Cell insight最新文献_第4页

Integrated 4D label-free proteome and SUMOylated proteome in glioma uncover novel pathological mechanisms and pave the way for precision therapy 脑胶质瘤中4D无标记蛋白质组和summoylated蛋白质组的整合揭示了新的病理机制，为精准治疗铺平了道路

Cell insight

Pub Date : 2025-05-19 DOI: 10.1016/j.cellin.2025.100253

Jiazheng Wang , Zhuo Li , Kaijie Mu , Qichao Qi , Zeli Zhang , Can Yan , Xukai Jiang , Anjing Chen

Glioma, the most common primary intracranial tumor, has seen increased scrutiny with the advent of high-throughput detection technologies, yet many aspects of its tumorigenesis and progression remain enigmatic. In this study, we utilized 4D label-free mass quantitative proteomics to analyze glioma protein expression, with a focus on SUMOylated proteins through SUMO peptide enrichment. Bioinformatics analysis was applied to identify differentially expressed proteins (DEPs) and differentially SUMOylated proteins, elucidating their functions and interactions. By integrating proteomics and transcriptomics data, we pinpointed core proteins with consistent upregulation and assessed their potential as drug targets in glioma through virtual screening of eight cytoplasmic proteins with small molecule binding cavities. Our findings reveal that low-grade glioma (LGG) exhibits more DEPs than glioblastoma (GBM) when compared to normal brain tissue, but GBM shows more disrupted functions. LGG is characterized by a higher number of SUMOylated proteins in key processes, whereas GBM has fewer, with these SUMOylated proteins implicated in diverse functions, including RNA and protein regulation, metabolism, and immunity. There is also a significant discrepancy between RNA and protein levels for most molecules. The virtual docking of core oncogenic molecules suggests potential therapeutic targets and transformation opportunities. This study deepens our comprehension of glioma proteomics and SUMOylation, revealing novel pathological mechanisms and laying the groundwork for targeted glioma therapies.

神经胶质瘤是最常见的原发性颅内肿瘤，随着高通量检测技术的出现，人们对其进行了越来越多的研究，但其肿瘤发生和进展的许多方面仍然是谜。在本研究中，我们利用4D无标记的大量定量蛋白质组学分析胶质瘤蛋白的表达，重点是通过SUMO肽富集研究SUMO化蛋白。应用生物信息学分析鉴定差异表达蛋白（DEPs）和差异summoylated蛋白，阐明它们的功能和相互作用。通过整合蛋白质组学和转录组学数据，我们确定了具有一致上调的核心蛋白，并通过虚拟筛选8种具有小分子结合腔的细胞质蛋白，评估了它们作为胶质瘤药物靶点的潜力。我们的研究结果表明，与正常脑组织相比，低级别胶质瘤（LGG）比胶质母细胞瘤（GBM）表现出更多的dep，但GBM表现出更多的功能破坏。LGG的特点是在关键过程中有较多的SUMOylated蛋白，而GBM则较少，这些SUMOylated蛋白涉及多种功能，包括RNA和蛋白质调节、代谢和免疫。对于大多数分子来说，RNA和蛋白质的水平也存在显著差异。核心致癌分子的虚拟对接提示了潜在的治疗靶点和转化机会。该研究加深了我们对胶质瘤蛋白质组学和SUMOylation的理解，揭示了新的病理机制，为胶质瘤靶向治疗奠定了基础。

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引用次数: 0

The roles of macrophages and monocytes in COVID-19 Severe Respiratory Syndrome 巨噬细胞和单核细胞在COVID-19严重呼吸综合征中的作用

Cell insight

Pub Date : 2025-05-08 DOI: 10.1016/j.cellin.2025.100250

Jun Li , Rui Shan , Heather Miller , Alexander Filatov , Maria G. Byazrova , Lu Yang , Chaohong Liu

The global COVID-19 pandemic has highlighted the pivotal role of the immune system in the development of severe respiratory symptoms, termed COVID-19 Severe Respiratory Syndrome (COVID-19-SR). This review aims to dissect the involvement of lung macrophages and monocytes in orchestrating immune responses to SARS-CoV-2, influencing disease severity and outcomes. Initially, we provide an overview of SARS-CoV-2's invasion process and the body's primary immune defense mechanisms, including the antibody complement system and cytokine production. We then delve into the roles of the monocyte-macrophage system in mediating hyperinflammation and cytokine storms, discussing how abnormal cytokine and chemokine levels contribute to disease progression. Subsequent sections examine the perturbations and overactivation of the monocyte-macrophage compartment during infection, linking these changes to the observed immune dysregulation in COVID-19 patients. In light of these insights, we explore therapeutic strategies targeting macrophages, such as dexamethasone, antisense lipid nanoparticles(ALN), and inhaled recombinant human granulocyte-macrophage colony-stimulating factor (rh-GM-CSF), which aim to modulate inflammation, suppress viral replication, and enhance viral clearance. Additional potential treatments include GSDMD inhibitors and GPR183 antagonists, which warrant further investigation. This review synthesizes current understanding of the immunopathology underlying COVID-19-SR, proposing macrophage- and monocyte-centered therapeutic avenues and outlining future research priorities essential for advancing clinical management and improving patient outcomes.

