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DUBs in Alzheimer's disease: mechanisms and therapeutic implications. 阿尔茨海默病中的 DUBs:机制和治疗意义。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-20 DOI: 10.1038/s41420-024-02237-3
Biying Qin, Xiaodong Chen, Feng Wang, Yanfeng Wang

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid β protein (Aβ) and the hyper-phosphorylation of the microtubule-associated protein Tau. The ubiquitin-proteasome system (UPS) plays a pivotal role in determining the fate of proteins, and its dysregulation can contribute to the buildup of Aβ and Tau. Deubiquitinating enzymes (DUBs), working in conjunction with activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3), actively maintain the delicate balance of protein homeostasis. DUBs specifically remove ubiquitin tags from proteins marked for degradation, thereby averting their proteasomal breakdown. Several DUBs have demonstrated their capacity to regulate the levels of Aβ and Tau by modulating their degree of ubiquitination, underscoring their potential as therapeutic targets for AD. In this context, we present a comprehensive review of AD-associated DUBs and elucidate their physiological roles. Moreover, we delve into the current advancements in developing inhibitors targeting these DUBs, including the determination of cocrystal structures with their respective targets. Additionally, we assess the therapeutic efficacy of these inhibitors in AD, aiming to establish a theoretical foundation for future AD treatments.

阿尔茨海默病(AD)是一种常见的神经退行性疾病,其特征是淀粉样β蛋白(Aβ)的积累和微管相关蛋白Tau的过度磷酸化。泛素-蛋白酶体系统(UPS)在决定蛋白质的命运方面起着关键作用,它的失调会导致 Aβ 和 Tau 的积累。去泛素化酶(DUB)与激活酶(E1)、泛素结合酶(E2)和泛素连接酶(E3)共同作用,积极维持蛋白质平衡的微妙平衡。DUBs 能特异性地从标记为降解的蛋白质上去除泛素标签,从而避免其被蛋白酶体分解。一些 DUBs 已证明它们有能力通过调节 Aβ 和 Tau 的泛素化程度来调节它们的水平,这突显了它们作为 AD 治疗靶点的潜力。在此背景下,我们全面回顾了与AD相关的DUBs,并阐明了它们的生理作用。此外,我们还深入探讨了目前针对这些 DUBs 开发抑制剂的进展,包括确定其与各自靶标的共晶体结构。此外,我们还评估了这些抑制剂对AD的疗效,旨在为未来的AD治疗奠定理论基础。
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引用次数: 0
Chromatin landscape dynamics during reprogramming towards human naïve and primed pluripotency reveals the divergent function of PRDM1 isoforms. 人类原始多能性和原始多能性重编程过程中的染色质景观动态揭示了 PRDM1 同工型的不同功能。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-19 DOI: 10.1038/s41420-024-02230-w
Jianfeng Zhou, Mingyue Guo, Guang Yang, Xinyu Cui, Jindian Hu, Tan Lin, Hong Wang, Shaorong Gao, Cizhong Jiang, Liping Wang, Yixuan Wang

Induced pluripotent stem cells (iPSCs) technology holds great potential in both scientific research and clinical applications. It enables the generation of naïve and primed iPSCs from various cell types through different strategies. Despite extensive characterizations of transcriptional and epigenetic factors, the intricacies of chromatin landscape dynamics during naïve and primed reprogramming, particularly in humans, remain poorly understood. In this study, we employed ATAC-seq and RNA-seq analyses to delineate and compare the chromatin landscape of naïve and primed pluripotency through the human secondary reprogramming system. Our investigations revealed several key transcriptional and epigenetic factors pivotal for reprogramming-associated chromatin remodeling. Notably, we found two isoforms of PRDM1, PRDM1α, and PRDM1β, bind to distinct genomic loci and play different roles in the naïve reprogramming process. We proposed an auto-regulatory model explaining the distinct functions of PRDM1α and PRDM1β. Overall, our findings highlight the complexity and diversity of transcription factors in shaping chromatin landscape dynamics and directing the fates of pluripotent cells.

