Genes & Diseases最新文献

英文中文

Rare variants in NRSN2 cause non-syndromic orofacial cleft through dysregulation of TGF-β signaling NRSN2的罕见变异通过TGF-β信号的失调导致非综合征性口面裂

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-23 DOI: 10.1016/j.gendis.2025.101865

Xiaowen Zheng , Xuqin Liang , Xiantao Wu , Qing He , Chunyan Yin , Yuhua Jiao , Yanhao Wang , Yuxia Hou , Yi Ding , Huaxiang Zhao

引用次数: 0

The role of immunoproteasome in diabetes and diabetes-related complications 免疫蛋白酶体在糖尿病及其相关并发症中的作用。

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-20 DOI: 10.1016/j.gendis.2025.101861

Mengwen Wang , Lingyun Luo , Lei Dai , Hesong Zeng , Hongjie Wang

The immunoproteasome represents a specialized isoform of the proteasome that is integral to the processes of antigen presentation and protein degradation. While it is primarily expressed in hematopoietic cells, its expression can also be induced in non-hematopoietic cells in response to various inflammatory stimuli. Recent research has highlighted the role of the immunoproteasome in modulating islet β-cell apoptosis and glycolipid metabolism, both of which are critical mechanisms in the pathogenesis of diabetes. Furthermore, the immunoproteasome has been demonstrated to play a significant role in the development of diabetic complications through the activation of various downstream cytokines. Investigating how the immunoproteasome is activated and involved in the pathophysiological processes of diabetes and its complications may provide innovative and promising approaches for diabetes treatment. This review aims to present a comprehensive summary of current research on the role of immunoproteasome in diabetes and its associated complications, ultimately identifying novel strategies for diabetes management and therapy.

免疫蛋白酶体是蛋白酶体的一种特殊异构体，在抗原呈递和蛋白质降解过程中起着不可或缺的作用。虽然它主要在造血细胞中表达，但在各种炎症刺激下，它也可以在非造血细胞中被诱导表达。最近的研究强调了免疫蛋白酶体在调节胰岛β细胞凋亡和糖脂代谢中的作用，这两者都是糖尿病发病的关键机制。此外，免疫蛋白酶体已被证明通过激活各种下游细胞因子在糖尿病并发症的发展中发挥重要作用。研究免疫蛋白酶体如何被激活并参与糖尿病及其并发症的病理生理过程可能为糖尿病治疗提供创新和有前途的方法。本综述旨在全面总结免疫蛋白酶体在糖尿病及其相关并发症中的作用，最终确定糖尿病管理和治疗的新策略。

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引用次数: 0

Network pharmacology reveals that Yanghe Decoction inhibits osteosarcoma progression via ROS-induced mitochondrial dysfunction and enhances cisplatin sensitivity 网络药理学研究表明，洋河汤通过ros诱导的线粒体功能障碍抑制骨肉瘤进展，并增强顺铂敏感性

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-20 DOI: 10.1016/j.gendis.2025.101862

Yanran Huang , Dagang Tang , Runhan Zhao , Jun Zhang , Xiao Qu , Ningdao Li , Yi Ren , Xiaoji Luo

Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and frequent chemoresistance. Yanghe Decoction (YHD), a traditional Chinese medicine formula, has demonstrated anti-tumor potential, but its mechanisms in OS remain unclear. In this study, we employed a network pharmacology approach to identify 67 active components and 101 OS-related targets of YHD, with core targets including AKT1, TP53, MAPK14, and CASP3, mainly enriched in the PI3K/AKT and MAPK signaling pathways. Molecular docking confirmed strong binding affinities between representative compounds and these targets. Functional experiments revealed that YHD inhibited OS cell proliferation, migration, and invasion, and promoted apoptosis by elevating intracellular reactive oxygen species levels and inducing mitochondrial dysfunction. Mechanistically, YHD suppressed the PI3K/AKT pathway while activating p38 MAPK signaling. Importantly, YHD enhanced the sensitivity of OS cells to cisplatin, demonstrating a synergistic inhibitory effect in vitro and in an orthotopic OS mouse model. These findings suggest that YHD exerts its anti-osteosarcoma effects via reactive oxygen species-mediated mitochondrial disruption and pathway modulation, and may serve as a promising adjuvant to conventional chemotherapy.

