Genes & Diseases最新文献

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The role of long non-coding RNAs in NK cell biology and diseases 长链非编码rna在NK细胞生物学和疾病中的作用

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-25 DOI: 10.1016/j.gendis.2025.101833

Dan Zhang , Siqiao Wei , Qianqiu Wei , Zhansong Lin , Xiaoming Sun

Long non-coding RNAs (lncRNAs) are pivotal regulators of gene expression, increasingly recognized for their roles in immune responses and disease progression. Natural killer (NK) cells, essential cytotoxic lymphocytes of the innate immune system, orchestrate immune responses through cytokine secretion and direct cytotoxicity. This review elucidates the immunomodulatory functions of lncRNAs in NK cell biology and their implications in pathological conditions. LncRNAs intricately govern key NK cell processes, including development, differentiation, activation, recruitment, cytotoxic function, and immune infiltration within the tumor microenvironment. These regulatory effects are mediated through diverse mechanisms, such as transcriptional control of effector molecules, miRNA sponging, metabolic reprogramming, protein ubiquitination, and epigenetic modifications. Focusing on NK cell infiltration in tumors, we classify lncRNAs into mechanistically defined and uncharacterized groups, highlighting their roles in tumor-associated competing endogenous RNA (ceRNA) networks, epigenetic regulation, and cell death pathways. By integrating these perspectives, this review enhances our understanding of lncRNA-mediated immune regulation and underscores their potential as therapeutic targets for diseases involving NK cell dysfunction.

长链非编码rna （lncRNAs）是基因表达的关键调控因子，在免疫反应和疾病进展中发挥着越来越重要的作用。自然杀伤细胞（NK）是先天免疫系统中必不可少的细胞毒性淋巴细胞，通过细胞因子的分泌和直接的细胞毒性来协调免疫反应。本文综述了lncrna在NK细胞生物学中的免疫调节功能及其病理意义。LncRNAs复杂地控制着关键的NK细胞过程，包括肿瘤微环境中的发育、分化、激活、募集、细胞毒性功能和免疫浸润。这些调节作用是通过多种机制介导的，如效应分子的转录控制、miRNA海绵、代谢重编程、蛋白质泛素化和表观遗传修饰。关注NK细胞在肿瘤中的浸润，我们将lncrna分为机制定义的和未表征的两组，强调了它们在肿瘤相关的竞争性内源性RNA （ceRNA）网络、表观遗传调控和细胞死亡途径中的作用。通过整合这些观点，本综述增强了我们对lncrna介导的免疫调节的理解，并强调了它们作为涉及NK细胞功能障碍疾病的治疗靶点的潜力。

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引用次数: 0

Epigenetic insights into minimal residual disease detection in cancer 对癌症最小残留疾病检测的表观遗传学见解

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-22 DOI: 10.1016/j.gendis.2025.101830

Lingao Ju , Gang Wang , Zilin Xu , Wan Xiang , Hongwei Peng , Mengxue Yu , Shenjuan Li , Yi Zhang , Kaiyu Qian , Yu Xiao

引用次数: 0

Machine learning-based stratification of Parkinson’s disease progression using dysautonomia symptoms and transcriptomic signatures 基于机器学习的帕金森病进展分层，使用自主神经异常症状和转录组特征

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-22 DOI: 10.1016/j.gendis.2025.101831

Su-Jin Baek , Hyeong Joon Jun , Jae Hyeok Han , SeoHyun Lee , HuiYan Zhao , Muhammad Umar , Jae Young Jang , Jung-Hee Jang

引用次数: 0

Elevated TOR1B expression predicts poor survival outcomes in patients with breast cancer 升高的TOR1B表达预示着乳腺癌患者较差的生存结果

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-21 DOI: 10.1016/j.gendis.2025.101826

Kun Fang , Suxiao Jiang , Zhengjie Xu , Meng Luo , Yinling Ma , Changsheng Yan

引用次数: 0

Targeting fatty acid synthase to overcome PARP inhibitor resistance and to create an artificial synthetic lethality for triple-negative breast cancer 以脂肪酸合酶为靶点，克服PARP抑制剂耐药性，为三阴性乳腺癌创造人工合成致死性

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-20 DOI: 10.1016/j.gendis.2025.101817

Sophia Josephraj , Chao J. Wang , Qingbin Cui , Zizheng Dong , Jing-Yuan Liu , Jian-Ting Zhang