诱导多能干细胞(iPSCs)技术在科学研究和临床应用方面都具有巨大潜力。它能通过不同的策略,从各种细胞类型中生成幼稚和原始的 iPSCs。尽管对转录和表观遗传因子进行了广泛表征,但人们对原始和初始重编程过程中染色质景观动态的复杂性仍然知之甚少,尤其是在人类中。在本研究中,我们采用 ATAC-seq 和 RNA-seq 分析方法,通过人类二次重编程系统,描述并比较了幼稚多能性和原始多能性的染色质景观。我们的研究揭示了重编程相关染色质重塑的几个关键转录和表观遗传因子。值得注意的是,我们发现PRDM1的两种异构体PRDM1α和PRDM1β与不同的基因组位点结合,并在幼稚重编程过程中发挥不同的作用。我们提出了一个自动调节模型来解释 PRDM1α 和 PRDM1β 的不同功能。总之,我们的研究结果凸显了转录因子在塑造染色质景观动态和引导多能细胞命运方面的复杂性和多样性。
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引用次数: 0
NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination. NEDD4L 通过促进 xCT 泛素化,有助于食管鳞状细胞癌的铁变态和细胞生长抑制。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-18 DOI: 10.1038/s41420-024-02243-5
Zhen Chen, Weilong Wang, Jinghan Hou, Can Gao, Meili Song, Zijun Zhao, Ruirui Guan, Jingsheng Chen, Huicheng Wu, Siti Razila Abdul Razak, Tao Han, Junbo Zhang, Lidong Wang, Nor Hazwani Ahmad, Xiumin Li

The oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what specific regulatory mechanism of xCT by ubiquitin ligases in human cancers. Here, we reported that NEDD4L, an E3 ubiquitin ligases, inhibited esophageal squamous cell carcinoma (ESCC) tumor growth and facilitated ferroptosis by ubiquitination of xCT. NEDD4L expression was declined in ESCC and was associated with tumor invasion, lymph node metastasis and distant metastasis. Silencing NEDD4L triggered ESCC tumor growth. Meanwhile, knock down of NEDD4L prevented the accumulation of ROS, elevated the level of GSH, reduced the content of MDA in ESCC cells, thereby inhibiting ferroptosis. Mechanistically, NEDD4L directly bound to the ∆CT domain of xCT through its WW and HECT domain. More importantly, NEDD4L promoted xCT degradation by facilitating its polyubiquitination in ESCC cells. Collectively, these findings suggest that NEDD4L is crucial in governing the stability of xCT and mediating ferroptosis in ESCC.

癌基因 xCT 通过保护癌细胞免受氧化应激和铁变态反应的影响,在肿瘤生长过程中发挥着不可或缺的作用。新的证据表明,xCT 的功能受到翻译后修饰(尤其是泛素化)的严格控制。然而,目前仍不清楚泛素连接酶在人类癌症中对xCT的具体调控机制。在这里,我们报道了一种E3泛素连接酶NEDD4L通过泛素化xCT抑制食管鳞状细胞癌(ESCC)肿瘤的生长并促进铁变态反应。NEDD4L在ESCC中表达下降,与肿瘤侵袭、淋巴结转移和远处转移有关。沉默NEDD4L会诱发ESCC肿瘤生长。同时,敲除NEDD4L可阻止ROS的积累,提高GSH水平,降低ESCC细胞中MDA的含量,从而抑制铁变态反应。从机理上讲,NEDD4L通过其WW和HECT结构域直接与xCT的ΔCT结构域结合。更重要的是,NEDD4L通过促进其在ESCC细胞中的多泛素化来促进xCT的降解。总之,这些研究结果表明,NEDD4L在调控xCT的稳定性和介导ESCC中的铁变态反应方面至关重要。
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引用次数: 0
Therapeutic advances in the targeting of ROR1 in hematological cancers. 针对血液肿瘤中 ROR1 的治疗进展。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-17 DOI: 10.1038/s41420-024-02239-1
Adrian-Bogdan Tigu, Raluca Munteanu, Cristian Moldovan, Drula Rares, David Kegyes, Radu Tomai, Vlad Moisoiu, Gabriel Ghiaur, Ciprian Tomuleasa, Hermann Einsele, Diana Gulei, Carlo M Croce

