Molecules and Cells最新文献_第10页

Intestinal bacteria-derived extracellular vesicles in metabolic dysfunction-associated steatotic liver disease: From mechanisms to therapeutics 肠道细菌来源的细胞外囊泡与代谢功能障碍相关的脂肪变性肝病：从机制到治疗

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-04-14 DOI: 10.1016/j.mocell.2025.100216

Li-Na Qin , Yun-Feng Yu , Lie Ma , Rong Yu

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disease that affects the health of approximately one-third of the world's population. It is the primary cause of end-stage liver disease, liver malignancy, and liver transplantation, resulting in a great medical burden. No medications have yet been approved by the US Food and Drug Administration for treating MASLD without liver inflammation or scarring. Therefore, the development of specific drugs to treat MASLD remains a key task in the ongoing research objective. Extracellular vesicles (EVs) play an important role in the communication between organs, tissues, and cells. Recent studies have found that intestinal microbiota are closely related to the pathogenesis and progression of MASLD. EVs produced by bacteria (BEVs) play an indispensable role in this process. Thus, this study provides a new direction for MASLD treatment. However, the mechanism by which BEVs affect MASLD remains unclear. Therefore, this study investigated the influence and function of intestinal microbiota in MASLD. Additionally, we focus on the research progress of BEVs in recent years and explain the relationship between BEVs and MASLD from the perspectives of glucose and lipid metabolism, immune responses, and intestinal homeostasis. Finally, we summarized the potential therapeutic value of BEVs and EVs from other sources, such as adipocytes, immunocytes, stem cells, and plants.

代谢功能障碍相关的脂肪变性肝病（MASLD）是一种进行性疾病，影响着世界上大约三分之一的人口的健康。它是导致终末期肝病、肝恶性肿瘤和肝移植的主要原因，造成巨大的医疗负担。美国食品和药物管理局还没有批准治疗MASLD而不引起肝脏炎症或疤痕的药物。因此，开发治疗MASLD的特异性药物仍然是正在进行的研究目标中的关键任务。细胞外囊泡（EVs）在器官、组织和细胞之间的通讯中起着重要作用。近年来的研究发现，肠道菌群与MASLD的发病和进展密切相关。细菌生产的电动汽车（bev）在这一过程中发挥着不可或缺的作用。本研究为MASLD的治疗提供了新的方向。然而，电动汽车影响MASLD的机制尚不清楚。因此，本研究探讨了肠道菌群对MASLD的影响和功能。此外，我们重点介绍了bev近年来的研究进展，并从糖脂代谢、免疫反应、肠道稳态等方面阐述了bev与MASLD的关系。最后，我们总结了其他来源的bev和ev的潜在治疗价值，如脂肪细胞、免疫细胞、干细胞和植物。

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引用次数: 0

Decoding SPP1 regulation: Genetic and nongenetic insights into its role in disease progression 解码SPP1调控：其在疾病进展中的作用的遗传和非遗传见解

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-04-08 DOI: 10.1016/j.mocell.2025.100215

Sungju Jung , Jiseon Ha , Jong Hoon Park , Kyung Hyun Yoo

Secreted phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional glycoprotein that plays a critical role in various physiological processes, including cell adhesion, chemotaxis, immune regulation, and tissue remodeling. Originally identified as a key component of the bone matrix, SPP1 is now recognized for its broad involvement in numerous tissues and significant impact on both normal physiology and disease progression. Dysregulation of SPP1 has been strongly implicated in the pathogenesis and progression of several diseases, including cancer, cardiovascular diseases, autoimmune disorders, and chronic inflammatory conditions. The expression of SPP1 is tightly regulated by genetic and nongenetic mechanisms. Genetic alterations, such as single-nucleotide polymorphisms, insertions and deletions, and structural variations within the SPP1 gene, have been associated with increased susceptibility to various diseases, influencing disease severity and outcomes. Additionally, nongenetic regulations, including DNA methylation, histone modifications, and long noncoding RNAs, play crucial roles in modulating SPP1 expression in response to environmental and cellular signals. This review provides a comprehensive overview of the genetic and nongenetic regulatory mechanisms governing SPP1 and examines their implications in disease pathogenesis. By integrating recent findings, this review highlights the complex interplay between genetic predispositions and nongenetic regulations in determining SPP1 activity and offers new insights into its role as a potential biomarker and therapeutic target. Understanding these regulatory pathways is essential for the development of targeted interventions for diseases in which SPP1 plays a pivotal role.

