: 0
Author Correction: FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression. 作者更正:FUT8 介导的 SEMA7A N-糖基化异常促进头颈部鳞状细胞癌的进展。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-07-02 DOI: 10.1038/s41368-024-00307-x
Zhonglong Liu, Xiaoyan Meng, Yuxin Zhang, Jingjing Sun, Xiao Tang, Zhiyuan Zhang, Liu Liu, Yue He
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引用次数: 0
Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma. 通过 STT3B 介导的 N-糖基化稳定 EREG 是头颈部鳞状细胞癌中 PDL1 上调和免疫逃避的关键。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-07-01 DOI: 10.1038/s41368-024-00311-1
Shengming Xu, Haifeng Wang, Yu Zhu, Yong Han, Liu Liu, Xiangkai Zhang, Jingzhou Hu, Wuchang Zhang, Shengzhong Duan, Jiong Deng, Zhiyuan Zhang, Shuli Liu

Dysregulated Epiregulin (EREG) can activate epidermal growth factor receptor (EGFR) and promote tumor progression in head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying EREG dysregulation remain largely unknown. Here, we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues. Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway. Of note, we found that N-glycosylation of EREG was essential for its stability, membrane location, biological function, and upregulation of its downstream target PDL1 in HNSCC. EREG was glycosylated at N47 via STT3B glycosyltransferases, whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG. Consistently, knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells. Moreover, treatment of HNSCC cells with NGI-1, an inhibitor of STT3B, blocked STT3B-mediated glycosylation of EREG, leading to its degradation and suppression of PDL1. Finally, combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo. Taken together, STT3B-mediated N-glycosylation is essential for stabilization of EREG, which mediates PDL1 upregulation and immune evasion in HNSCC.

表皮生长因子受体(EGFR)失调可激活表皮生长因子受体,并促进头颈部鳞状细胞癌(HNSCC)的肿瘤进展。然而,EREG失调的机制在很大程度上仍然未知。在这里,我们发现EREG失调与HNSCC组织中PDL1的增强高度相关。用EREG处理HNSCC细胞会导致PDL1通过c-myc途径上调。值得注意的是,我们发现EREG的N-糖基化对其在HNSCC中的稳定性、膜位置、生物功能及其下游靶标PDL1的上调至关重要。EREG通过STT3B糖基转移酶在N47位点进行糖基化,而N47位点的突变会减弱N-糖基化并破坏EREG的稳定性。同样,在 HNSCC 细胞中敲除 STT3B 可抑制糖基化的 EREG 并抑制 PDL1。此外,用 STT3B 的抑制剂 NGI-1 处理 HNSCC 细胞可阻断 STT3B 介导的 EREG 糖基化,导致其降解并抑制 PDL1。最后,NGI-1治疗与抗PDLl治疗相结合,可协同提高HNSCC体内免疫疗法的疗效。综上所述,STT3B介导的N-糖基化对EREG的稳定至关重要,EREG介导了HNSCC中PDL1的上调和免疫逃避。
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引用次数: 0
Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast crosstalk and induces the development of oral submucosal fibrosis. 源自上皮细胞的外泌体 miR-17-5p 参与了上皮细胞与成纤维细胞的异常串扰,并诱发了口腔黏膜下纤维化的发展。
IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2024-06-20 DOI: 10.1038/s41368-024-00302-2
Changqing Xie, Liang Zhong, Hui Feng, Rifu Wang, Yuxin Shi, Yonglin Lv, Yanjia Hu, Jing Li, Desheng Xiao, Shuang Liu, Qianming Chen, Yongguang Tao

Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.

口腔黏膜下纤维化(OSF)是一种由咀嚼槟榔引起的慢性炎症性黏膜疾病,属于口腔潜在恶性疾病。成纤维细胞分化异常导致胶原代谢紊乱是口腔黏膜下纤维化发生的核心过程。上皮是抵御外界环境的第一道防线,可以将外界信号转化为病理信号,并参与纤维化微环境的重塑。然而,上皮细胞驱动成纤维细胞分化的具体机制仍不清楚。在这项研究中,我们发现暴露于甲状腺素的上皮细胞通过分泌外泌体与纤维化微环境进行交流。MiR-17-5p 被包裹在上皮细胞衍生的外泌体中,并被成纤维细胞吸收,促进了细胞分泌、收缩、迁移和纤维化标志物(α-SMA 和 I 型胶原)的表达。其潜在的分子机制涉及 miR-17-5p 靶向 Smad7 并通过 E3 泛素化连接酶 WWP1 抑制 TGF-β 受体 1(TGFBR1)的降解,从而促进下游 TGF-β 通路信号的传递。用miR-17-5p抑制剂处理成纤维细胞可逆转上皮源性外泌体诱导的收缩和迁移表型。外泌体 miR-17-5p 被证实是成纤维细胞表型转化的关键调节因子。总之,我们证明了阿雷科林会引发上皮细胞-成纤维细胞的异常串联,并发现上皮细胞衍生的miR-17-5p通过经典的TGF-β纤维化途径介导成纤维细胞分化,这为OSF的诊断和治疗提供了新的视角和策略。
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引用次数: 0
Nociceptive adenosine A2A receptor on trigeminal nerves orchestrates CGRP release to regulate the progression of oral squamous cell carcinoma 三叉神经上的痛觉腺苷 A2A 受体协调 CGRP 的释放以调节口腔鳞状细胞癌的进展
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-06-18 DOI: 10.1038/s41368-024-00308-w
Lanxin Jiang, Ying Zhou, Shijie Tang, Dan Yang, Yixin Zhang, Jiuge Zhang, Fan Yang, Tong Zhou, Xiaoqiang Xia, Qianming Chen, Lu Jiang, Yuchen Jiang, Xiaodong Feng

Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor (A2AR) on trigeminal ganglia. Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A2AR. Therefore, we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

口腔鳞状细胞癌(OSCC)相关疼痛通常预示着患者的不良事件。这一临床特征表明,在恶性肿瘤的发展过程中,感觉神经元上的痛觉感受器参与其中。然而,靶向与癌细胞相关的痛觉感受器是否能阻碍 OSCC 的发展尚待确定。在这项研究中,我们报告了临床样本和小鼠肿瘤异种移植中浸润的痛觉末梢与较差的临床结果有关,并在体内推动肿瘤进展,这一点已通过临床组织芯片分析和小鼠舌神经支配得到证实。我们观察到,由于 CD73 的上调,OSCC 微环境具有过量腺苷的特征,这对 TCGA-HNSC 患者队列的临床预后具有负面预测作用。值得注意的是,这种富含腺苷的 OSCC 龛与三叉神经节上的腺苷 A2A 受体(A2AR)刺激有关。使用选择性 A2AR 抑制剂 SCH58261 拮抗三叉神经 A2AR 会阻碍 OSCC 在体内的生长。我们发现,在 OSCC 异种移植物中过度刺激三叉神经 A2AR 不会导致三叉神经节中 CGRP 的转录水平发生任何变化,但会显著引发 CGRP 的释放,SCH58261 可抵消这种效应。我们给小鼠喂食临床批准的 CGRP 受体拮抗剂 rimegepant,抑制了 ERK 和 YAP 的激活,从而进一步证明了 CGRP 的促肿瘤作用。最后,我们用异曲菲林(一种针对神经元 A2AR 的临床可用药物)减轻了 CGRP 对 OSCC 的影响。因此,我们将三叉神经A2AR介导的CGRP释放确定为治疗OSCC的一种有前景的药物回路。
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引用次数: 0
Expert consensus on endodontic therapy for patients with systemic conditions 关于对患有全身性疾病的患者进行牙髓治疗的专家共识
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-06-17 DOI: 10.1038/s41368-024-00312-0
Xin Xu, Xin Zheng, Fei Lin, Qing Yu, Benxiang Hou, Zhi Chen, Xi Wei, Lihong Qiu, Chen Wenxia, Jiyao Li, Lili Chen, Zuomin Wang, Hongkun Wu, Zhiyue Lu, Jizhi Zhao, Yuhong Liang, Jin Zhao, Yihuai Pan, Shuang Pan, Xiaoyan Wang, Deqin Yang, Yanfang Ren, Lin Yue, Xuedong Zhou

The overall health condition of patients significantly affects the diagnosis, treatment, and prognosis of endodontic diseases. A systemic consideration of the patient’s overall health along with oral conditions holds the utmost importance in determining the necessity and feasibility of endodontic therapy, as well as selecting appropriate therapeutic approaches. This expert consensus is a collaborative effort by specialists from endodontics and clinical physicians across the nation based on the current clinical evidence, aiming to provide general guidance on clinical procedures, improve patient safety and enhance clinical outcomes of endodontic therapy in patients with compromised overall health.

患者的整体健康状况对牙髓疾病的诊断、治疗和预后有很大的影响。在确定牙髓治疗的必要性和可行性以及选择适当的治疗方法时,对患者整体健康状况和口腔状况的系统考虑至关重要。这份专家共识是由全国牙髓病学专家和临床医师根据当前的临床证据共同制定的,旨在为整体健康状况不佳的患者提供临床治疗程序的一般指导,提高患者的安全性,并改善牙髓治疗的临床效果。
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引用次数: 0
Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC 单细胞和大容量转录组的整合分析揭示了丝氨酸-甘氨酸-一碳代谢的异质性与 HNSCC 的不同预后和治疗脆弱性的关系
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-06-17 DOI: 10.1038/s41368-024-00310-2
Lixuan Wang, Rongchun Yang, Yue Kong, Jing Zhou, Yingyao Chen, Rui Li, Chuwen Chen, Xinran Tang, Xiaobing Chen, Juan Xia, Xijuan Chen, Bin Cheng, Xianyue Ren

