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Lactate-mitochondrial crosstalk: A new direction in the treatment of sepsis-induced acute kidney injury 乳酸-线粒体串联:治疗败血症所致急性肾损伤的新方向
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1002/cbin.12240
Zhixiong Wu, Wei Qing Liu, Liang Tang, Qiong Yuan, Yaling Li, Hongyu Hu, Xin Luo, Fan Ouyang

Independent risk factors for sepsis-associated acute kidney injury (S-AKI) patients include elevated lactate levels, but the specific mechanism remains unclear. Recently, An et al. discovered that excessive acetylation and inactivation of PDHA1 lead to overproduction of lactate, resulting in mitochondrial fragmentation, ATP depletion, excessive mtROS production, and mitochondrial apoptosis, thereby exacerbating AKI in sepsis. Therefore, understanding the pathophysiological processes of mitochondrial function and lactate generation in SAKI is essential and can aid in the development of novel therapeutic strategies. This review elucidates the pathological mechanisms of mitochondrial autophagy and dynamics in AKI. We also discuss the sources of lactate in SAKI and some consequences of lactonization, which may provide new strategies for improving renal injury and delaying the progression of these diseases.

脓毒症相关急性肾损伤(S-AKI)患者的独立危险因素包括乳酸水平升高,但具体机制仍不清楚。最近,An 等人发现,PDHA1 的过度乙酰化和失活导致乳酸生成过多,导致线粒体破碎、ATP 耗竭、mtROS 生成过多和线粒体凋亡,从而加剧了脓毒症中的 AKI。因此,了解 SAKI 中线粒体功能和乳酸生成的病理生理过程至关重要,有助于开发新的治疗策略。本综述阐明了 AKI 中线粒体自噬和动态的病理机制。我们还讨论了 SAKI 中乳酸的来源以及乳酸化的一些后果,这可能会为改善肾损伤和延缓这些疾病的进展提供新的策略。
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引用次数: 0
Lysosomes accumulate at the perinuclear region of muscle cells during chick myogenesis 小鸡肌肉发生过程中溶酶体在肌肉细胞核周区域聚集
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1002/cbin.12238
Kayo Moreira Bagri, Miria Gomes Pereira, Kamila Souto Leichtweis, Jose G. Abreu, Manoel Luis Costa, Claudia Mermelstein

Lysosomes are involved in a myriad of cellular functions, such as degradation of macromolecules, endocytosis and exocytosis, modulation of several signaling pathways, and regulation of cell metabolism. To fulfill these diverse functions, lysosomes can undergo several dynamic changes in their content, size, pH, and location within cells. Here, we studied some of these parameters during embryonic chick skeletal muscle cells. We used an anti-lysosome-associated membrane protein 2 (LAMP2) antibody to specifically determine the intracellular localization of lysosomes in these cells. Our data shows that lysosomes are highly enriched in the perinuclear region of chick embryonic muscle cells. We also showed that the wingless signaling pathway (Wnt)/β-catenin signaling pathway can modulate the location of LAMP2 in chick myogenic cells. Our results highlight the role of lysosomes during muscle differentiation and particularly the presence of a subcellular population of lysosomes that are concentrated in the perinuclear region of muscle cells.

溶酶体参与了大量的细胞功能,如降解大分子、内吞和外吞、调节多种信号通路以及调节细胞新陈代谢。为了实现这些不同的功能,溶酶体的含量、大小、pH 值和在细胞内的位置都会发生一些动态变化。在这里,我们研究了胚胎期小鸡骨骼肌细胞中的一些参数。我们使用抗溶酶体相关膜蛋白2(LAMP2)抗体特异性地确定了溶酶体在这些细胞中的胞内定位。我们的数据显示,溶酶体高度富集于鸡胚肌肉细胞的核周区域。我们还发现,无翼信号通路(Wnt)/β-catenin 信号通路可调节 LAMP2 在小鸡肌原细胞中的位置。我们的研究结果突显了溶酶体在肌肉分化过程中的作用,尤其是溶酶体亚细胞群的存在,它们集中在肌肉细胞的核周区域。
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引用次数: 0
Deciphering the cellular landscape and potential targets of nasopharyngeal and oral cancers using single-cell RNA sequencing 利用单细胞 RNA 测序破解鼻咽癌和口腔癌的细胞图谱和潜在靶点。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1002/cbin.12236
Yanfei Zhang, Xiaoyu Qin, Weihua Lou, Liang Wang, Wuhao Lu, Changhui Gao, Shousen Hu