Receptor tyrosine kinases (RTKs) are key cell surface receptors involved in cell communication and signal transduction, with great importance in cell growth, differentiation, survival, and metabolism. Dysregulation of RTKs, such as EGFR, VEGFR, HER2 or ROR, could lead to various diseases, particularly cancers. ROR1 has emerged as a promising target in hematological malignancies. The development of ROR1 targeted therapies is continuously growing leading to remarkable novel therapeutical approaches using mAbs, antibody-drug conjugates, several small molecules or CAR T cells which have shown encouraging preclinical results. In the hematological field, mAbs, small molecules, BiTEs or CAR T cell therapies displayed promising outcomes with the clinical trials data encouraging the use of anti-ROR1 therapies. This paper aims to offer a comprehensive analysis of the current landscape of ROR1-targeted therapies in hematological malignancies marking the innovative approaches with promising preclinical and clinical. Offering a better understanding of structural and functional aspects of ROR1 could lead to new perspectives in targeting a wide spectrum of malignancies.

受体酪氨酸激酶(RTK)是参与细胞通讯和信号转导的关键细胞表面受体,在细胞生长、分化、存活和新陈代谢中具有重要作用。表皮生长因子受体(EGFR)、血管内皮生长因子受体(VEGFR)、HER2 或 ROR 等 RTK 的失调可导致各种疾病,尤其是癌症。ROR1 已成为血液恶性肿瘤中一个很有前景的靶点。ROR1 靶向疗法的开发正在不断发展,利用 mAbs、抗体药物共轭物、多种小分子或 CAR T 细胞的新型治疗方法令人瞩目,临床前研究结果令人鼓舞。在血液学领域,mAbs、小分子、BiTEs 或 CAR T 细胞疗法显示出了令人鼓舞的成果,临床试验数据鼓励使用抗 ROR1 疗法。本文旨在全面分析目前血液恶性肿瘤中 ROR1 靶向疗法的现状,指出临床前和临床中前景看好的创新方法。更好地了解 ROR1 的结构和功能可为靶向治疗各种恶性肿瘤提供新的视角。
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引用次数: 0
DDX3 is critical for female fertility via translational control in oogenesis. DDX3 在卵子生成过程中通过翻译控制对雌性生育能力至关重要。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-17 DOI: 10.1038/s41420-024-02242-6
Shang-Yu Tsai, Chih-Hung Lin, Yu-Ting Jiang, Guo-Jen Huang, Haiwei Pi, Hsin-Yuan Hung, Woan-Yuh Tarn, Ming-Chih Lai

DEAD-box RNA helicase 3 (DDX3) and its homologs play a vital role in translation initiation by unwinding secondary structures of selected mRNAs. The human DDX3 gene is located on the sex chromosomes, so there are DDX3X and DDX3Y. DDX3X is ubiquitously expressed in almost all tissues and critical for embryonic development, whereas DDX3Y is only expressed in the testis and essential for male fertility. Drosophila belle (bel) is the single ortholog of DDX3, and mutations in bel cause male and female infertility. Using Drosophila bel mutants and Ddx3x conditional knockout (cKO) mice, we confirmed the pivotal role of DDX3 in female fertility and ovarian development. Drosophila bel mutants exhibited female infertility and immature egg chambers. Consistently, oocyte-specific Ddx3x knockout in mice resulted in female infertility and impaired oogenesis. We further found that immature egg chambers in Drosophila bel mutants and impaired follicular development in oocyte-specific Ddx3x cKO mice were caused by excessive apoptosis. We also identified a set of DDX3 target genes involved in oocyte meiosis and maturation and demonstrated that DDX3 is involved in their translation in human cells. Our results suggest that DDX3 is critical for female fertility via translational control in oogenesis.