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

代谢异质性在维持不受控制的癌细胞增殖和塑造肿瘤微环境(TME)方面发挥着核心作用,这严重影响了头颈部鳞状细胞癌(HNSCC)患者的临床疗效和治疗反应。这凸显出迫切需要明确代谢脆弱性的内在异质性和生物学作用,以推进精准肿瘤学的发展。利用单细胞RNA测序(scRNA-seq)图谱确定了恶性细胞的代谢异质性,并通过大体转录组进行了验证。筛选出丝氨酸-甘氨酸-一碳(SGOC)代谢是导致HNSCC患者恶性侵袭性和预后不良的原因。通过LASSO-COX回归分析构建的4-SGOC基因预后特征对总生存期和治疗反应有良好的预测作用。低风险组患者的CD8+ T细胞浸润程度更高,接受免疫疗法和化疗后的临床疗效更好。相反,高危患者表现出冷肿瘤的特征,IMPDH1介导的嘌呤生物合成增强,导致对目前疗法的反应不佳。IMPDH1 成为潜在的治疗代谢靶点。用IMPDH抑制剂治疗可有效抑制HNSCC细胞的增殖和转移,并通过引发GTP耗竭核应激诱导体外和体内细胞凋亡。我们的研究结果强调了 HNSCC 的代谢脆弱性,有助于对患者进行准确分层和个体化的精准代谢靶向治疗。
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引用次数: 0
A multi-platform analysis of human gingival crevicular fluid reveals ferroptosis as a relevant regulated cell death mechanism during the clinical progression of periodontitis 对人类牙龈缝隙液的多平台分析揭示了牙周炎临床进展过程中的一种相关调控细胞死亡机制--铁突变
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-27 DOI: 10.1038/s41368-024-00306-y
Alfredo Torres, M. Angélica Michea, Ákos Végvári, Marion Arce, Valentina Pérez, Marcela Alcota, Alicia Morales, Rolando Vernal, Mauricio Budini, Roman A. Zubarev, Fermín E. González

Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases, yet its association with progressive periodontitis remains unexplored. To investigate the involvement and significance of ferroptosis in periodontitis progression, we assessed sixteen periodontitis-diagnosed patients. Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid (GCF) collection was performed for further analyses. Clinical metrics, proteomic data, in silico methods, and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis. Subsequent western blot analyses validated key findings. Finally, a single-cell RNA sequencing (scRNA-seq) dataset (GSE164241) for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression. Periodontitis progression was identified as occurring at a faster rate than traditionally thought. GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles. In addition, specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins, including SNCA, CA1, HBB, SLC4A1, and ANK1 was strongly associated with the clinical progression status of periodontitis. Moreover, we found specific proteins - drivers or suppressors - associated with ferroptosis (SNCA, FTH1, HSPB1, CD44, and GCLC), revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis. Additionally, the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis. Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients, which offer new insights into the molecular mechanisms of progressive periodontal disease. These findings may lead to novel diagnostic and therapeutic strategies.

铁蛋白沉积与许多慢性炎症性疾病的发病机制有关,但它与进展性牙周炎的关系仍未得到探讨。为了研究铁蛋白沉积在牙周炎进展过程中的参与和意义,我们对 16 名牙周炎确诊患者进行了评估。在十二周的时间里,我们通过每周一次的临床评估对患者的病情进展进行临床监测,并收集牙龈缝隙液(GCF)进行进一步分析。临床指标、蛋白质组数据、硅学方法和生物信息学工具相结合,确定了与牙周炎进展相关的蛋白质特征,并探索了它们与铁沉积的潜在联系。随后的 Western 印迹分析验证了主要发现。最后,分析了牙龈组织的单细胞 RNA 测序(scRNA-seq)数据集(GSE164241),以阐明牙周炎进展过程中的细胞动态。研究发现,牙周炎进展的速度比传统观点认为的要快。来自进展期和非进展期牙周部位的 GCF 样本显示出不同数量和质量的蛋白质组特征。此外,研究还揭示了进展期牙周炎的特定生物过程和分子功能,包括 SNCA、CA1、HBB、SLC4A1 和 ANK1 在内的一组枢纽蛋白与牙周炎的临床进展状态密切相关。此外,我们还发现了与铁突变相关的特定蛋白--驱动蛋白或抑制蛋白(SNCA、FTH1、HSPB1、CD44 和 GCLC),揭示了在牙周炎的临床进展过程中,这种特定类型的调控细胞死亡同时存在。此外,定量蛋白质组数据与 scRNA-seq 分析的整合表明,成纤维细胞易受铁变态反应的影响。我们的分析首次揭示了牙周病患者体内与铁变性有关的蛋白质和过程,为研究牙周病进展的分子机制提供了新的视角。这些发现可能会带来新的诊断和治疗策略。
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International Journal of Oral Science
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