骨肉瘤（OS）是一种高度侵袭性的骨恶性肿瘤，治疗选择有限，经常出现化疗耐药。中药洋河汤（YHD）具有抗肿瘤的潜力，但其在OS中的作用机制尚不清楚。在本研究中，我们采用网络药理学方法鉴定了YHD的67个有效成分和101个os相关靶点，核心靶点包括AKT1、TP53、MAPK14和CASP3，主要富集于PI3K/AKT和MAPK信号通路。分子对接证实了代表性化合物与这些靶标之间的强结合亲和力。功能实验显示，YHD通过提高细胞内活性氧水平和诱导线粒体功能障碍，抑制OS细胞增殖、迁移和侵袭，促进细胞凋亡。在机制上，YHD抑制PI3K/AKT通路，同时激活p38 MAPK信号。重要的是，YHD增强了OS细胞对顺铂的敏感性，在体外和原位OS小鼠模型中显示出协同抑制作用。这些发现表明，YHD通过活性氧介导的线粒体破坏和途径调节发挥其抗骨肉瘤作用，并可能作为传统化疗的一种有希望的辅助药物。

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引用次数: 0

Chloride channel accessory 4 suppresses stem cell-like properties of colorectal cancer and enhances anti-PD-1 immunotherapy 氯离子通道附件4抑制结直肠癌干细胞样特性并增强抗pd -1免疫治疗。

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-20 DOI: 10.1016/j.gendis.2025.101859

Fang Wei , Qi Zou , Qihui Sun , Tingting Jiang , Tian Cai , Xiaojia Li , Keping Xie

Reduced chloride channel accessory 4 (CLCA4) levels are linked to cancer development, while its role and mechanism in cancer stem cells (CSCs) remain unclear. In this study, we discovered that decreased CLCA4 expression was evident in CD133⁺CD44⁺ colorectal CSCs and chemoresistant colorectal cancer (CRC) cells. Increased expression of CLCA4 inhibited the expression of stemness genes, reduced tumorsphere formation, suppressed the self-renewal, migratory, and invasive capabilities of colorectal CSCs in vitro, and suppressed the tumorigenicity of colorectal CSCs in vivo. Mechanistically, CLCA4 interacted with vimentin, leading to FAK pathway inactivation and subsequent suppression of CSC expansion, while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal. Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens. Increased CLCA4 expression promoted the infiltration of cytotoxic CD8⁺ T cells and enhanced the anti-PD-1 therapeutic efficacy. Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway, potentially reducing tumor cell stemness and evading immune surveillance. The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.

氯离子通道附件4 （CLCA4）水平的降低与癌症的发展有关，但其在癌症干细胞（CSCs）中的作用和机制尚不清楚。在本研究中，我们发现CD133+CD44+结直肠CSCs和化疗耐药结直肠癌（CRC）细胞中CLCA4表达明显降低。CLCA4表达增加抑制干性基因的表达，减少肿瘤球的形成，在体外抑制结直肠CSCs的自我更新、迁移和侵袭能力，在体内抑制结直肠CSCs的致瘤性。在机制上，CLCA4与vimentin相互作用，导致FAK通路失活，进而抑制CSC扩张，而vimentin上调减弱CLCA4下调的作用，确立其在CLCA4介导的结直肠CSC自我更新中的作用。临床标本中CLCA4表达降低与结直肠CSC标志物和波形蛋白呈正相关。CLCA4表达升高可促进细胞毒性CD8+ T细胞浸润，增强抗pd -1治疗效果。我们的研究结果表明，CLCA4可能通过与vimentin相互作用抑制FAK信号通路，从而阻碍结直肠CSC的自我更新，从而潜在地降低肿瘤细胞的干性并逃避免疫监视。这些关于结直肠癌发生和发展的细胞和分子机制的新发现可能为结直肠癌的潜在干预和治疗提供新的视角。