分泌磷蛋白1 (SPP1)，又称骨桥蛋白，是一种多功能糖蛋白，在细胞粘附、趋化、免疫调节和组织重塑等多种生理过程中发挥关键作用。SPP1最初被认为是骨基质的关键成分，现在被认为广泛参与许多组织，并对正常生理和疾病进展产生重大影响。SPP1的失调与多种疾病的发病和进展密切相关，包括癌症、心血管疾病、自身免疫性疾病和慢性炎症。SPP1的表达受到遗传和非遗传机制的严格调控。遗传改变，如SPP1基因内的单核苷酸多态性、插入和缺失以及结构变异，与各种疾病的易感性增加有关，影响疾病的严重程度和结果。此外，非遗传调控，包括DNA甲基化、组蛋白修饰和长链非编码rna，在调节SPP1表达以响应环境和细胞信号方面发挥关键作用。这篇综述提供了控制SPP1的遗传和非遗传调控机制的全面概述，并研究了它们在疾病发病机制中的意义。通过整合最近的研究结果，本综述强调了遗传易感性和非遗传调控在决定SPP1活性方面的复杂相互作用，并对其作为潜在生物标志物和治疗靶点的作用提供了新的见解。了解这些调控途径对于开发针对SPP1起关键作用的疾病的靶向干预措施至关重要。

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引用次数: 0

Cholesterol sulfate as a negative regulator of cellular cholesterol homeostasis 硫酸胆固醇作为细胞胆固醇稳态的负调节因子。

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-03-14 DOI: 10.1016/j.mocell.2025.100209

Le Ba Nam , Sung-Jin Kim , Tan Khanh Nguyen , Chang-Yun Jeong , June-Yong Lee , Jun-Seok Lee , Jeong Taeg Seo , Seok Jun Moon

Cholesterol sulfate (CS), one of the most abundant cholesterol derivatives, recently emerged as a key regulatory molecule in several physiological processes. Here, we demonstrate multiple mechanisms by which CS reduces intracellular cholesterol levels. CS promotes the proteasomal degradation of 3-hydroxy-3-methylglutaryl-CoA reductase reductase by enhancing insulin-induced gene-mediated ubiquitination, thereby inhibiting cholesterol synthesis. In addition, CS blocks low-density lipoprotein receptor endocytosis, reducing low-density lipoprotein cholesterol uptake. CS further suppresses the proteolytic activation of sterol regulatory element-binding protein 2, a master transcription factor governing cholesterol synthesis and uptake. Using in vitro and in vivo models, we show that CS lowers cholesterol by targeting both the cholesterol synthesis and uptake pathways, while also modulating an important feedback loop via sterol regulatory element-binding protein 2. These findings highlight the potential of CS as a modulator of cholesterol metabolism, offering new therapeutic insights into cholesterol-related disorders.

硫酸胆固醇（CS）是一种含量最丰富的胆固醇衍生物，近年来作为一种关键的生理调控分子而被发现。在这里，我们证明了CS降低细胞内胆固醇水平的多种机制。CS通过增强insg介导的泛素化，促进HMG-CoA还原酶（HMGCR）的蛋白酶体降解，从而抑制胆固醇合成。此外，CS阻断低密度脂蛋白（LDL）受体内吞作用，减少LDL- c摄取。CS进一步抑制甾醇调节元件结合蛋白2 （SREBP2）的蛋白水解激活，SREBP2是控制胆固醇合成和摄取的主要转录因子。通过体外和体内模型，我们发现CS通过靶向胆固醇合成和摄取途径降低胆固醇，同时也通过SREBP2调节一个重要的反馈回路。这些发现突出了CS作为胆固醇代谢调节剂的潜力，为胆固醇相关疾病的治疗提供了新的见解。

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引用次数: 0

Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress eIF2α的磷酸化抑制内质网应激对GSH/NADPH稳态的损害，并减轻细胞死亡途径的激活，包括铁凋亡。

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-03-13 DOI: 10.1016/j.mocell.2025.100210

