Gene最新文献_第9页

Functional analysis of two component signaling system in Mycobacterium tuberculosis 结核分枝杆菌双组分信号系统的功能分析。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-07 DOI: 10.1016/j.gene.2025.149868

Karthikeyan Sundaram , Sridhar Rathinam

Tuberculosis is a fatal infection transmitted through airborne droplet nuclei. The etiological agent is Mycobacterium tuberculosis, an acid-fast bacillus. Drug-resistant tuberculosis poses a global challenge, with specific mycobacterial genes intricately associated with drug resistance. Numerous factors are implicated in the etiology of the condition. This review specifically aims to examine ClpCP, an ATPase belonging to the AAA + protease family, and the genes of the two-component sensor system related with disease etiology. Mycobacterium TB depends significantly on protein degradation to regulate their quantity and quality, which is crucial for its proliferation and pathogenicity involving Clp. The two-component sensor system comprises histidine kinase (HK) and response regulator (RR), which governs responses to stress situations, starvation, nutritional abundance, persistence, hypoxia, dormancy, and primarily disease pathogenesis. Within the two-component system, there exist 12 pairs, including SenX3/RegX3, PhoP/PhoR, DosR/DosS, MtrA/MtrB, and PdtaS/PdtaR, alongside 6 response regulators Rv0195, Rv0260c, Rv0818, PdtaR, Rv2884, and Rv3143 encoded in the Mycobacterium tuberculosis genome. The PhoPR genes have been extensively researched, and the pathogenicity of Mycobacterium tuberculosis (MTB) is contingent upon the sensor kinase of the PhoPR two-component regulatory system, known as PhoR. This review will examine the roles of genes related to the factors associated with mycobacterial growth and pathogenesis.

结核病是一种通过空气传播的飞沫核传播的致命传染病。病原是结核分枝杆菌，一种抗酸杆菌。耐药结核病是一项全球性挑战，特定的分枝杆菌基因与耐药有着错综复杂的关系。许多因素涉及到该病的病因学。这篇综述特别旨在研究ClpCP，一种属于AAA + 蛋白酶家族的atp酶，以及与疾病病因相关的双组分传感器系统基因。结核分枝杆菌主要依靠蛋白质降解来调节其数量和质量，这对其涉及Clp的增殖和致病性至关重要。这种双组分传感器系统包括组氨酸激酶（HK）和反应调节因子（RR），它们控制对应激情况、饥饿、营养丰富、持久性、缺氧、休眠和主要疾病发病机制的反应。在双组分体系中，共编码SenX3/RegX3、PhoP/PhoR、DosR/DosS、MtrA/MtrB、PdtaS/PdtaR等12对，以及Rv0195、Rv0260c、Rv0818、PdtaR、Rv2884、Rv3143 6个应答调控因子。PhoPR基因已被广泛研究，结核分枝杆菌（MTB）的致病性取决于PhoPR双组分调控系统（PhoR）的传感器激酶。本文将探讨与分枝杆菌生长和发病相关的基因的作用。

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引用次数: 0

Unravelling the role of Neurotrimin (NTM), a member of the IgLON family, in mild intellectual disability and anxiety-like behaviors 揭示IgLON家族成员Neurotrimin （NTM）在轻度智力残疾和焦虑样行为中的作用。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-07 DOI: 10.1016/j.gene.2025.149876

Mirella Vinci , Simone Treccarichi , Pinella Failla , Antonino Musumeci , Angelo Gloria , Miriam Virgillito , Concetta Federico , Salvatore Saccone , Francesco Calì