DEAD-box RNA 螺旋酶 3(DDX3)及其同源物通过解开选定 mRNA 的二级结构,在翻译启动过程中发挥着重要作用。人类的 DDX3 基因位于性染色体上,因此有 DDX3X 和 DDX3Y 之分。DDX3X 在几乎所有组织中普遍表达,对胚胎发育至关重要,而 DDX3Y 只在睾丸中表达,对男性生育力至关重要。果蝇belle(bel)是DDX3的单个直向同源物,bel突变会导致雄性和雌性不育。利用果蝇bel突变体和Ddx3x条件性基因敲除(cKO)小鼠,我们证实了DDX3在雌性生育能力和卵巢发育中的关键作用。果蝇bel突变体表现出雌性不孕和卵室不成熟。同样,小鼠卵母细胞特异性 Ddx3x 基因敲除也会导致雌性不孕和卵子生成障碍。我们进一步发现,果蝇bel突变体中不成熟的卵室和卵母细胞特异性Ddx3x cKO小鼠中受损的卵泡发育是由过度的细胞凋亡造成的。我们还发现了一组参与卵母细胞减数分裂和成熟的 DDX3 靶基因,并证明 DDX3 参与了这些基因在人体细胞中的翻译。我们的研究结果表明,DDX3 在卵子发生过程中通过翻译控制对女性生育至关重要。
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引用次数: 0
Broad-spectrum inflammasome inhibition by thiomuscimol. 硫代麝香草酚的广谱炎症小体抑制作用
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-16 DOI: 10.1038/s41420-024-02238-2
Marisa J Anderson, Andreas B den Hartigh, Wendy P Loomis, Susan L Fink

Inflammasome formation, arising from pathogen or internal activating signals, is a key step in canonical pyroptosis, a gasdermin-mediated inflammatory cell death. Inhibition of pyroptosis has great clinical relevance due to its involvement in many different disease states. Current inhibitors of pyroptosis either only inhibit the final lytic step, which still allows inflammatory signal release, or only inhibit a single inflammasome, which does not account for inherent redundancy in activation of other inflammatory pathways. Here, we show that thiomuscimol, a structural analog of the lysis inhibitor muscimol, exhibits unique inhibitory activity upstream of plasma membrane rupture. We find that thiomuscimol inhibits inflammasome formation, as well as downstream caspase-1 activation, initiated by multiple pyroptotic signals, regardless of whether NLR recruitment of caspase-1 to the inflammasome relies on the ASC adapter protein. The ability of thiomuscimol to block multiple different inflammasomes opens the door for development of therapeutics with increased applications to broadly inhibit pyroptosis in multiple pathological settings.

炎症小体的形成源于病原体或内部激活信号,是典型热蛋白沉积(一种由气体蛋白介导的炎症细胞死亡)的关键步骤。由于热蛋白沉积参与了许多不同的疾病状态,因此抑制热蛋白沉积具有重要的临床意义。目前的热凋亡抑制剂要么只抑制最后的裂解步骤,仍允许炎症信号的释放,要么只抑制单一的炎性体,无法解释激活其他炎症通路的内在冗余。在这里,我们发现硫代麝香草酚是裂解抑制剂麝香草酚的结构类似物,它在质膜破裂上游表现出独特的抑制活性。我们发现,无论 NLR 将 caspase-1 招募到炎性体是否依赖于 ASC 适配器蛋白,硫代麝香草酚都能抑制炎性体的形成以及下游 caspase-1 的活化。硫代麝香草酚能够阻断多种不同的炎性体,这为开发更多应用于多种病理情况下广泛抑制热蛋白沉积的治疗药物打开了大门。
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引用次数: 0
Identification of PDLIM1 as a glioblastoma stem cell marker driving tumorigenesis and chemoresistance. 鉴定 PDLIM1 为胶质母细胞瘤干细胞标记物,可驱动肿瘤发生和化疗抗药性。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-15 DOI: 10.1038/s41420-024-02241-7
Xiaopeng Shen, Yun Zhao, Yang Cao, Yunfeng Liu, Jian Ruan, Chunguang Wang, Meng Li, Huaizhang Jin, Shan Lu, Guoping Zhu

Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis, largely due to the presence of glioblastoma stem cells (GSCs). These cells drive tumor progression, recurrence, and chemoresistance, making them critical targets for therapy. This study aims to identify novel GSC markers for improved diagnosis and targeted treatment. We utilized single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to identify PDLIM1 as a novel GSC marker. PDLIM1 was specifically expressed in GSCs and was associated with poor prognosis and advanced tumor stages. Functional assays demonstrated that PDLIM1 overexpression enhanced GBM cell proliferation, reduced apoptosis, increased GSC proportions, and promoted chemoresistance and tumorigenesis. Conversely, PDLIM1 knockdown inhibited these processes. Mechanistically, PDLIM1 was found to exert its effects likely by promoting the PI3K-AKT pathway. In conclusion, PDLIM1 may serve as a potential marker of GSCs associated with poor prognosis, tumorigenesis, and chemoresistance in GBM, representing a potential therapeutic target for improving GBM patient outcomes.

胶质母细胞瘤(GBM)是一种侵袭性脑肿瘤,预后较差,这主要是由于胶质母细胞瘤干细胞(GSC)的存在。这些细胞驱动肿瘤进展、复发和化疗耐药性,使其成为治疗的关键靶点。本研究旨在鉴定新型GSC标记物,以改进诊断和靶向治疗。我们利用单细胞RNA测序(scRNA-seq)和大量RNA-seq数据确定了PDLIM1作为新型GSC标记物。PDLIM1在GSC中特异性表达,与预后不良和肿瘤晚期有关。功能测试表明,PDLIM1过表达会增强GBM细胞增殖,减少细胞凋亡,增加GSC比例,促进化疗耐受性和肿瘤发生。相反,PDLIM1 基因敲除则会抑制这些过程。从机理上讲,PDLIM1 可能是通过促进 PI3K-AKT 通路来发挥其作用的。总之,PDLIM1 可作为与 GBM 预后不良、肿瘤发生和化疗耐药相关的 GSC 的潜在标志物,是改善 GBM 患者预后的潜在治疗靶点。
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引用次数: 0
Identification of apelin/APJ signaling dysregulation in a human iPSC-derived granulosa cell model of Turner syndrome. 鉴定特纳综合征人类 iPSC 衍生颗粒细胞模型中的凋亡素/APJ 信号失调。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-14 DOI: 10.1038/s41420-024-02231-9
Wei-Ju Chen, Yi-Ya Chao, Wei-Kai Huang, Wei-Fang Chang, Chii-Ruey Tzeng, Chi-Hsuan Chuang, Pei-Lun Lai, Scott C Schuyler, Long-Yuan Li, Jean Lu

The interaction between germ cells and somatic cells in the ovaries plays a crucial role in establishing the follicle reserve in mammals. Turner syndrome (TS) predominantly affects females who have a partial or complete loss of one X chromosome. Our understanding of the role that granulosa cells (GCs) play in TS disease progression and pathogenesis remains limited. In this study, we achieved GC differentiation efficiency of up to 80% from iPSCs. When attempting to replicate the differentiation process of embryonic granulosa cells, we observed the downregulation of specific genes-GATA4, FOXL2, AMHR2, CYP19A1, and FSH-in Turner syndrome-derived granulosa cells (TS-GCs). Additionally, we identified dysregulation of the cell cycle in TS-GCs. To uncover the endogenous defects in TS-GCs, we compared global transcriptome patterns between iPSC-derived granulosa cells from healthy individuals and those with Turner syndrome. The apelin/APJ pathway exhibited differential signaling between the healthy and TS groups. Supplementation with apelin ligands and activation of apelin/APJ downstream signaling via Akt/PKB restored cell cycle progression and marker gene expression. We hypothesize that during early embryonic development, failures in apelin/APJ signaling in GCs of Turner syndrome patients lead to abnormalities in ovarian development, ultimately resulting in early oocyte loss and infertility.