Cellular heterogeneity in nasopharyngeal cancer (NPC) and oral cancer remains unclear. In the current study, using single-cell RNA sequencing techniques, we investigated the cellular landscape in NPC and oral cancers. We identified a diverse range of cell types within the tumor microenvironment (TME) and variations in cell infiltration between NPC and oral cancer. In oral cancer, we observed a predominant infiltration of epithelial cells, fibroblasts, and endothelial cells (ECs), while T cells were the main infiltrating cell population in NPCs. We further classified these infiltrating cells into subclusters. Additionally, we observed complex interactions among cells that led to distinct trajectories. In particular, a unique epithelial subcluster with high expression of major histocompatibility complex class II (MHC-II) molecules was correlated with a favorable outcome and infiltration of CD4+ T cells. In addition, MHC-II+ epithelial cells inhibited mouse tumor growth and promoted T-cell infiltration. Consequently, our findings provide a deep understanding of the TME showing a significant prognostic value and therapeutic potential.

鼻咽癌和口腔癌的细胞异质性仍不清楚。在本研究中,我们利用单细胞 RNA 测序技术研究了鼻咽癌和口腔癌的细胞结构。我们发现了肿瘤微环境(TME)中的多种细胞类型,以及鼻咽癌和口腔癌细胞浸润的变化。在口腔癌中,我们观察到上皮细胞、成纤维细胞和内皮细胞(EC)的主要浸润,而在鼻咽癌中,T 细胞是主要的浸润细胞群。我们进一步将这些浸润细胞划分为亚群。此外,我们还观察到细胞间复杂的相互作用导致了不同的轨迹。特别是,主要组织相容性复合体 II 类(MHC-II)分子高表达的独特上皮亚群与良好的预后和 CD4+ T 细胞的浸润相关。此外,MHC-II+上皮细胞还能抑制小鼠肿瘤生长并促进T细胞浸润。因此,我们的研究结果提供了对TME的深入了解,显示了其重要的预后价值和治疗潜力。
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引用次数: 0
Prediction of clinical prognosis and drug sensitivity in hepatocellular carcinoma through the combination of multiple cell death pathways 通过结合多种细胞死亡途径预测肝细胞癌的临床预后和药物敏感性。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-27 DOI: 10.1002/cbin.12235
QingKun Chen, ChenGuang Zhang, Tao Meng, Ke Yang, QiLi Hu, Zhong Tong, XiaoGang Wang

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor, highlighting a significant need for reliable predictive models to assess clinical prognosis, disease progression, and drug sensitivity. Recent studies have highlighted the critical role of various programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, NETotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis, in tumor development. Therefore, by investigating these pathways, we aimed to develop a predictive model for HCC prognosis and drug sensitivity. We analyzed transcriptome, single-cell transcriptome, genomic, and clinical information using data from the TCGA-LIHC, GSE14520, GSE45436, and GSE166635 datasets. Machine learning algorithms were used to establish a cell death index (CDI) with seven gene signatures, which was validated across three independent datasets, showing that high CDI correlates with poorer prognosis. Unsupervised clustering revealed three molecular subtypes of HCC with distinct biological processes. Furthermore, a nomogram integrating CDI and clinical information demonstrated good predictive performance. CDI was associated with immune checkpoint genes and tumor microenvironment components using single-cell transcriptome analysis. Drug sensitivity analysis indicated that patients with high CDI may be resistant to oxaliplatin and cisplatin but sensitive to axitinib and sorafenib. In summary, our model offers a precise prediction of clinical outcomes and drug sensitivity for patients with HCC, providing valuable insights for personalized treatment strategies.