Neurotrimin (NTM) (OMIM #607938), a member of the IgLON family, collaborates with other neural cell adhesion proteins to regulate neurite outgrowth, axonal fasciculation, and synapse formation. Disruption of NTM function in animal models has been associated with deficits in emotional learning and increased anxiety-like behaviours. In this study, we examined an individual presenting with mild intellectual disability, anxiety-like behaviours, and low frustration tolerance, along with generalised hypotonia. Trio-based whole exome sequencing (WES) identified a de novo nucleotides insertion, c.788_791dup, in the NTM (NM_001144058) gene. NTM currently lacks a MIM phenotype entry linking it to a specific disorder, and has been predicted to follow both autosomal dominant and recessive inheritance patterns. The variant was classified as pathogenic according to ACMG guidelines and displays a very low frequency in the gnomAD population (0.000006829). It is located at a highly conserved site (PhyloP: 7.674). In-silico analysis predicted that the variant induces nonsense-mediated decay (NMD) of the transcript, resulting in loss of NTM protein production. However, if the transcript escapes NMD, the insertion is expected to cause a frameshift, altering codons beyond amino acid 262, resulting in Ile263, a novel Asp264, and a premature stop codon (TGA) in position 265. This mutation is predicted to disrupt NTM homodimerization and heterodimerization with other IgLON family proteins (OPCML, LSAMP, NEGR1, and IgLON5), regardless of whether degradation of the transcript occurs or a truncated protein is produced. These findings suggest a potential link between NTM dysfunction and neurodevelopmental phenotypes and highlight its possible role as a candidate gene for mild cognitive and behavioural disorders.

Neurotrimin (NTM) （omim# 607938）是IgLON家族的一员，与其他神经细胞粘附蛋白协同调节神经突生长、轴突束化和突触形成。在动物模型中，NTM功能的破坏与情绪学习缺陷和焦虑样行为的增加有关。在这项研究中，我们检查了一个表现为轻度智力残疾、焦虑样行为、低挫折容忍度以及广泛性张力低下的个体。三基全外显子组测序（WES）在NTM （NM_001144058）基因中发现了一个新的核苷酸插入c.788_791dup。NTM目前缺乏将其与特定疾病联系起来的MIM表型条目，并且预测其遵循常染色体显性和隐性遗传模式。根据ACMG指南，该变异被归类为致病性，在gnomAD人群中出现的频率非常低（0.000006829）。它位于一个高度保守的位点（PhyloP: 7.674）。计算机分析预测，该变异诱导转录物的无义介导的衰变（NMD），导致NTM蛋白生产的损失。然而，如果转录本逃脱NMD，插入预计会引起移码，改变262号氨基酸以外的密码子，导致Ile263、新的Asp264和265号位置的过早终止密码子（TGA）。预计该突变将破坏NTM与其他IgLON家族蛋白（OPCML、LSAMP、NEGR1和IgLON5）的同二聚化和异二聚化，无论转录物是否降解或产生截断蛋白。这些发现表明NTM功能障碍与神经发育表型之间存在潜在联系，并突出了其作为轻度认知和行为障碍候选基因的可能作用。

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引用次数: 0

Influence of sleep duration on cumulative genetic effects on obesity and related anthropometric traits among preschool children 睡眠时间对学龄前儿童肥胖及相关人体测量特征累积遗传效应的影响

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-06 DOI: 10.1016/j.gene.2025.149880

Mengna Zhang , Jianfei Lin , Shijian Liu , Yanrui Jiang , Min Meng , Qi Zhu , Guanghai Wang , Fan Jiang , Hao Mei

Objective

This study assesses the influence of genetic variations over 9 genes (FTO, CLOCK, ARNTL, CRP, IL6, NR3C1, LEP, GHRL, and ADIPOQ) involved in energy homeostasis and stress regulation on children’s anthropometric traits and examines the impact of sleep duration on these genetic associations.

Methods

We analyzed 255 preschool children from Shanghai, China, and sequenced genetic variants from the nine candidate genes. Three genetic risk scores (GRS) were derived: GRS_all, derived from all filtered SNPs; GRS_BMI, based on three SNPs identified in a BMI GWAS reference; and uGRS₅ constructed from locally identified SNPs. Linear regression and Firth’s logistic regression were applied to assess GRS effects, and stratified analyses were performed to evaluate sleep impact on GRS associations.

Results

After adjusting for age, sex, and appetite with FDR correction, GRS_all showed marginal associations with several anthropometric measures; GRS_BMI demonstrated stronger associations with more anthropometric traits and smaller p-values; and uGRS₅ exhibited the strongest associations overall. Stratified analyses showed that GRS associations were evident only in children with adequate sleep, while the associations were absent in the short sleep group.