卵巢中生殖细胞和体细胞之间的相互作用对哺乳动物卵泡储备的建立起着至关重要的作用。特纳综合征(TS)主要影响部分或完全缺失一条X染色体的女性。我们对颗粒细胞(GCs)在TS疾病进展和发病机制中所起作用的了解仍然有限。在这项研究中,我们从 iPSCs 中获得了高达 80% 的 GC 分化效率。在试图复制胚胎颗粒细胞的分化过程时,我们观察到特纳综合征衍生颗粒细胞(TS-GCs)中特定基因--GATA4、FOXL2、AMHR2、CYP19A1和FSH的下调。此外,我们还发现TS-GCs的细胞周期失调。为了揭示TS-GCs的内源性缺陷,我们比较了来自健康人和特纳综合征患者的iPSC衍生颗粒细胞的全局转录组模式。在健康组和 TS 组之间,凋亡素/APJ 通路显示出不同的信号传导。补充apelin配体并通过Akt/PKB激活apelin/APJ下游信号,可恢复细胞周期进程和标记基因表达。我们推测,在早期胚胎发育过程中,特纳综合征患者GC中的apelin/APJ信号传导失败会导致卵巢发育异常,最终导致早期卵母细胞丢失和不孕。
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引用次数: 0
N-Acetylneuraminic acid triggers endothelial pyroptosis and promotes atherosclerosis progression via GLS2-mediated glutaminolysis pathway. N-乙酰神经氨酸通过 GLS2 介导的谷氨酰胺溶解途径引发内皮细胞热解并促进动脉粥样硬化的进展。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-13 DOI: 10.1038/s41420-024-02233-7
Zhaohong Liu, Peng Xiang, Shengmei Zeng, Ping Weng, Yilin Wen, Wanping Zhang, Hui Hu, Dezhang Zhao, Limei Ma, Chao Yu

Vascular endothelial injury initiates atherosclerosis (AS) progression. N-Acetylneuraminic acid (Neu5Ac) metabolic disorder was found to intensify endothelial mitochondrial damage. And GLS2-associated glutaminolysis disorder contributed to mitochondrial dysfunction. However, mechanisms underlying Neu5Ac-associated mitochondrial dysfunction as well as its association with GLS2 remains unclear. In this study, we constructed GLS2-/-ApoE-/- mice by using HBLV-GLS2 shRNA injection. And methods like immunofluorescence, western blotting, transmission electron microscopy were applied to detect profiles of endothelial injury and AS progression both in vivo and in vitro. We demonstrated that Neu5Ac accumulation increased GLS2 expression and promoted glutaminolysis disorder, which further induced endothelial mitochondrial dysfunction via a pyroptosis-dependent pathway in vivo and in vitro. Mechanically, Neu5Ac interacted with SIRT3 and led to FOXO3a deacetylation and phosphorylation, further facilitated c-Myc antagonism and ultimately increased GLS2 levels. Inhibition of GLS2 could improve mitochondrial function and mitigate pyroptosis process. In addition, blocking Neu5Ac production using neuraminidases (NEUs) inhibitor could rescue endothelial damage and alleviate AS development in ApoE-/- mice. These findings proposed that Neu5Ac induced GLS2-mediated glutaminolysis disorder and then promoted mitochondrial dysfunction in a pyroptosis-dependent pathway. Targeting GLS2 or inhibiting Neu5Ac production could prevent AS progression.