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引用次数: 0

eQTL analysis: A bridge from genome to mechanism eQTL分析：从基因组到机制的桥梁

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-17 DOI: 10.1016/j.gendis.2025.101850

Zhe Jia , Jing Xu , Yingnan Ma , Siyu Wei , Chen Sun , Xingyu Chen , Jingxuan Kang , Haiyan Chen , Chen Zhang , Yu Dong , Junxian Tao , Xuying Guo , Hongchao Lv , Guoping Tang , Yongshuai Jiang , Mingming Zhang

Expression quantitative trait locus (eQTL) refers to a genetic variation associated with the expression of specific genes. It has been widely applied to explain the regulatory mechanisms linking genetic variations to complex traits or diseases. Several eQTLs have been identified from tissues and single cells in individuals. Furthermore, the integration of eQTL and other omics data can be used to detect novel susceptibility genes and consequently understand the dynamic regulation of trait-associated genetic variations at the system level. Here, we review the identification methods, analysis tools, research progress, and common data resources of eQTLs, as well as their role in four typical diseases. Finally, we discussed the application fields, challenges, and future development perspectives of eQTL.

表达数量性状位点（eQTL）是指与特定基因表达相关的遗传变异。它已被广泛应用于解释将遗传变异与复杂性状或疾病联系起来的调控机制。已经从个体的组织和单细胞中鉴定出了几个eqtl。此外，eQTL和其他组学数据的整合可以用于检测新的易感基因，从而在系统水平上理解性状相关遗传变异的动态调控。本文综述了eqtl的鉴定方法、分析工具、研究进展、常用数据来源及其在四种典型疾病中的作用。最后讨论了eQTL的应用领域、面临的挑战以及未来的发展前景。

引用次数: 0

Serum tRF-4575 may regulate osteoclast differentiation and serve as a promising biomarker for enthesitis-related arthritis diagnosis 血清tRF-4575可能调节破骨细胞的分化，并作为一种有前景的生物标志物用于关节炎的诊断

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-10 DOI: 10.1016/j.gendis.2025.101848

Jing Jin, Lingzhi Qiu, Yuting Pan, Yifan Xie, Xiaoyan Shao, Zhidan Fan, Haiguo Yu

引用次数: 0

The functions of FXYD family members in human health and disease FXYD家族成员在人类健康和疾病中的作用

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-10 DOI: 10.1016/j.gendis.2025.101847

Xi Li , Min Long , Shangwei Zhong , Jun-Li Luo

The FXYD family (FXYD domain-containing ion transport regulators) proteins consist of short, single-pass transmembrane proteins that primarily regulate the Na⁺/K⁺-ATPase (NKA) pump, a key player in maintaining cellular ion homeostasis. Ranging from 60 to 160 amino acids in length, FXYD proteins display tissue-specific expression patterns and influence not only NKA activity but also the function of other ion channels, including potassium, sodium, and chloride channels. These proteins interact with NKA in diverse ways, modulating its activity to meet the specific needs of different tissues. In addition to their physiological roles, FXYD proteins are implicated in the development and progression of various diseases, such as cancer, cardiovascular disorders, renal diseases, and neurological conditions. This review offers an overview of the structures, biological functions, and molecular mechanisms through which FXYD proteins regulate ion transport. Furthermore, we explore their emerging roles in disease pathogenesis and discuss potential therapeutic strategies for targeting FXYD proteins in disease management.