Conclusions

Our findings suggest that genetic variants in the nine candidate genes, particularly those from FTO, LEP and GHRL, exert cumulative effects on anthropometric traits. GRS constructed from SNPs with modest effects can serve as a predictive tool for anthropometric outcomes and obesity risk, while GRS based on GWAS-identified SNPs can offer greater predictive power than GRS based on all eligible SNPs. Importantly, adequate sleep is essential for the manifestation of these genetic effects, whereas insufficient sleep may attenuate or mask them. These results highlight the importance of incorporating sleep as a key environmental factor in genetic studies and support personalized strategies for managing obesity risk in children.

目的：本研究评估了9个参与能量稳态和应激调节的基因（FTO、CLOCK、ARNTL、CRP、IL6、NR3C1、LEP、GHRL和ADIPOQ）对儿童人体测量特征的影响，并研究了睡眠时间对这些遗传关联的影响。方法：对来自中国上海的255名学龄前儿童进行分析，并对9个候选基因的遗传变异进行测序。得到三个遗传风险评分（GRS）： GRSall，来自所有过滤的snp；GRSBMI，基于BMI GWAS参考文献中鉴定的三个snp；和uGRS5由本地识别的snp构建。采用线性回归和Firth逻辑回归来评估GRS效应，并采用分层分析来评估睡眠对GRS关联的影响。结果：在FDR校正年龄、性别和食欲后，GRSall与几个人体测量指标显示出边际相关性；GRSBMI与更多的人体特征和较小的p值有较强的相关性；和uGRS5总体上表现出最强的相关性。分层分析显示，只有在睡眠充足的儿童中，GRS关联才很明显，而在睡眠不足的儿童中，这种关联则不存在。结论：我们的研究结果表明，9个候选基因的遗传变异，特别是来自FTO、LEP和GHRL的基因变异，对人体测量特征具有累积效应。由具有适度效应的snp构建的GRS可以作为人体测量结果和肥胖风险的预测工具，而基于gwas识别的snp的GRS比基于所有符合条件的snp的GRS具有更大的预测能力。重要的是，充足的睡眠对这些遗传效应的表现至关重要，而睡眠不足可能会减弱或掩盖这些影响。这些结果强调了将睡眠作为基因研究中关键环境因素的重要性，并支持了管理儿童肥胖风险的个性化策略。

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引用次数: 0

Revealing the genetic blueprint: A transcriptomic approach to deciphering blue iris color formation in Nili-Ravi buffalo 揭示遗传蓝图：一种转录组学方法来破译Nili-Ravi水牛蓝色虹膜颜色的形成。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-06 DOI: 10.1016/j.gene.2025.149878

Dong Wang , Yixue Xu , Chaobin Qin , Xinhui Song , Hui Li , Xiaoxian Xu , Muhammad Farhan Khan , Kuiqing Cui , Zhipeng Li , Qingyou Liu

Water buffalo are economically significant livestock worldwide, yet the genetic basis of the blue iris in Nili-Ravi buffalo remains elusive. We collected mixed iris–lens samples from two Murrah buffaloes (black iris) and two Nili-Ravi buffaloes (blue iris) and performed paired-end RNA-seq. After quality control, 64.53 Gb of high-quality data (Q30 ≥ 89.92 %) were obtained. Differential analysis (DESeq2,|log₂FoldChange| ≥ 2 and padj < 0.05) revealed 1,289 differentially expressed genes and 248 differentially expressed lncRNAs between blue and black irises. GO and KEGG enrichment highlighted melanogenesis, tyrosine metabolism, cysteine metabolism, and phototransduction pathways. Key differential genes related to eye development and melanin production—including the hub mRNAs KIT, MGST1, GNGT1, and TYRP1—were identified. Network analysis further showed that lncRNA MSTRG.14079.1 directly targets protein tyrosine phosphatase receptor T (PTPRT), and this interaction is significantly down-regulated in blue irises. Together, our study provides the first molecular network underlying the blue iris phenotype and establishes a theoretical basis for using this non-invasive marker to enhance breeding efficiency in buffalo.