COVID-19全球大流行凸显了免疫系统在严重呼吸道症状（称为COVID-19- sr）发展中的关键作用。本综述旨在剖析肺巨噬细胞和单核细胞在协调对SARS-CoV-2的免疫反应、影响疾病严重程度和结局中的作用。首先，我们概述了SARS-CoV-2的入侵过程和人体的主要免疫防御机制，包括抗体补体系统和细胞因子的产生。然后，我们深入研究单核-巨噬细胞系统在介导高炎症和细胞因子风暴中的作用，讨论异常细胞因子和趋化因子水平如何促进疾病进展。随后的章节研究了感染期间单核-巨噬细胞室的扰动和过度激活，将这些变化与COVID-19患者观察到的免疫失调联系起来。鉴于这些见解，我们探索了针对巨噬细胞的治疗策略，如地塞米松，反义脂质纳米颗粒（ALN）和吸入重组人粒细胞-巨噬细胞集落刺激因子（rh-GM-CSF），旨在调节炎症，抑制病毒复制，增强病毒清除。其他潜在的治疗方法包括GSDMD抑制剂和GPR183拮抗剂，值得进一步研究。本综述综合了目前对COVID-19-SR免疫病理学基础的理解，提出了以巨噬细胞和单核细胞为中心的治疗途径，并概述了未来的研究重点，这对推进临床管理和改善患者预后至关重要。

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引用次数: 0

cGAS, an innate dsDNA sensor with multifaceted functions cGAS，一种具有多方面功能的先天dsDNA传感器

Cell insight

Pub Date : 2025-04-17 DOI: 10.1016/j.cellin.2025.100249

Yutong Liu , Pinglong Xu

Cyclic GMP-AMP synthase (cGAS) functions as a pivotal intracellular sensor for the innate immune sensing of double-stranded DNA (dsDNA), monitoring those nucleic acids from foreign and endogenous sources. Upon assembling into cellular condensates with dsDNA and regulators, cGAS synthesizes 2′3′-cGAMP that activates the downstream STING signaling. This activation triggers a variety of intracellular responses, including autophagy, mRNA translation, interferon signaling, and inflammatory responses. Context-dependently, cGAS resides in diverse cellular compartments, including the nucleus, micronuclei, plasma membrane, and organelle surfaces. Beyond its DNA-sensing role, cGAS can play complex roles in these locations, such as DNA damage repairing, membrane restoration, chromatin condensation, angiogenesis, and aging regulation. This comprehensive review summarizes recent advances in the activation, regulation, and pharmacological management of cGAS, focusing on its molecular mechanisms, post-translational modifications (PTMs), and therapeutic interventions. The functional implications of cGAS in various disease contexts, including infectious diseases, autoinflammatory diseases, autoimmune diseases, aging, and cancers, are also covered.

环GMP-AMP合成酶（cGAS）作为双链DNA （dsDNA）先天免疫传感的关键细胞内传感器，监测来自外源和内源的核酸。在与dsDNA和调节因子组装成细胞凝聚体后，cGAS合成2 ' 3 ' -cGAMP，激活下游STING信号传导。这种激活触发多种细胞内反应，包括自噬、mRNA翻译、干扰素信号传导和炎症反应。与环境相关，cGAS存在于不同的细胞室中，包括细胞核、微核、质膜和细胞器表面。除了DNA传感作用外，cGAS还可以在这些位置发挥复杂的作用，如DNA损伤修复、膜修复、染色质凝聚、血管生成和衰老调节。本文综述了近年来在cGAS的激活、调控和药理管理方面的研究进展，重点介绍了其分子机制、翻译后修饰（PTMs）和治疗干预措施。cGAS在各种疾病背景下的功能含义，包括感染性疾病、自身炎症性疾病、自身免疫性疾病、衰老和癌症，也被涵盖。