Despite advances in cancer treatment with targeted therapies and immunotherapies, triple-negative breast cancer (TNBC) has not significantly benefited from these developments. Although poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for breast cancer, their clinical use is largely limited to the small subset of HER2-negative patients with germline BRCA1/2 mutations, and resistance is frequently observed. Previously, we demonstrated that proton pump inhibitors (PPIs), including lansoprazole and its metabolite, 5-hydroxy lansoprazole sulfide (5HLS), reduce PARP1 expression by inhibiting fatty acid synthase (FASN), a key enzyme in de-novo lipid synthesis. We also found that PPIs synergize with DNA-damaging agents by regulating PARP1 expression and impairing non-homologous end joining (NHEJ) repair of DNA damage. These findings led to the hypothesis that PPIs synergize with PARPi independently of BRCA mutation, potentially expanding the utility of PARPi to a broader TNBC population. In this study, we show that FASN contributes to PARPi resistance, and that lansoprazole and 5HLS strongly synergize with olaparib and talazoparib in both BRCA1-mutant and wild-type TNBC cells. This synergy occurs through FASN inhibition and subsequent impairment of NHEJ repair of double-strand breaks induced by PARPi trapping. 5HLS also facilitates PARPi-induced PARP1 trapping and inhibits BRCA1 expression by inhibiting FASN, contributing to the synergy with PARPi in both BRCA1 wild-type and mutant TNBC cells. Together, these findings suggest that inhibiting FASN with PPIs creates an artificial synthetic lethality, providing a rationale for combining PPIs with PARPi to expand their utility to TNBC patients without germline BRCA1 mutations and to overcome PARPi resistance.

尽管靶向治疗和免疫治疗在癌症治疗方面取得了进展，但三阴性乳腺癌（TNBC）并未从这些发展中显著受益。尽管聚（adp -核糖）聚合酶（PARP）抑制剂（PARPi）已被批准用于乳腺癌，但其临床应用在很大程度上仅限于her2阴性的生殖系BRCA1/2突变患者的一小部分，并且经常观察到耐药。之前，我们证明质子泵抑制剂（PPIs），包括兰索拉唑及其代谢物5-羟基兰索拉唑硫醚（5HLS），通过抑制脂肪酸合成酶（FASN）来降低PARP1的表达，FASN是脂质合成的关键酶。我们还发现PPIs通过调节PARP1表达和损害DNA损伤的非同源末端连接（NHEJ）修复与DNA损伤剂协同作用。这些发现导致PPIs与PARPi协同作用独立于BRCA突变的假设，可能将PARPi的效用扩大到更广泛的TNBC人群。在本研究中，我们发现FASN有助于PARPi耐药，并且在brca1突变型和野生型TNBC细胞中，兰索拉唑和5HLS与奥拉帕尼和talazoparib具有强协同作用。这种协同作用通过FASN抑制和随后PARPi捕获诱导的NHEJ双链断裂修复损伤发生。5HLS还促进PARPi诱导的PARP1捕获，并通过抑制FASN抑制BRCA1表达，在BRCA1野生型和突变型TNBC细胞中与PARPi协同作用。总之，这些发现表明，用PPIs抑制FASN可产生人工合成致死性，这为PPIs与PARPi联合使用提供了理论依据，可将其应用于没有种系BRCA1突变的TNBC患者，并克服PARPi耐药性。

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引用次数: 0

In vivo gene therapy: A strategy for mutations, degenerations, and tumors 体内基因治疗：一种治疗突变、变性和肿瘤的策略

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-19 DOI: 10.1016/j.gendis.2025.101808

Tao Wang , Mingyang Yu , Ping Liu , Zhiqiang Song , Cheng Li , Jianmin Yang , Na Liu

Gene mutations, organ function degeneration, and carcinogenesis are the primary threats to human health. Gene therapy, which involves the addition, deletion, regulation, and editing of genes, as well as the development of genetic vaccines, can potentially cure genetic mutation disorders, degenerative diseases, and cancers. Ex vivo gene therapy has recently been used to treat monogenetic mutation diseases of the hematopoietic system and cancers. However, in vivo gene therapy remains inapplicable. The primary elements of in vivo gene therapy include deoxyribonucleic acid (DNA) nucleases (e.g., zinc finger nucleases, transcription activator-like effector nucleases), CRISPR-Cas system, base editors, prime editors, and delivery vectors (e.g., viral and non-viral vehicles). According to the development of DNA nucleases and delivery vectors, in vivo gene therapy can be made available for future clinical use. The current review summarizes the development of DNA nucleases and delivery vectors for in vivo gene therapy, emphasizing recent progress.