水牛是世界范围内具有重要经济意义的牲畜，但尼利-拉维水牛蓝虹膜的遗传基础仍然难以捉摸。我们采集了两只Murrah水牛（黑色虹膜）和两只Nili-Ravi水牛（蓝色虹膜）的混合虹膜透镜样本，并进行了对端rna测序。经质量控制，获得高质量数据64.53 Gb （Q30 ≥ 89.92 %）。差异分析(DESeq2， | log2FoldChange |≥2和padj

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引用次数: 0

Retraction notice to “Role of CYP1A2*1F polymorphism in cancer risk: evidence from a meta-analysis of 46 case-control studies”. [Gene 524 (2013) 168–174] 撤回“CYP1A2*1F多态性在癌症风险中的作用：来自46个病例对照研究的荟萃分析的证据”。[基因524(2013)168-174]。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-05 DOI: 10.1016/j.gene.2025.149822

Zhong Tian , Yi-Ling Li , Lin Zhao , Chen-Liang Zhang

引用次数: 0

Core role of H19 LncRNA in gastric cancer: From tumor ecosystem reprogramming to precision therapy H19 LncRNA在胃癌中的核心作用：从肿瘤生态系统重编程到精准治疗

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-05 DOI: 10.1016/j.gene.2025.149871

Binbin Zeng , Jianing Zhu , Yaping Wang , Chen Gu , Wenxu Zhu , Qingqing Xu , Yuxuan Wu , Juping Chen , Yang Ai , Tianyu Zhou , Ying Lin , Lixin Hua , Yayun Qian

Gastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Owing to its insidious onset, most patients are diagnosed at advanced stages, marked by high recurrence, frequent metastasis, and multidrug resistance, resulting in poor outcomes. Optimizing therapeutic strategies therefore remains an urgent priority. Increasing evidence links GC initiation and progression to dysregulated expression of both coding and non-coding genes. Among them, long non-coding RNAs (lncRNAs) which recognized as pivotal regulators of gene expression have emerged as promising biomarkers and therapeutic targets. This review focuses on the lncRNA H19, highlighting its role as a central molecular hub in gastric tumor progression. H19 modulates the tumor microenvironment, promotes invasion and metastasis, reprograms cellular metabolism, and contributes to therapeutic resistance. By integrating molecular, cellular, and clinical perspectives, we provide a refined understanding of H19-driven gastric tumorigenesis and underscore its potential as a biomarker and therapeutic target. These insights offer new opportunities for early diagnosis, personalized treatment, and the development of RNA-targeted therapies for gastric cancer.

胃癌（GC）是世界上第五大最常见的恶性肿瘤，也是第四大癌症相关死亡原因。由于其发病隐匿，大多数患者诊断为晚期，特点是高复发，频繁转移和多药耐药，导致预后差。因此，优化治疗策略仍然是当务之急。越来越多的证据表明GC的发生和发展与编码和非编码基因的表达失调有关。其中，长链非编码rna （lncRNAs）被认为是基因表达的关键调控因子，已成为有希望的生物标志物和治疗靶点。这篇综述的重点是lncRNA H19，强调其在胃肿瘤进展中的中心分子枢纽作用。H19调节肿瘤微环境，促进侵袭和转移，重编程细胞代谢，并有助于治疗耐药。通过整合分子、细胞和临床观点，我们提供了对h19驱动的胃肿瘤发生的精细理解，并强调了其作为生物标志物和治疗靶点的潜力。这些见解为胃癌的早期诊断、个性化治疗和rna靶向治疗的发展提供了新的机会。

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引用次数: 0

Profile of cystic fibrosis transmembrane conductance regulator (CFTR) gene variants across India and their variability in different geographic regions 印度囊性纤维化跨膜传导调节因子（CFTR）基因变异及其在不同地理区域的变异性

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-05 DOI: 10.1016/j.gene.2025.149870