血管内皮损伤是动脉粥样硬化(AS)进展的起因。研究发现,N-乙酰神经氨酸(Neu5Ac)代谢紊乱会加剧内皮线粒体损伤。与 GLS2 相关的谷氨酰胺溶解紊乱也导致了线粒体功能障碍。然而,Neu5Ac 相关的线粒体功能障碍及其与 GLS2 的关联机制仍不清楚。在本研究中,我们通过注射 HBLV-GLS2 shRNA 构建了 GLS2-/-ApoE-/- 小鼠。并应用免疫荧光、Western 印迹、透射电子显微镜等方法检测了体内和体外内皮损伤和强直性脊柱炎进展的特征。我们发现,Neu5Ac的积累增加了GLS2的表达,并促进了谷氨酰胺溶解紊乱,从而进一步通过体内和体外的嗜热依赖途径诱导内皮线粒体功能障碍。在机制上,Neu5Ac 与 SIRT3 相互作用,导致 FOXO3a 去乙酰化和磷酸化,进一步促进 c-Myc 拮抗作用,最终提高 GLS2 水平。抑制 GLS2 可改善线粒体功能,缓解热凋亡过程。此外,使用神经氨酸酶(NEUs)抑制剂阻断Neu5Ac的产生,可以挽救内皮损伤,缓解载脂蛋白E-/-小鼠强直性脊柱炎的发展。这些研究结果表明,Neu5Ac可诱导GLS2介导的谷氨酰胺溶解紊乱,进而促进线粒体功能障碍,而线粒体功能障碍是一个依赖于火变态反应的途径。以GLS2为靶点或抑制Neu5Ac的产生可预防强直性脊柱炎的发展。
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引用次数: 0
Advances in smart nanotechnology-supported photodynamic therapy for cancer. 智能纳米技术支持的癌症光动力疗法的进展。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-11 DOI: 10.1038/s41420-024-02236-4
Guangyao Li, Cong Wang, Binghui Jin, Tao Sun, Kang Sun, Shuang Wang, Zhe Fan

Cancer has emerged as a formidable challenge in the 21st century, impacting society, public health, and the economy. Conventional cancer treatments often exhibit limited efficacy and considerable side effects, particularly in managing the advanced stages of the disease. Photodynamic therapy (PDT), a contemporary non-invasive therapeutic approach, employs photosensitizers (PS) in conjunction with precise light wavelengths to selectively target diseased tissues, inducing the generation of reactive oxygen species and ultimately leading to cancer cell apoptosis. In contrast to conventional therapies, PDT presents a lower incidence of side effects and greater precision in targeting. The integration of intelligent nanotechnology into PDT has markedly improved its effectiveness, as evidenced by the remarkable synergistic antitumor effects observed with the utilization of multifunctional nanoplatforms in conjunction with PDT. This paper provides a concise overview of the principles underlying PS and PDT, while also delving into the utilization of nanomaterial-based PDT in the context of cancer treatment.

癌症已成为 21 世纪的一项严峻挑战,对社会、公众健康和经济都产生了影响。传统的癌症治疗方法往往疗效有限,副作用较大,尤其是在治疗晚期癌症时。光动力疗法(PDT)是当代一种非侵入性治疗方法,它利用光敏剂(PS)与精确波长的光相结合,选择性地靶向病变组织,诱导活性氧的产生,最终导致癌细胞凋亡。与传统疗法相比,PDT 的副作用更低,靶向性更精确。将智能纳米技术融入光动力疗法可显著提高其疗效,多功能纳米平台与光动力疗法结合使用可产生显著的协同抗肿瘤效果。本文简要概述了 PS 和 PDT 的基本原理,同时还深入探讨了基于纳米材料的 PDT 在癌症治疗中的应用。
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引用次数: 0
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Cell Death Discovery
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