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引用次数: 0

Corrigendum to “STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy” [Cell Insight 3 (2024) 100147] “STING引导STX17-SNAP29-VAMP8复合物组装控制自噬”的勘误表[Cell Insight 3 (2024) 100147]

Cell insight

Pub Date : 2025-04-11 DOI: 10.1016/j.cellin.2025.100239

Xiaoyu Song , Yufeng Xi , Ming Dai , Tao Li , Shihao Du , Yuxin Zhu , Mengjie Li , Yunze Li , Siqi Liu , Xia Ding , Xuebiao Yao , Ying Lai , Xing Liu

引用次数: 0

Targeting PD-1 post-translational modifications for improving cancer immunotherapy 靶向PD-1翻译后修饰改善癌症免疫治疗

Cell insight

Pub Date : 2025-04-10 DOI: 10.1016/j.cellin.2025.100248

Jie Shi , Chuan He , Li Chen , Xixin Xing , Wenyi Wei , Jinfang Zhang

Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.

程序性细胞死亡蛋白1 （PD-1）是一种重要的免疫检查点受体，主要通过与PD-L1的相互作用抑制免疫反应。肿瘤利用这种机制逃避免疫监视，定位靶向PD-1/PD-L1轴的免疫检查点抑制剂是癌症治疗的突破性进展。然而，这些疗法的总体有效性往往受到对潜在机制的不完全理解的限制。最近的研究揭示了PD-1的各种翻译后修饰（PTMs），包括泛素化，ufmy化，磷酸化，棕榈酰化和糖基化，在调节其蛋白质稳定性，定位和蛋白质-蛋白质相互作用中的关键作用。同样，这些ptm的失调可以驱动pd -1介导的免疫逃避，并有助于治疗抵抗。值得注意的是，在临床前小鼠模型和临床试验中，用小分子抑制剂或单克隆抗体（mab）靶向PD-1 PTMs已显示出增强抗肿瘤免疫的潜力。本综述重点介绍了PD-1 ptm的最新发现，并探讨了旨在调节这些修饰的新兴治疗策略。通过整合这些机制的见解，癌症免疫联合疗法的发展可以进一步合理推进，为更有效和持久的治疗提供新的途径。

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引用次数: 0

Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting 肿瘤内HIF-1α调节一种病毒质配体的产生，导致宿主消瘦

Cell insight

Pub Date : 2025-04-08 DOI: 10.1016/j.cellin.2025.100247

Gen Xiao , Yingge Li , Yanhui Hu , Kai Tan , Mengyang Wang , Kerui Zhu , Mingkui San , Qian Cheng , Dilinigeer Tayier , Tingting Hu , Peixuan Dang , Jiaying Li , Chen Cheng , Norbert Perrimon , Zhiyong Yang , Wei Song

Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the production or secretion of these cachectic proteins, however, still remain largely unknown. In this study, we used different Drosophila cachexia models to investigate how malignant tumors regulate biosynthesis of ImpL2, a conserved cachectic protein that inhibits systemic insulin/IGF signaling and suppresses anabolism of host organs. Through bioinformatic and biochemical analysis, we found that hypoxia-inducible factor HIF-1α/Sima directly binds to the promoter region of ImpL2 gene for the first time, promoting its transcription in both tumors and non-tumor cells. Interestingly, expressing HphA to moderately suppress HIF-1α/Sima activity in adult yki^3SA gut tumors or larval scrib¹ Ras^V12 disc tumors sufficiently decreased ImpL2 expression and improved organ wasting, without affecting tumor growth. We further revealed conserved regulatory mechanisms conserved across species, as intratumor HIF-1α enhances the production of IGFBP-5, a mammalian homolog of fly ImpL2, contributing to organ wasting in both tumor-bearing mice and patients. Therefore, our study provides novel insights into the mechanisms by which tumors regulate production of cachectic ligands and the pathogenesis of cancer-induced cachexia.

肿瘤-宿主相互作用在癌症相关恶病质中起关键作用。先前的研究已经确定了肿瘤分泌的几种恶病质蛋白，它们破坏了多个器官的代谢稳态，导致宿主消瘦。然而，恶性肿瘤调节这些恶病质蛋白产生或分泌的分子机制在很大程度上仍然未知。在这项研究中，我们使用不同的果蝇恶病质模型来研究恶性肿瘤如何调节ImpL2的生物合成，ImpL2是一种保守的恶病质蛋白，可抑制全身胰岛素/IGF信号传导并抑制宿主器官的合成代谢。通过生物信息学和生化分析，我们首次发现缺氧诱导因子HIF-1α/Sima直接结合到ImpL2基因的启动子区域，促进其在肿瘤细胞和非肿瘤细胞中的转录。有趣的是，在成人yki3SA肠道肿瘤或幼虫scrib1 RasV12椎间盘肿瘤中，表达HphA可适度抑制HIF-1α/Sima活性，充分降低ImpL2表达并改善器官消耗，而不影响肿瘤生长。我们进一步揭示了跨物种保守的调控机制，如肿瘤内HIF-1α增强IGFBP-5的产生，IGFBP-5是苍蝇ImpL2的哺乳动物同源物，有助于荷瘤小鼠和患者的器官消耗。因此，我们的研究为肿瘤调节恶病质配体产生的机制和癌症诱导恶病质的发病机制提供了新的见解。