基因突变、器官功能退化和致癌是人类健康的主要威胁。基因治疗包括基因的添加、删除、调节和编辑，以及基因疫苗的开发，有可能治愈基因突变疾病、退行性疾病和癌症。体外基因治疗最近被用于治疗造血系统的单基因突变疾病和癌症。然而，体内基因治疗仍然不适用。体内基因治疗的主要元素包括脱氧核糖核酸（DNA）核酸酶（如锌指核酸酶、转录激活物样效应核酸酶）、CRISPR-Cas系统、碱基编辑器、引物编辑器和传递载体（如病毒和非病毒载体）。随着DNA核酸酶和传递载体的发展，体内基因治疗可用于未来的临床应用。本文综述了用于体内基因治疗的DNA核酸酶和传递载体的研究进展，重点介绍了近年来的研究进展。

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引用次数: 0

Magnolol mitigates morphine-induced analgesic tolerance via EGFR-mediated inhibition of microglial activation and neuroinflammatory reduction 厚朴酚通过egfr介导的小胶质细胞激活抑制和神经炎症减少来减轻吗啡诱导的镇痛耐受

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-15 DOI: 10.1016/j.gendis.2025.101802

Weixin Lin , Yuxuan Wang , Qisheng Wang , Jiamin Huang , Ziting Zhou , Yongwei Jiang , Fenfen Qin , Zhonghao Li , Hui Wang , Zijing Wang , Haotian Pan , Qian Wang , Shanzhong Tan , Zhigang Lu

引用次数: 0

Multifaceted role of T-box transcription factor 4: From embryonic development to disease pathogenesis T-box转录因子4的多面作用：从胚胎发育到疾病发病机制

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-14 DOI: 10.1016/j.gendis.2025.101811

Lin Yi , Li Zhou , Bianfei Shao , Tingxiu Xiang , Jingyi Tang

T-box transcription factor 4 (TBX4), a crucial member of the T-box gene family, is essential for embryonic development, particularly in the formation of hindlimbs and lungs. Beyond these developmental roles, TBX4 is integral for maintaining the structural integrity and function of the respiratory, motor, and nervous systems. Dysregulation of TBX4 is implicated in serious diseases, including pulmonary hypertension, small patella syndrome, and tracheal stenosis, with mutations and aberrant expression patterns emerging as potential diagnostic markers. Additionally, TBX4 contributes to tumorigenesis in cancers such as pancreatic, lung, and bladder cancers, where recent studies suggest DNA methylation as a primary mechanism underlying TBX4 suppression, positioning it as a promising prognostic marker. Despite these advances, the precise functions and regulatory mechanisms of TBX4 remain insufficiently understood. This review consolidates current knowledge on the roles and molecular mechanisms of TBX4 in mammalian embryonic development and its association with diseases, highlighting the need for further research into its contributions to human health.

T-box转录因子4 （TBX4）是T-box基因家族的重要成员，对胚胎发育，特别是后肢和肺的形成至关重要。除了这些发育作用外，TBX4对于维持呼吸、运动和神经系统的结构完整性和功能也是不可或缺的。TBX4的失调与严重疾病有关，包括肺动脉高压、小髌骨综合征和气管狭窄，突变和异常表达模式成为潜在的诊断标志。此外，TBX4有助于胰腺癌、肺癌和膀胱癌等癌症的肿瘤发生，最近的研究表明DNA甲基化是TBX4抑制的主要机制，将其定位为有希望的预后标志物。尽管取得了这些进展，TBX4的确切功能和调控机制仍未得到充分的了解。这篇综述整合了目前关于TBX4在哺乳动物胚胎发育中的作用和分子机制及其与疾病的关联的知识，强调需要进一步研究其对人类健康的贡献。

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引用次数: 0

Druggable target ATAD2 enhances the malignant progression and cooperates with E2F1 to up-regulate PDK1 expression in glioma 可药物靶点ATAD2促进胶质瘤的恶性进展，并与E2F1协同上调PDK1的表达

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-14 DOI: 10.1016/j.gendis.2025.101810

Shenghua Zhuo , Liangwang Yang , Zhimin Chen , Shenbo Chen , Shuo Yang , Taixue Chen , Wen-Shu Wu , Kai Wang , Kun Yang