肝细胞癌(HCC)是第六大常见恶性肿瘤,因此亟需可靠的预测模型来评估临床预后、疾病进展和药物敏感性。最近的研究强调了各种程序性细胞死亡途径在肿瘤发生发展中的关键作用,包括细胞凋亡、坏死、热凋亡、铁凋亡、杯凋亡、内生性细胞死亡、网状细胞死亡、副凋亡、溶酶体依赖性细胞死亡、自噬依赖性细胞死亡、碱凋亡、氧凋亡和二硫化硫。因此,通过研究这些通路,我们旨在建立一个预测 HCC 预后和药物敏感性的模型。我们利用来自 TCGA-LIHC、GSE14520、GSE45436 和 GSE166635 数据集的数据分析了转录组、单细胞转录组、基因组和临床信息。利用机器学习算法建立了具有七个基因特征的细胞死亡指数(CDI),并在三个独立数据集上进行了验证,结果表明高CDI与较差的预后相关。无监督聚类揭示了具有不同生物学过程的三种 HCC 分子亚型。此外,整合了 CDI 和临床信息的提名图显示了良好的预测性能。通过单细胞转录组分析,CDI与免疫检查点基因和肿瘤微环境成分相关。药物敏感性分析表明,高CDI患者可能对奥沙利铂和顺铂耐药,但对阿西替尼和索拉非尼敏感。总之,我们的模型可以精确预测HCC患者的临床结果和药物敏感性,为个性化治疗策略提供了宝贵的见解。
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引用次数: 0
OTUD6B promotes cholangiocarcinoma growth by regulating STAT3 phosphorylation through deubiquitination of PTK2 OTUD6B 通过去泛素化 PTK2 来调节 STAT3 磷酸化,从而促进胆管癌的生长。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-27 DOI: 10.1002/cbin.12234
Guoqiang Xing, Hekai Chen, Zhiyue Guo, Yu Cui, Yongyuan Li, Jianwei Shen

Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO-IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment.

胆管癌(Colangiocarcinoma,CCA)是一种细胞增殖失控、预后差、死亡率高的肝胆癌。卵巢肿瘤结构域(OTU)含蛋白6B(OTUD6B)属于OTU去泛素家族,在肿瘤发生发展中至关重要。然而,它在 CCA 中的表达和生物学功能仍然未知。我们利用 TIMER2.0、UALCAN 和 GEO 数据库分析了 OTUD6B 在 CCA 中的表达。MTT、克隆形成试验、免疫荧光染色、免疫组化染色和流式细胞术检测了 OTUD6B 对细胞增殖、周期和凋亡的调控。使用异种移植肿瘤模型评估了 OTUD6B 对肿瘤体积和重量的影响。通过Western印迹和CO-IP检测了PTK2和STAT3的活性。生物数据库发现 OTUD6B 在 CCA 中上调。在CCA细胞中,敲除OTUD6B可减少CCA细胞增殖并促进细胞凋亡。细胞周期分析表明,OTUD6B 下调后,细胞周期停止在 G0/G1 期。此外,在异种移植肿瘤模型中,敲除 OTUD6B 会导致肿瘤体积和重量的减少。从机理上讲,OTUD6B 参与了 PTK2 的去泛素化。PTK2 进一步影响 STAT3 的磷酸化,从而调控 CCA 进程。我们的研究表明,敲除 OTUD6B 参与了 PTK2 的泛素化和 STAT3 的磷酸化,从而缓解了 CCA 的进程。这些结果表明,OTUD6B 可能是治疗 CCA 的一种潜在新策略。
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引用次数: 0
Shikonin protects skin cells against oxidative stress and cellular dysfunction induced by fine particulate matter Shikonin 可保护皮肤细胞免受微粒物质引起的氧化应激和细胞功能障碍的影响。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-21 DOI: 10.1002/cbin.12233
Kristina Shilnikova, Kyoung Ah Kang, Mei Jing Piao, Herath Mudiyanselage Udari Lakmini Herath, Pincha Devage Sameera Madushan Fernando, Hye-Jin Boo, Sang Pil Yoon, Jin Won Hyun

Shikonin, an herbal naphthoquinone, demonstrates a broad spectrum of pharmacological properties. Owing to increasingly adverse environmental conditions, human skin is vulnerable to harmful influences from dust particles. This study explored the antioxidant capabilities of shikonin and its ability to protect human keratinocytes from oxidative stress induced by fine particulate matter (PM2.5). We found that shikonin at a concentration of 3 µM was nontoxic to human keratinocytes and effectively scavenged reactive oxygen species (ROS) while increasing the production of reduced glutathione (GSH). Furthermore, shikonin enhanced GSH level by upregulating glutamate-cysteine ligase catalytic subunit and glutathione synthetase mediated by nuclear factor-erythroid 2-related factor. Shikonin reduced ROS levels induced by PM2.5, leading to recovering PM2.5-impaired cellular biomolecules and cell viability. Shikonin restored the GSH level in PM2.5-exposed keratinocytes via enhancing the expression of GSH-synthesizing enzymes. Notably, buthionine sulphoximine, an inhibitor of GSH synthesis, diminished effect of shikonin against PM2.5-induced cell damage, confirming the role of GSH in shikonin-induced cytoprotection. Collectively, these findings indicated that shikonin could provide substantial cytoprotection against the adverse effects of PM2.5 through direct ROS scavenging and modulation of cellular antioxidant system.