Madhumita Roy Chowdhury , Indu Kumari , Kana Ram Jat , Nitin Dhochak , Rakesh Lodha , Sneha Varkki , Prawin Kumar , Jagdish Prasad Goyal , Javeed Iqbal Bhat , SK Kabra , Aaron Chapla , Jhuma Sankar , Madhan Kumar , Sumita Danda , Neerja Gupta , Princy Bamal , Priyanka Medhi , Ruchi Gaba , Madhulika Kabra

Cystic Fibrosis (CF) is increasingly diagnosed in non-European populations, including Indian children, with wide regional and ethnic variation in CFTR genotypic spectrum. This study aimed to document the CFTR genetic profile in Indian children and assess regional variability.

In a multicentric effort to strengthen CF services in India, data were collected from children with confirmed CF at AIIMS New Delhi, SKIMS Srinagar, AIIMS Jodhpur, and CMC Vellore. A stepwise testing strategy was used: initial screening for two common variants via Sanger sequencing and RFLP, followed by NGS and MLPA for broader variant detection.

Among 260 children (520chromosomes), 105 CFTR variants were identified. The most common variant, p.Phe508del, had an allele frequency of 29–34% across regions—substantially lower than the 70–80% seen in Europeans. Each region showed 4–5 common variants. The genotypic spectrum in southern/eastern India resembled that of West/Southwest Asia, while northern/western India showed similarity to Western Europe. Fourteen novel variants were detected: seven pathogenic, three likely pathogenic, and four of uncertain significance.

This is one of the most comprehensive studies to reveal region-specific CFTR variants in India. The lower prevalence of p.Phe508del and distinct genotypic patterns across regions highlight the need for customized diagnostic algorithm. There is an urgent need to evaluate the efficacy of current CFTR modulators and to explore the development of new treatments based on the unique Indian molecular spectrum.

囊性纤维化（CF）越来越多地在非欧洲人群中被诊断出来，包括印度儿童，CFTR基因型谱存在广泛的区域和种族差异。本研究旨在记录印度儿童CFTR的遗传谱，并评估区域差异。在加强印度CF服务的多中心努力中，收集了新德里AIIMS、斯利那加SKIMS、焦特布尔AIIMS和韦洛CMC确诊CF儿童的数据。采用逐步检测策略：首先通过Sanger测序和RFLP筛选两种常见变异，然后通过NGS和MLPA进行更广泛的变异检测。在260名儿童（520条染色体）中，鉴定出105个CFTR变异。最常见的变体p.Phe508del在不同地区的等位基因频率为29-34%，大大低于欧洲地区的70-80%。每个区域显示4-5个常见变异。印度南部/东部的基因型谱与西/西南亚相似，而印度北部/西部的基因型谱与西欧相似。检测到14种新的变异：7种致病，3种可能致病，4种意义不确定。这是揭示印度特定区域CFTR变异的最全面的研究之一。p.Phe508del的低患病率和不同地区的不同基因型模式突出了定制诊断算法的必要性。目前迫切需要评估现有CFTR调节剂的疗效，并根据印度独特的分子光谱探索新的治疗方法。

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引用次数: 0

N1 and N2 neutrophil phenotypes may play differential roles in stimulating the endochondral ossification behaviors of ATDC5 cells N1和N2中性粒细胞表型可能在刺激ATDC5细胞软骨内成骨行为中发挥不同的作用。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-04 DOI: 10.1016/j.gene.2025.149874

Fangzhou Lu , Andy Cremers , Martijn Poeze , Martijn van Griensven , Tim J.M. Welting , Taco J. Blokhuis , Marjolein M.J. Caron

Objective

Endochondral ossification is vital for bone healing, with neutrophils playing a crucial role in the osteoimmune system. While N1 (pro-inflammatory) and N2 (regenerative) neutrophils are documented in other contexts, their role in endochondral ossification remains unclear. This study investigates their effects on ATDC5 cells.

Methods

Neutrophils from five healthy volunteers were isolated and polarized into N0 (unstimulated), N1, or N2 phenotypes. After culturing for 4 h, neutrophil-conditioned media was mixed (20 % v/v) with chondrogenic differentiation media (DM). ATDC5 cells were cultured with mixture or DM alone for 24 h, followed by continued DM culturing. On days 7 and 14, several gene expressions, ALP activity, and TGF-β3 levels were assessed.