FXYD家族（含FXYD结构域的离子运输调节因子）蛋白由短的单通道跨膜蛋白组成，主要调节Na+/K+- atp酶（NKA）泵，这是维持细胞离子稳态的关键角色。FXYD蛋白的长度从60到160个氨基酸不等，具有组织特异性表达模式，不仅影响NKA活性，还影响其他离子通道的功能，包括钾、钠和氯离子通道。这些蛋白质以不同的方式与NKA相互作用，调节其活性以满足不同组织的特定需求。除了它们的生理作用外，FXYD蛋白还涉及各种疾病的发生和进展，如癌症、心血管疾病、肾脏疾病和神经系统疾病。本文就FXYD蛋白调控离子转运的结构、生物学功能和分子机制作一综述。此外，我们探讨了它们在疾病发病机制中的新作用，并讨论了针对FXYD蛋白在疾病管理中的潜在治疗策略。

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引用次数: 0

Salt-inducible kinase 1 is a key gene in suppressing EVD68-induced asthma by modulating antiviral immunity 盐诱导激酶1是通过调节抗病毒免疫抑制evd68诱导哮喘的关键基因。

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-10 DOI: 10.1016/j.gendis.2025.101845

Juntong Liu , Yue Wang , Lingyun Zou , Xinyue Han , Mingqi Lv , Xichuan Deng , Jingjing Liao , Guangchao Zang , Lei Xu , Tianle Gu , Nan Lu , Guangyuan Zhang

Asthma is a complex inflammatory disease of the airways, affecting over 300 million individuals globally. Infection with enterovirus D68 (EV-D68) has been identified as a risk factor for asthma. However, the biological mechanisms of EV-D68-related asthma remain unclear. In this study, using machine learning techniques, we identified salt-inducible kinase 1 (SIK1), which plays a crucial role in associating with the asthma phenotype and EV-D68 infection. Concretely, a negative correlation between SIK1 expression and asthma risk has been revealed through Mendelian randomization. Immune infiltration analyses showed that SIK1 was negatively correlated with mast cell activity and positively correlated with T cell responses. Using weighted gene co-expression network analysis, we demonstrated SIK1's role in antiviral immune responses in asthma. Further in vitro and in vivo experiments confirmed that SIK1 was up-regulated in virus infection, and it exerted antiviral effects in various viral infections. Finally, in the asthma exacerbation model of HDM combined with EV-D68 infection, SIK1 activation effectively mitigated EV-D68-induced asthma exacerbation in mice. Taken together, our findings suggest that SIK1 serves as a protective factor in EV-D68-induced asthma by modulating antiviral immune responses, which provide new insights into potential treatments for EV-D68-induced asthma attacks.

哮喘是一种复杂的气道炎症性疾病，影响着全球3亿多人。肠道病毒D68 （EV-D68）感染已被确定为哮喘的危险因素。然而，ev - d68相关哮喘的生物学机制尚不清楚。在这项研究中，我们使用机器学习技术鉴定了盐诱导激酶1 (SIK1)，它在哮喘表型和EV-D68感染中起着至关重要的作用。具体而言，通过孟德尔随机化研究揭示了SIK1表达与哮喘风险呈负相关。免疫浸润分析显示，SIK1与肥大细胞活性呈负相关，与T细胞反应呈正相关。通过加权基因共表达网络分析，我们证实了SIK1在哮喘的抗病毒免疫反应中的作用。进一步的体外和体内实验证实SIK1在病毒感染中表达上调，并在多种病毒感染中发挥抗病毒作用。最后，在HDM合并EV-D68感染的哮喘加重模型中，SIK1激活能有效减轻EV-D68诱导的小鼠哮喘加重。综上所述，我们的研究结果表明SIK1通过调节抗病毒免疫反应在ev - d68诱导的哮喘中起保护作用，这为ev - d68诱导的哮喘发作的潜在治疗提供了新的见解。

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引用次数: 0

Three-dimensional interactive network: Mitochondrial-metabolic-calcium homeostasis driving Alzheimer’s disease 三维互动网络：线粒体-代谢-钙稳态驱动阿尔茨海默病

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-10 DOI: 10.1016/j.gendis.2025.101846