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引用次数: 0

Cover 封面

Cell insight

Pub Date : 2025-04-01 DOI: 10.1016/S2772-8927(25)00015-X

引用次数: 0

The role of TRPV4 in acute sleep deprivation-induced memory impairment: Mechanisms of calcium dysregulation and synaptic plasticity disruption TRPV4在急性睡眠剥夺引起的记忆障碍中的作用：钙调节失调和突触可塑性破坏的机制

Cell insight

Pub Date : 2025-03-31 DOI: 10.1016/j.cellin.2025.100240

Meimei Guo , Feiyang Zhang , Sha Liu , Yi Zhang , Lesheng Wang , Jian Song , Wei Wei , Xiang Li

Acute sleep deprivation (ASD) impairs memory formation, but the underlying mechanisms remain unclear. In this study, we employed an ASD model combined with fear conditioning to investigate these mechanisms. mRNA sequencing revealed upregulated expression of Transient Receptor Potential Vanilloid 4 (TRPV4), a nonselective Ca²⁺-permeable cation channel critical for calcium signaling, in mice with ASD-induced memory impairments. Notably, TRPV4 knockdown reversed ASD-induced memory deficits. ASD was associated with increased intracellular Ca²⁺ concentrations, reduced spine density, and decreased expression of postsynaptic density protein 95 (PSD95), a key regulator of synaptic plasticity. These findings suggest that ASD may cause Ca²⁺ overload, leading to disrupted synaptic plasticity and impaired learning and memory. Importantly, TRPV4 knockdown significantly reduced Ca²⁺ concentrations, mitigated synaptic plasticity impairments, and contributed to memory restoration. Together, these findings demonstrate a protective role of TRPV4 knockdown against ASD-induced memory deficits and highlight TRPV4 as a potential therapeutic target for memory impairment associated with ASD.

急性睡眠剥夺（ASD）会损害记忆的形成，但其潜在机制尚不清楚。在本研究中，我们采用ASD模型结合恐惧条件反射来研究这些机制。mRNA测序显示，在asd诱导的记忆障碍小鼠中，瞬时受体电位香草样蛋白4 （TRPV4）的表达上调，TRPV4是一种非选择性Ca2+渗透性阳离子通道，对钙信号传导至关重要。值得注意的是，TRPV4敲除逆转了asd诱导的记忆缺陷。ASD与细胞内Ca2+浓度升高、脊柱密度降低和突触后密度蛋白95 （PSD95）表达降低有关，PSD95是突触可塑性的关键调节因子。这些发现表明，ASD可能导致Ca2+超载，导致突触可塑性被破坏，学习和记忆受损。重要的是，TRPV4敲除显著降低Ca2+浓度，减轻突触可塑性损伤，并有助于记忆恢复。总之，这些发现证明了TRPV4敲除对ASD诱导的记忆缺陷的保护作用，并突出了TRPV4作为ASD相关记忆障碍的潜在治疗靶点。

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引用次数: 0

Unveiling racial disparities in prostate cancer using an integrative genomic and transcriptomic analysis 利用综合基因组学和转录组学分析揭示前列腺癌的种族差异

Cell insight

Pub Date : 2025-02-17 DOI: 10.1016/j.cellin.2025.100238

Abdalla Elbialy , Akshay Sood , Shang-Jui Wang , Peng Wang , Ahmed Fadiel , Anil V. Parwani , Steven Huang , Gennady Shvets , Nagireddy Putluri , Jenny Li , Xuefeng Liu

Prostate cancer exhibits significant racial disparities, with African American (AA) individuals showing ∼64% higher incidence and 2.3 times greater mortality rates compared to their Caucasian (CA) counterparts. Understanding the complex interplay of genetic, environmental, lifestyle, socioeconomic, and healthcare access factors is crucial for developing effective interventions to reduce this disproportionate burden.