Hien Thi Le , Yonghwan Kim , Mi-Jeong Kim , Seung Hwa Hyun , Hyeeun Kim , Su Wol Chung , Yeonsoo Joe , Hun Taeg Chung , Dong-Myung Shin , Sung Hoon Back

eIF2α Phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (A/A) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven 1-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of A/A cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1. ATF4 overexpression suppressed impairment of GSH homeostasis in A/A cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of A/A cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.

eIF2α磷酸化有助于维持细胞稳态，并通过转录和翻译重编程克服内质网（ER）应激。本研究旨在阐明内质网应激下eIF2α磷酸化对谷胱甘肽（GSH）和NADPH稳态的转录调控及其对细胞死亡的影响。eIF2α磷酸化缺陷（A/A）细胞表现出参与GSH合成和NADPH产生的多个基因的表达减少，导致细胞和线粒体GSH以及线粒体NADPH在内质网应激下耗竭加剧。GSH稳态受损是由于内质网应激中参与抗氧化反应的关键转录因子ATF4和/或其依赖因子Nrf2表达不足所致。相反，NADPH耗竭的加剧可能主要归因于线粒体丝氨酸驱动的单碳代谢途径基因的表达失调，这些基因在内质网应激过程中受到一种未知的eIF2α磷酸化依赖机制的调节。此外，eIF2α磷酸化- atf4轴在内质网应激下负责上调抑铁基因和下调抑铁基因。因此，内质网应激强烈诱导A/A细胞铁下垂，而细胞渗透性谷胱甘肽和铁下垂抑制剂铁抑素-1 （fer1）可显著抑制铁下垂。ATF4过表达通过促进下游靶基因的表达，抑制内质网应激时A/A细胞GSH稳态受损。因此，ATF4过表达减轻了内质网应激下A/A细胞的铁下垂和凋亡。我们的研究结果强调了eIF2α磷酸化在维持GSH/NADPH稳态和通过ATF4和未识别的eIF2α磷酸化依赖靶标介导的内质网应激介导的转录重编程抑制铁凋亡中的重要性。

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引用次数: 0

Cover and caption 封面和标题

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-03-13 DOI: 10.1016/S1016-8478(25)00035-4

引用次数: 0

Editorial Board Members/Copyright 编辑委员会成员/版权

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-03-13 DOI: 10.1016/S1016-8478(25)00037-8

引用次数: 0

Cryo-EM structures of mouse bestrophin 1 channel in closed and partially open conformations 小鼠strophin - 1通道封闭和部分开放构象的低温电镜结构。

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-03-03 DOI: 10.1016/j.mocell.2025.100208

Kwon-Woo Kim , Euna Lee , Ara Ko , Junmo Hwang , Kunwoong Park , Byoung-Cheol Lee , Ki Woo Kim , Won-Jong Oh , Kyuhyung Kim , Hyun-Ho Lim

Bestrophin 1 (BEST1) channels are calcium-activated Cl⁻ channels involved in diverse physiological processes, including gliotransmitter release in astrocytes. Although human and chicken BEST1 orthologs have been extensively studied, the structural and functional properties of mouse BEST1 (mBEST1) remain poorly understood. In this study, we characterized the structure-function of mBEST1-BF, a C–terminally tagged variant, using whole-cell patch-clamp recordings, surface biotinylation assays, and single-particle cryo-electron microscopy. Cryo-electron microscopy structural analysis of mBEST1-BF revealed closed and partially open conformations. Comparative analysis with human and chicken BEST1 orthologs highlighted conserved calcium-binding and gating mechanisms, with distinct features in mBEST1, including a wider aperture sufficient to accommodate dehydrated Cl⁻ ions and potential anion-binding sites near Val205 and Gln208 residues. The disordered C-terminal region of mBEST1 remains unresolved, suggesting it may require stabilizing factors for structural determination. Additionally, the autoinhibitory domain, which includes Ser354, likely plays a key role in regulating gating, with Ser354 potentially serving as a phosphorylation site that modulates channel activity. Our findings provide structural and functional insights into mBEST1 and suggest mechanisms underlying its unique gating and ion permeation properties.