Shikonin 是一种草本萘醌,具有广泛的药理特性。由于环境条件日益恶劣,人类皮肤很容易受到尘埃微粒的有害影响。本研究探讨了紫杉素的抗氧化能力及其保护人体角质细胞免受细颗粒物(PM2.5)诱导的氧化应激的能力。我们发现,浓度为 3 µM 的紫杉素对人类角质细胞无毒,能有效清除活性氧(ROS),同时增加还原型谷胱甘肽(GSH)的生成。此外,通过上调谷氨酸-半胱氨酸连接酶催化亚基和谷胱甘肽合成酶(由核因子-红细胞 2 相关因子介导),紫杉素还能提高 GSH 水平。Shikonin 降低了 PM2.5 诱导的 ROS 水平,从而恢复了受 PM2.5 影响的细胞生物大分子和细胞活力。紫杉素通过增强GSH合成酶的表达,恢复了暴露于PM2.5的角朊细胞的GSH水平。值得注意的是,GSH合成抑制剂丁硫磺酰亚胺降低了紫杉素对PM2.5诱导的细胞损伤的作用,证实了GSH在紫杉素诱导的细胞保护中的作用。总之,这些研究结果表明,紫杉素可以通过直接清除ROS和调节细胞抗氧化系统,对PM2.5的不利影响提供实质性的细胞保护。
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引用次数: 0
The role of soluble epoxide hydrolase in the intestine 可溶性环氧化物水解酶在肠道中的作用。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-20 DOI: 10.1002/cbin.12232
Yanbei Ren, Ting Wang, Jiuheng Yin

The soluble epoxide hydrolase (sEH; encoded by the EPHX2 gene) is an α/β hydrolase fold protein that is, widely distributed throughout the body. Recent studies have highlighted that sEH, in the metabolism of polyunsaturated fatty acids, plays a part in the pathogenesis of various diseases, including cardiovascular disease, Alzheimer's disease and intestine-associated disease. This review discusses the current findings on the role of sEH in the development of intestine- and intestine-associated diseases, including colitis, colorectal cancer, and other intestinal diseases, as well as the potential underlying mechanisms involved.

可溶性环氧化物水解酶(sEH;由 EPHX2 基因编码)是一种α/β水解酶折叠蛋白,广泛分布于人体各处。最近的研究表明,sEH 在多不饱和脂肪酸的代谢过程中参与了多种疾病的发病机制,包括心血管疾病、阿尔茨海默病和肠道相关疾病。本综述将讨论目前关于 sEH 在肠道疾病和肠道相关疾病(包括结肠炎、结肠直肠癌和其他肠道疾病)发病过程中的作用的研究结果,以及潜在的内在机制。
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引用次数: 0
Inhibitors of the mTOR signaling pathway can play an important role in breast cancer immunopathogenesis mTOR 信号通路抑制剂可在乳腺癌免疫发病机制中发挥重要作用。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-20 DOI: 10.1002/cbin.12231
Sulieman I. Shelash Al-Hawary, Farag M. A. Altalbawy, Saade Abdalkareem Jasim, Renuka Jyothi S, Azfar Jamal, Mohammed M. Naiyer, Shriya Mahajan, Hitesh Kalra, Mohammed Abed Jawad, Ahmed Hussein Zwamel