Results

SOX9 peaked in the ATDC5 (A)/N2 group on day 7, while the A/N1 group showed the highest levels on day 14. COL2A1 was elevated in the A/N0 group on day 7. RUNX2 was higher in A/N1 and A/N2 on day 7, with A/N1 remaining elevated on day 14. MMP-13 was significantly higher in A/N1 on day 7. COL10A1 expression showed no significant changes. COL1A1 and COX2 were continually elevated in the A/N1 group. ALP activity was consistently enhanced in the A/N1 group, and TGF-β3 was lower in both A/N1 and A/N2 on day 14.

Conclusions

This study indicates that N1 neutrophils may promote chondrocyte maturation and osteogenic differentiation, while N2 neutrophils may support proliferation, hypertrophy, and maturation, providing a cell reservoir for ossification. These findings highlight their distinct roles in directing chondrogenic progenitors toward bone rather than cartilage formation.

目的：软骨内成骨对骨愈合至关重要，中性粒细胞在骨免疫系统中起着至关重要的作用。虽然在其他情况下记录了N1（促炎）和N2（再生）中性粒细胞，但它们在软骨内成骨中的作用尚不清楚。本研究探讨了它们对ATDC5细胞的影响。方法：从5名健康志愿者中分离中性粒细胞，并将其极化为N0（未刺激）、N1和N2表型。培养4 h后，将中性粒细胞条件培养基（20 % v/v）与软骨分化培养基（DM）混合。ATDC5细胞分别与混合液或DM单独培养24 h，然后继续DM培养。在第7天和第14天，评估几个基因表达、ALP活性和TGF-β3水平。结果：ATDC5 (A)/N2组SOX9在第7天达到峰值，而A/N1组SOX9在第14天达到峰值。第7天，A/N0组COL2A1升高。第7天时，RUNX2在A/N1和A/N2中升高，第14天时，A/N1仍升高。第7天，MMP-13在A/N1中显著升高。COL10A1表达无明显变化。A/N1组COL1A1、COX2持续升高。第14天，A/N1组ALP活性持续增强，TGF-β3在A/N1和A/N2组均降低。结论：本研究提示N1中性粒细胞可能促进软骨细胞成熟和成骨分化，而N2中性粒细胞可能支持增殖、肥大和成熟，为骨化提供细胞库。这些发现强调了它们在引导软骨祖细胞向骨而不是软骨形成方面的独特作用。

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引用次数: 0

Vitamin D regulation of gut microbiota-derived butyrate as a potential inhibitor of breast cancer proliferation 维生素D调节肠道微生物来源的丁酸盐作为乳腺癌增殖的潜在抑制剂。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-04 DOI: 10.1016/j.gene.2025.149872

Fuhong Gong , Nianqiu Liu , Jingge Miao , Chenxi Wang , Mengping Lin , Biqing Luan , Jiayi Chen , Yilin Chen , Xin Chen , Fei Ge , Wenlin Chen

Vitamin D is a fat-soluble vitamin implicated in the etiology, progression, and prognosis of breast cancer, yet its precise mechanisms of action remain elusive. We have integrated the latest insights from both basic and clinical research to find that in the human body, vitamin D is activated by hydroxylase to form the active form 1,25(OH)₂D. 1,25(OH)₂D may stimulate the abundance of butyrate-producing bacteria by upregulating their abundance, and butyrate can regulate the intestinal microenvironment and modulate the immune system to inhibit the proliferation of breast cancer. Notably, our investigations reveal a novel role of vitamin D in modulating the gut microbiome, particularly in stimulating the production of butyrate and other metabolites, which exhibit potent anti-proliferative effects on breast cancer cells. These findings open promising avenues for innovative clinical approaches in breast cancer therapy. This review delves into the intricate interplay between vitamin D, butyrate, and breast cancer, aiming to propose novel therapeutic strategies.