besstrophin -1 （BEST1）通道是钙激活的Cl-通道，参与多种生理过程，包括星形胶质细胞中的胶质递质释放。尽管人类和鸡的BEST1同源基因已被广泛研究，但小鼠BEST1 （mBEST1）的结构和功能特性仍然知之甚少。在这项研究中，我们利用全细胞膜片钳记录、表面生物素化测定和单粒子冷冻电镜（cro - em）表征了mBEST1-BF的结构-功能，这是一种c末端标记的变体。mBEST1-BF的Cryo-EM结构分析显示为封闭和部分开放构象。与人类和鸡BEST1同源物的比较分析强调了保守的钙结合和门控机制，mBEST1具有明显的特征，包括足够大的孔径以容纳脱水Cl-离子和靠近Val205和Gln208残基的潜在阴离子结合位点。mBEST1的紊乱c端区域仍未得到解决，这表明可能需要稳定因子来确定其结构。此外，包括Ser354在内的自抑制结构域可能在调节门控中起关键作用，Ser354可能作为调节通道活性的磷酸化位点。我们的研究结果提供了mBEST1的结构和功能见解，并提出了其独特的门控和离子渗透特性的机制。

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引用次数: 0

Protein-O-fucosylation of coreceptors may be required for Nodal signaling in Xenopus 非洲爪蟾的节点信号可能需要共受体的蛋白o聚焦。

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-03-03 DOI: 10.1016/j.mocell.2025.100207

Yeon-Jin Kim , Seung-Joo Nho , Soo Young Lee , Chang-Yeol Yeo

Nodal-related ligands of TGF-β family play pivotal roles for mesoderm induction and body axis formation during vertebrate early embryogenesis. Nodal ligands are distinct from most other TGF-β ligands family as they require EGF-CFC factors as coreceptors for signaling, in addition to their cognate type I and type II TGF-β receptors. In amphibian Xenopus laevis embryos, 5 Nodal-related genes (Xnr1/2/4/5/6) and 2 EGF-CFC genes (XCR1, XCR3) play roles in mesoderm induction and the accumulation of phosphorylated Smad2, while in mammalian embryos, 1 Nodal gene and 1 EGF-CFC gene (Cripto) play roles during mesoderm induction. Mammalian EGF-CFC factors are reported to be O-fucosylated at a conserved threonine residue of the EGF-like motif by protein-O-fucosyltransferase 1 (Pofut1), but this O-fucose modification is shown to be dispensable for Nodal signaling in mammalian embryos. In this study, we investigated the developmental roles of Xenopus laevis Pofut1 (XPofut1) and its potential function in Nodal signaling. We found that morpholino antisense-mediated knockdown of XPofut1 causes reduction of Smad2 phosphorylation in late blastula and axial truncation in neurula. We also found that the O-fucosyltransferase activity of XPofut1 is important in the marginal zone, but not in the vegetal pole region, of blastula. Interestingly, XPofut1 is necessary for Smad2 phosphorylation induced by Xnr1 or Xnr2, but not by Xnr5 or Xnr6. Among the Nodal signaling components, only EGF-CFC factors are known to be modified by Pofut1. Therefore, based on our current observation, we propose that XPofut1 regulates signaling of a subset of nodal ligands in pregastrulation embryos possibly through modulating the function of EGF-CFC factors.

TGF-β家族节点相关配体在脊椎动物早期胚胎发生过程中对中胚层诱导和体轴形成起关键作用。节点配体与其他大多数TGF-β配体家族不同，除了同源的I型和II型TGF-β受体外，它们还需要EGF-CFC因子作为信号传导的共受体。在两栖动物非洲爪蟾胚胎中，5个节点相关基因（Xnr1/2/4/5/6）和2个EGF-CFC基因（XCR1、XCR3）参与中胚层诱导和磷酸化Smad2的积累，而在哺乳动物胚胎中，1个节点基因和1个EGF-CFC基因（Cripto）参与中胚层诱导。据报道，哺乳动物EGF-CFC因子通过蛋白O-聚焦转移酶1 （Pofut1）在egf样基的保守苏氨酸残基上进行O-聚焦，但这种O-聚焦修饰被证明是哺乳动物胚胎中节点信号传递所必需的。在这项研究中，我们研究了非洲爪蟾（Xenopus laevis） Pofut1 （XPofut1）在发育中的作用及其在节点信号传导中的潜在功能。我们发现，morpholino反义介导的XPofut1敲低导致晚期囊胚Smad2磷酸化减少和神经鞘轴向截断。我们还发现XPofut1的O- focusyltransferase活性在囊胚的边缘区很重要，而在植物极区则不重要。有趣的是，XPofut1是Xnr1或Xnr2诱导的Smad2磷酸化所必需的，而不是Xnr5或Xnr6。在节点信号成分中，已知只有EGF-CFC因子被Pofut1修饰。因此，根据我们目前的观察，我们提出XPofut1可能通过调节EGF-CFC因子的功能来调节原肠胚形成前胚胎中一组结配体的信号传导。