This study explores the critical role of inhibitors targeting the mammalian target of rapamycin (mTOR) signaling pathway in breast cancer research and treatment. The mTOR pathway, a central regulator of cellular processes, has been identified as a crucial factor in the development and progression of breast cancer. The essay explains the complex molecular mechanisms through which mTOR inhibitors, such as rapamycin and its analogs, exert their anticancer effects. These inhibitors can stop cell growth, proliferation, and survival in breast cancer cells by blocking critical signaling pathways within the mTOR pathway. Furthermore, the essay discusses the implications of using mTOR inhibitors as a comprehensive therapeutic strategy. It emphasizes the potential benefits of combining mTOR inhibitors with other treatment approaches to enhance the effectiveness of breast cancer treatment. The evolving landscape of breast cancer research underscores the significance of mTOR as a therapeutic target and highlights ongoing efforts to improve and optimize mTOR inhibitors for clinical use. In conclusion, the essay asserts that inhibitors of the mTOR signaling pathway offer a promising approach in the fight against breast cancer. These inhibitors provide a focused and effective intervention targeting specific dysregulations within the mTOR pathway. As research advances, the integration of mTOR inhibitors into customized combination therapies holds excellent potential for shaping a more effective and personalized approach to breast cancer treatment, ultimately leading to improved outcomes for individuals affected by this complex and diverse disease.

本研究探讨了针对哺乳动物雷帕霉素靶标(mTOR)信号通路的抑制剂在乳腺癌研究和治疗中的关键作用。mTOR 通路是细胞过程的核心调节因子,已被确定为乳腺癌发生和发展的关键因素。文章解释了雷帕霉素及其类似物等 mTOR 抑制剂发挥抗癌作用的复杂分子机制。这些抑制剂可通过阻断 mTOR 通路中的关键信号通路,阻止乳腺癌细胞的生长、增殖和存活。此外,文章还讨论了将 mTOR 抑制剂作为一种综合治疗策略的意义。文章强调了将 mTOR 抑制剂与其他治疗方法相结合以提高乳腺癌治疗效果的潜在益处。乳腺癌研究的不断发展突显了 mTOR 作为治疗靶点的重要性,并强调了目前为改进和优化 mTOR 抑制剂以用于临床所做的努力。总之,文章认为,mTOR 信号通路抑制剂为抗击乳腺癌提供了一种前景广阔的方法。这些抑制剂针对 mTOR 通路中的特定失调提供了有针对性的有效干预。随着研究的深入,将 mTOR 抑制剂整合到定制的综合疗法中,有望为乳腺癌的治疗提供更有效、更个性化的方法,最终改善这种复杂多样疾病患者的治疗效果。
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引用次数: 0
Tyrosine kinase inhibitors in the treatment of leptomeningeal carcinomatosis 酪氨酸激酶抑制剂治疗脑膜外癌。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-13 DOI: 10.1002/cbin.12230
Hanyu Ni, Zilan Wang, Yanbing Tang, Jiaye Lu, Zixiang Zhu, Youjia Qiu, Zhouqing Chen, Zhong Wang

Leptomeningeal carcinomatosis (LMC) is a devastating complication of advanced cancers, such as lung cancer and breast cancer, which is usually indicative of a poor prognosis. The current treatments for LMC include palliative care, with others aiming to prolong survival and relieve neurological symptoms. Traditional treatments for LMC include radiotherapy, systemic chemotherapy, and intrathecal injection. Furthermore, the application of molecularly targeted agents, such as antiepidermal growth factor receptor (anti-EGFR), antihuman epidermal growth factor receptor 2 (anti-HER2), and anti-PD-1 monoclonal antibody, have prolonged the survival of LMC patients. Targeted therapy with tyrosine kinase inhibitors has also been proven to be an effective treatment. Tyrosine kinases can be overactive or expressed at high levels in some cancer cells; therefore, the use of tyrosine kinase inhibitors may prevent the activation of tumor-related pathways, preventing cancer cell growth. The EGFR family are cell surface receptors directly related to tumor occurrence with tyrosine kinase activity; it is the most widely used target for tyrosine kinase inhibitors in the treatment of LMC. In this review, we introduced the clinical manifestation and diagnostic criteria of LMC, clarified the treatment mechanism of tyrosine kinase inhibitors for LMC with mutations in EGFR, HER2, or anaplastic lymphoma kinase, reviewed the current application of various generation tyrosine kinase inhibitors in patients with LMC, and discussed new clinical trials and the future directions of tyrosine kinase inhibitor therapy.