This study aims to uncover the genetic and transcriptomic differences driving these disparities through a comprehensive analysis using RNA sequencing (RNA-seq) and exome sequencing of prostate cancer tissues from both Black and White patients.

Our transcriptomics analysis revealed enhanced activity in pathways linked to immune response and cellular interactions in AA prostate cancer samples, with notable regulation by histone-associated transcription factors (HIST1H1A, HIST1H1D, and HIST1H1B) suggests potential involvement of histone modification mechanisms. Additionally, pseudogenes and long non-coding RNAs (lncRNAs) among the regulated genes indicate non-coding elements' role in these disparities.

Exome sequencing identified unique variants in AA patient samples within key genes, including TP73 (tumor suppression), XYLB (metabolism), ALDH4A1 (oxidative stress), PTPRB (cellular signaling), and HLA-DRB5 (immune response). These genetic variations likely contribute to disease progression and therapy response disparities.

This study highlights the importance of considering genetic and epigenetic variations in developing tailored therapeutic approaches to improve treatment efficacy and reduce mortality rates across diverse populations.

前列腺癌表现出显著的种族差异，与白种人（CA）相比，非裔美国人（AA）的发病率高64%，死亡率高2.3倍。了解遗传、环境、生活方式、社会经济和医疗保健获取因素之间复杂的相互作用，对于制定有效的干预措施以减轻这种不成比例的负担至关重要。本研究旨在通过对黑人和白人患者前列腺癌组织的RNA测序（RNA-seq）和外显子组测序进行综合分析，揭示导致这些差异的遗传和转录组差异。我们的转录组学分析显示，AA前列腺癌样本中与免疫反应和细胞相互作用相关的通路活性增强，组蛋白相关转录因子（HIST1H1A， HIST1H1D和HIST1H1B）的显著调节表明可能参与组蛋白修饰机制。此外，调控基因中的假基因和长链非编码rna （lncRNAs）表明非编码元件在这些差异中发挥了作用。外显子组测序鉴定出AA患者样本中关键基因的独特变异，包括TP73（肿瘤抑制）、XYLB（代谢）、ALDH4A1（氧化应激）、PTPRB（细胞信号传导）和HLA-DRB5（免疫应答）。这些遗传变异可能导致疾病进展和治疗反应差异。这项研究强调了在开发量身定制的治疗方法以提高治疗效果和降低不同人群死亡率时考虑遗传和表观遗传变异的重要性。

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引用次数: 0

The interplay between Salmonella and host: Mechanisms and strategies for bacterial survival 沙门氏菌与宿主之间的相互作用：细菌生存的机制和策略

Cell insight

Pub Date : 2025-02-13 DOI: 10.1016/j.cellin.2025.100237

Hongyu Zhao , Xinyue Zhang , Ningning Zhang , Li Zhu , Huan Lian

Salmonella, an intracellular pathogen, infects both humans and animals, causing diverse diseases such as gastroenteritis and enteric fever. The Salmonella type III secretion system (T3SS), encoded within its pathogenicity islands (SPIs), is critical for bacterial virulence by directly delivering multiple effectors into eukaryotic host cells. Salmonella utilizes these effectors to facilitate its survival and replication within the host through modulating cytoskeletal dynamics, inflammatory responses, the biogenesis of Salmonella-containing vacuole (SCV), and host cell survival. Moreover, these effectors also interfere with immune responses via inhibiting innate immunity or antigen presentation. In this review, we summarize the current progress in the survival strategies employed by Salmonella and the molecular mechanisms underlying its interactions with the host. Understanding the interplay between Salmonella and host can enhance our knowledge of the bacterium's pathogenic processes and provide new insights into how it manipulates host cellular physiological activities to ensure its survival.

沙门氏菌是一种细胞内病原体，可以感染人类和动物，引起肠胃炎和肠道热等多种疾病。沙门氏菌III型分泌系统（T3SS）编码在其致病性岛（SPIs）内，通过将多种效应物直接传递到真核宿主细胞中，对细菌的毒力至关重要。沙门氏菌利用这些效应物通过调节细胞骨架动力学、炎症反应、含沙门氏菌液泡（SCV）的生物发生和宿主细胞存活来促进其在宿主内的生存和复制。此外，这些效应物还通过抑制先天免疫或抗原呈递来干扰免疫反应。本文就沙门氏菌的生存策略及其与宿主相互作用的分子机制的研究进展进行综述。了解沙门氏菌与宿主之间的相互作用可以增强我们对细菌致病过程的认识，并为沙门氏菌如何操纵宿主细胞生理活动以确保其生存提供新的见解。

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引用次数: 0