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引用次数: 0

Principles and therapeutics of cancer 癌症的原理和治疗。

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-02-28 DOI: 10.1016/j.mocell.2025.100201

Yoontae Lee

引用次数: 0

Omics technologies as powerful approaches to unravel colorectal cancer complexity and improve its management 组学技术是揭示结直肠癌复杂性和改善其管理的有力途径。

IF 3.7 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules and Cells

Pub Date : 2025-02-28 DOI: 10.1016/j.mocell.2025.100200

Zaynab Fatfat , Marwa Hussein , Maamoun Fatfat , Hala Gali-Muhtasib

Colorectal cancer (CRC) continues to rank among the deadliest and most prevalent cancers worldwide, necessitating an innovative and comprehensive approach that addresses this serious health challenge at various stages, from screening and diagnosis to treatment and prognosis. As CRC research progresses, the adoption of an omics-centered approach holds transformative potential to revolutionize the management of this disease. Advances in omics technologies encompassing genomics, transcriptomics, proteomics, metabolomics, and epigenomics allow to unravel the oncogenic alterations at these levels, elucidating the intricacies and the heterogeneous nature of CRC. By providing a comprehensive molecular landscape of CRC, omics technologies enable the discovery of potential biomarkers for early non-invasive detection of CRC, definition of CRC subtypes, prediction of its staging, prognosis, and overall survival of CRC patients. They also allow the identification of potential therapeutic targets, prediction of drug response, tracking treatment efficacy, detection of residual disease and cancer relapse, and deciphering the mechanisms of drug resistance. Moreover, they allow the distinction of non-metastatic CRC patients from metastatic ones as well as the stratification of metastatic risk. Importantly, omics technologies open up new opportunities to establish molecular-based criteria to guide the selection of effective treatment paving the way for the personalization of therapy for CRC patients. This review consolidates current knowledge on the omics-based preclinical discoveries in CRC research emphasizing the significant potential of these technologies to improve CRC screening, diagnosis, and prognosis and promote the implementation of personalized medicine to ultimately reduce CRC prevalence and mortality.

结直肠癌（CRC）仍然是全球最致命、发病率最高的癌症之一，因此有必要采用创新的综合方法，在筛查、诊断、治疗和预后等各个阶段应对这一严峻的健康挑战。随着 CRC 研究的不断深入，采用以 omics 为中心的方法有望彻底改变这种疾病的治疗方法。包括基因组学、转录物组学、蛋白质组学、代谢组学和表观基因组学在内的全局组学技术的进步可以在这些层面上揭示致癌物质的改变，从而阐明 CRC 的复杂性和异质性。通过提供全面的 CRC 分子图谱，omics 技术能够发现潜在的生物标记物，用于早期无创检测 CRC、定义 CRC 亚型、预测其分期、预后和 CRC 患者的总生存率。它们还能确定潜在的治疗靶点、预测药物反应、跟踪治疗效果、检测残留疾病和癌症复发，以及破译耐药机制。此外，它们还能将非转移性癌症患者与转移性癌症患者区分开来，并对转移风险进行分层。重要的是，omics 技术为建立基于分子的标准以指导选择有效的治疗方法提供了新的机遇，为 CRC 患者的个性化治疗铺平了道路。这篇综述整合了目前在 CRC 研究中基于 omics 的临床前发现的知识，强调了这些技术在改善 CRC 筛查、诊断和预后方面的巨大潜力，并促进了个性化医疗的实施，最终降低了 CRC 发病率和死亡率。

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引用次数: 0