脑膜癌肿(LMC)是肺癌和乳腺癌等晚期癌症的一种破坏性并发症,通常预示着不良的预后。目前治疗 LMC 的方法包括姑息治疗,以及其他旨在延长生存期和缓解神经症状的方法。LMC 的传统治疗方法包括放射治疗、全身化疗和鞘内注射。此外,抗表皮生长因子受体(anti-EGFR)、抗人表皮生长因子受体2(anti-HER2)和抗PD-1单克隆抗体等分子靶向药物的应用也延长了LMC患者的生存期。使用酪氨酸激酶抑制剂进行靶向治疗也被证明是一种有效的治疗方法。在某些癌细胞中,酪氨酸激酶会过度活跃或高水平表达;因此,使用酪氨酸激酶抑制剂可阻止肿瘤相关通路的激活,从而防止癌细胞生长。表皮生长因子受体(EGFR)家族是与肿瘤发生直接相关的细胞表面受体,具有酪氨酸激酶活性,是酪氨酸激酶抑制剂治疗LMC最广泛使用的靶点。在这篇综述中,我们介绍了LMC的临床表现和诊断标准,阐明了酪氨酸激酶抑制剂对EGFR、HER2或无性淋巴瘤激酶突变的LMC的治疗机制,回顾了目前各代酪氨酸激酶抑制剂在LMC患者中的应用,并讨论了新的临床试验和酪氨酸激酶抑制剂治疗的未来方向。
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引用次数: 0
METTL3 mediated ferroptosis in chondrocytes and promoted pain in KOA via HMGB1 m6A modification METTL3 通过 HMGB1 m6A 修饰介导软骨细胞的铁变态反应并促进 KOA 的疼痛。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-08-11 DOI: 10.1002/cbin.12229
Tianchi Bao, Taiyang Liao, Xuefeng Cai, Binjie Lu, Gaole Dai, Shuai Pei, Yunqing Zhang, Yuwei Li, Bo Xu

Methyltransferase-like 3 (METTL3) plays a role in the development of knee osteoarthritis (KOA). However, the mechanism underlying the role of METTL3 in KOA is unclear. This work investigated the effects of MELLT3 on ferroptosis and pain relief in in vitro and in vivo KOA models. Chondrocytes were treated with 10 ng/mL interleukin-1β (IL-1β) or 5 μM Erastin (ferroptosis inducer). IL-1β or Erastin treatment inhibited cell viability and glutathione levels; increased Fe2+, lipid reactive oxygen species and malondialdehyde production; and decreased glutathione peroxidase 4, ferritin light chain and solute carrier family 7 member 11 levels. The overexpression of METTL3 facilitated the N6-methyladenosine methylation of high mobility group box 1 (HMGB1). HMGB1 overexpression reversed the effect of sh-METTL3 on IL-1β-treated chondrocytes. A KOA rat model was established by the injection of monosodium iodoacetate into the joints and successful model establishment was confirmed by haematoxylin and eosin staining and Safranin O/Fast Green staining. METTL3 depletion alleviated cartilage damage, the inflammatory response, ferroptosis and knee pain in KOA model rats, and these effects were reversed by the addition of HMGB1. In conclusion, METTL3 depletion inhibited ferroptosis and the inflammatory response, and ameliorated cartilage damage and knee pain during KOA progression by regulating HMGB1.

甲基转移酶样 3(METTL3)在膝关节骨性关节炎(KOA)的发病过程中发挥着作用。然而,METTL3在KOA中发挥作用的机制尚不清楚。这项工作研究了MELLT3在体外和体内KOA模型中对铁蛋白沉积和疼痛缓解的影响。用 10 ng/mL 白细胞介素-1β(IL-1β)或 5 μM Erastin(铁凋亡诱导剂)处理软骨细胞。IL-1β 或 Erastin 处理抑制了细胞活力和谷胱甘肽水平;增加了 Fe2+、脂质活性氧和丙二醛的生成;降低了谷胱甘肽过氧化物酶 4、铁蛋白轻链和溶质运载家族 7 成员 11 的水平。METTL3 的过表达促进了高迁移率基团框 1(HMGB1)的 N6-甲基腺苷甲基化。HMGB1的过表达逆转了sh-METTL3对IL-1β处理的软骨细胞的影响。通过向关节注射碘乙酸钠建立了 KOA 大鼠模型,并通过血红素和伊红染色以及 Safranin O/Fast Green 染色证实了模型的成功建立。消耗 METTL3 可减轻 KOA 模型大鼠的软骨损伤、炎症反应、铁蛋白沉积和膝关节疼痛,而添加 HMGB1 则可逆转这些影响。总之,通过调节 HMGB1,消耗 METTL3 可抑制铁蛋白沉积和炎症反应,并改善 KOA 进展过程中的软骨损伤和膝关节疼痛。
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引用次数: 0
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Cell Biology International
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