Tingting Liu , Zongting Rong , Jingwen Li, Haojie Wu, Jianshe Wei

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, with its pathogenesis tightly linked to a “pathological triad”—mitochondrial dysfunction, metabolic dysregulation, and calcium homeostasis imbalance. This triad forms a mutually reinforcing network that amplifies AD pathology, yet its precise causal relationships and clinical relevance remain incompletely understood. Here, we critically synthesize evidence from human studies, animal models, and in vitro systems to dissect how these dysfunctions interact in vivo: mitochondrial structural damage and bioenergetic failure (e.g., reduced cytochrome c oxidase activity) impair ATP production, triggering metabolic reprogramming (e.g., astrocytic Warburg-like glycolysis, lactate shuttle dysfunction) and disrupting calcium buffering via mitochondrial calcium uniporter (MCU) dysregulation. Conversely, metabolic stress (e.g., hyperglycemia-induced mitochondrial overload) and calcium overload (e.g., NMDA receptor hyperactivation) exacerbate mitochondrial damage through reactive oxygen species (ROS) bursts and mitochondrial permeability transition pore (mPTP) opening. These processes are further amplified by amyloid β-protein (Aβ) and tau pathology: Aβ oligomers directly inhibit mitochondrial respiration and activate calcium channels, while hyperphosphorylated tau disrupts mitochondrial trafficking and exacerbates metabolic enzyme dysfunction. We evaluate the clinical translatability of preclinical findings, highlighting inconsistencies (e.g., conflicting results of CoQ10 trials) and gaps (e.g., human-specific metabolic signatures). Finally, we propose a framework prioritizing multi-target therapies that disrupt the triad’s vicious cycle, emphasizing the need for biomarkers to stratify patients based on triad dysregulation patterns.

阿尔茨海默病（AD）是一种以认知能力下降和神经元丧失为特征的进行性神经退行性疾病，其发病机制与“病理性三位一体”密切相关——线粒体功能障碍、代谢失调和钙稳态失衡。这三个因素形成了一个相互加强的网络，放大了阿尔茨海默病的病理，但其确切的因果关系和临床相关性仍然不完全清楚。在这里，我们批判性地综合了来自人类研究、动物模型和体外系统的证据，以解剖这些功能障碍如何在体内相互作用：线粒体结构损伤和生物能量衰竭（例如，细胞色素c氧化酶活性降低）损害ATP的产生，触发代谢重编程（例如，星形细胞warburg样糖酵解，乳酸穿梭功能障碍），并通过线粒体钙单转运体（MCU）失调破坏钙缓冲。相反，代谢应激（如高血糖诱导的线粒体过载）和钙超载（如NMDA受体过度激活）通过活性氧（ROS）爆发和线粒体通透性过渡孔（mPTP）打开加剧线粒体损伤。这些过程被淀粉样β蛋白（Aβ）和tau病理进一步放大：Aβ寡聚物直接抑制线粒体呼吸并激活钙通道，而过度磷酸化的tau破坏线粒体运输并加剧代谢酶功能障碍。我们评估了临床前研究结果的临床可翻译性，强调了不一致性（例如，辅酶q10试验的相互矛盾的结果）和空白（例如，人类特异性代谢特征）。最后，我们提出了一个框架，优先考虑破坏三联症恶性循环的多靶点治疗，强调需要生物标志物根据三联症失调模式对患者进行分层。

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引用次数: 0

Genetic variability in the PLIN4 gene: A new sequence duplication causing autophagic vacuolar myopathy PLIN4基因的遗传变异：引起自噬空泡性肌病的一个新的序列重复

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-09-10 DOI: 10.1016/j.gendis.2025.101849

Alessandra Carnazzi , Eliana Iannibelli , Sara Gibertini , Lucia Nicolini De Gaetano , Giorgia Riolo , Franco Salerno , Andrea Legati , Daniele Ghezzi , Lorenzo Maggi , Alessandra Ruggieri

引用次数: 0

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