维生素D是一种脂溶性维生素，与乳腺癌的病因、进展和预后有关，但其确切的作用机制尚不清楚。我们整合了基础研究和临床研究的最新见解，发现在人体内，维生素D被羟化酶激活形成活性形式1,25(OH)2D。1,25(OH)2D可能通过上调丁酸产生菌的丰度来刺激其丰度，而丁酸可以调节肠道微环境，调节免疫系统，抑制乳腺癌的增殖。值得注意的是，我们的研究揭示了维生素D在调节肠道微生物组中的新作用，特别是在刺激丁酸盐和其他代谢物的产生方面，这些代谢物对乳腺癌细胞具有强大的抗增殖作用。这些发现为乳腺癌治疗的创新临床方法开辟了有希望的途径。这篇综述深入研究了维生素D、丁酸盐和乳腺癌之间复杂的相互作用，旨在提出新的治疗策略。

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引用次数: 0

RoeA controls Pseudomonas aeruginosa motility via a diffusible c-di-GMP signal interpreted by the hierarchical PilZ, FlgZ, and TssZ receptors RoeA通过可扩散的c-di-GMP信号控制铜绿假单胞菌的运动，该信号由分层PilZ、FlgZ和TssZ受体解释。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-04 DOI: 10.1016/j.gene.2025.149873

Chengjian Wan, Haopu Dai, Wenyuan Ma, Yang Li, Xiaoshuo Liu, Jiaying Wang, Jinsong Li, Kewei Li

The second messenger cyclic di-GMP (c-di-GMP) is a central regulator of the lifestyle switch between motility and sessility in the opportunistic pathogen Pseudomonas aeruginosa. While numerous c-di-GMP metabolizing enzymes exist, the specific pathways linking individual enzymes to physiological outputs often remain unclear. Here, we elucidate a signaling pathway through which the diguanylate cyclase RoeA inhibits swimming motility. Using a combination of genetic, biochemical and phenotypic approaches, we demonstrate that RoeA synthesizes c-di-GMP to suppress motility by modulating flagellar function rather than biogenesis. A systematic screen of the eight PilZ-domain c-di-GMP receptors in P. aeruginosa identified PilZ, FlgZ, and TssZ as the essential downstream effectors. Genetic epistasis analysis revealed that these receptors function as a hierarchical module, with PilZ and FlgZ playing a primary, cooperative role. The function of all three receptors was dependent on a conserved arginine residue within their c-di-GMP binding motifs. Crucially, bacterial two-hybrid assays showed no direct physical interaction between RoeA and its downstream motility effectors. These findings support a “free diffusion-receptor capture” model, where RoeA generates a global c-di-GMP signal that is interpreted by spatially distributed PilZ-domain receptors to downregulate flagellar motor function, thus providing a key example of how signaling specificity is achieved within a global second messenger network.

第二信使环二gmp （c-二gmp）是机会致病菌铜绿假单胞菌生活方式在运动和惰性之间转换的中心调节器。虽然存在许多c-二gmp代谢酶，但将单个酶与生理输出联系起来的具体途径往往尚不清楚。在这里，我们阐明了二胍酸环化酶RoeA抑制游泳运动的信号通路。利用遗传、生化和表型方法的结合，我们证明了RoeA通过调节鞭毛功能而不是生物发生来合成c-di-GMP来抑制运动性。对铜绿假单胞菌中8个PilZ结构域c-二gmp受体的系统筛选发现，PilZ、FlgZ和TssZ是主要的下游效应物。遗传上位分析表明，这些受体作为一个分层模块发挥作用，其中PilZ和FlgZ起主要的合作作用。这三种受体的功能都依赖于其c-di-GMP结合基序内的保守精氨酸残基。关键是，细菌双杂交试验显示RoeA与其下游运动效应物之间没有直接的物理相互作用。这些发现支持“自由扩散-受体捕获”模型，其中RoeA产生全球c-di-GMP信号，该信号由空间分布的pilz结构域受体解释，从而下调鞭毛运动功能，从而提供了信号特异性如何在全球第二信使网络中实现的关键示例。

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