Gliomas are characterized by high mortality and disability rates. Cancer-testis antigens (CTAs) are among the most promising therapeutic targets for combating cancer. While several CTAs have been associated with the development and progression of gliomas, the role of ATPase family AAA domain-containing protein 2 (ATAD2) in this context has not been thoroughly investigated. In this study, both in vitro and in vivo experiments validated the role of ATAD2 in enhancing malignant phenotypes. The LN229 cell lines were employed for RNA-seq and proteomics to uncover downstream targets of ATAD2. Results showed that elevated ATAD2 expression was noted in glioblastoma (GBM). ATAD2 knockdown significantly reduced the proliferation, migration, and invasion capabilities of GBM cells, while its overexpression had the opposite effect. The knockdown of ATAD2 led to a decrease in subcutaneous tumor size and weight, a reduction in Ki67 expression, and an extension of survival in mice bearing intracranial in situ tumors. Mechanistically, a positive feedback loop involving ATAD2 and E2F transcription factor 1 (E2F1) was identified to enhance the transcriptional activation of pyruvate dehydrogenase kinase 1 (PDK1). Notably, the expression levels of these genes were found to be positively correlated, with patients exhibiting high levels of these genes tending to have poorer prognoses. These findings demonstrate that ATAD2 plays a pivotal role in the malignant progression of glioma and synergizes with E2F1 to promote PDK1 expression, suggesting its potential as a therapeutic target for glioma.

胶质瘤的特点是高死亡率和致残率。癌睾丸抗原（cta）是对抗癌症最有希望的治疗靶点之一。虽然一些cta与胶质瘤的发生和发展有关，但atp酶家族AAA结构域蛋白2 （ATAD2）在这方面的作用尚未得到彻底研究。在本研究中，体外和体内实验都验证了ATAD2在增强恶性表型中的作用。利用LN229细胞系进行RNA-seq和蛋白质组学分析，发现ATAD2的下游靶点。结果显示，ATAD2在胶质母细胞瘤（GBM）中表达升高。ATAD2敲低显著降低GBM细胞的增殖、迁移和侵袭能力，而过表达则相反。ATAD2的敲低导致颅内原位肿瘤小鼠皮下肿瘤的大小和重量减少，Ki67表达减少，生存期延长。机制上，一个涉及ATAD2和E2F转录因子1 （E2F1）的正反馈回路被发现可以增强丙酮酸脱氢酶激酶1 （PDK1）的转录激活。值得注意的是，这些基因的表达水平被发现是正相关的，表现出高水平这些基因的患者往往有较差的预后。这些发现表明，ATAD2在胶质瘤的恶性进展中起着关键作用，并与E2F1协同促进PDK1的表达，提示其可能成为胶质瘤的治疗靶点。

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引用次数: 0

Carnosine Dipeptidase(Cndp): An emerging therapeutic target for metabolic diseases and cancers 肌肽二肽酶（Cndp）：代谢性疾病和癌症的新靶点

IF 9.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & Diseases

Pub Date : 2025-08-13 DOI: 10.1016/j.gendis.2025.101804

Liang Zhou , Shuxia Zhang , Yunqi Zhang , Yun Luo , Xiaobo Sun

Metabolic diseases, associated with high morbidity and mortality rates, pose a challenge to global public health and a significant burden on society. Since the discovery of carnosinase-2(CNDP2)-mediated synthesis of lactate and phenylalanine, which subsequently forms N-Lactoyl-Phenylalanine (Lac-Phe) to inhibit food intake and obesity, the carnosine dipeptidases (CNDPs)have attracted increasing scientific interest. Although the role of CNDP in diabetic nephropathy has been extensively studied, its role in other metabolic diseases remains unclear. In this study, we have overviewed the enzymatic and other roles of CNDP proteins focusing on recent research demonstrating the regulatory roles of CNDP on various metabolic diseases. Increasing evidence indicates that carnosinase-1(CNDP1) and carnosinase-2 are crucial for the management of metabolic diseases under both physiological and pathological conditions. Moreover, interest in the pharmacological modulators of CNDP has been steadily increasing. Overall, we suggest that CNDP can be considered a promising therapeutic target for the effective treatment of metabolic diseases.

与高发病率和高死亡率相关的代谢性疾病对全球公共卫生构成挑战，对社会构成重大负担。自从发现肌肽酶-2（CNDP2）介导乳酸和苯丙氨酸的合成，随后形成n -乳酸-苯丙氨酸（Lac-Phe）来抑制食物摄入和肥胖以来，肌肽二肽酶（CNDPs）引起了越来越多的科学兴趣。虽然CNDP在糖尿病肾病中的作用已被广泛研究，但其在其他代谢性疾病中的作用尚不清楚。在本研究中，我们概述了CNDP蛋白的酶和其他作用，重点介绍了最近的研究表明CNDP在各种代谢疾病中的调节作用。越来越多的证据表明，肌肽酶-1（CNDP1）和肌肽酶-2在生理和病理条件下对代谢性疾病的管理至关重要。此外，对CNDP药理学调节剂的兴趣一直在稳步增加。总之，我们认为CNDP可以被认为是有效治疗代谢性疾病的一个有希望的治疗靶点。

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