Life sciences最新文献_第5页

Light exposure-induced circadian rhythm disruption impairs male reproductive health through oxidative stress and apoptosis 光照诱导的昼夜节律紊乱通过氧化应激和细胞凋亡损害男性生殖健康

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-26 DOI: 10.1016/j.lfs.2026.124222

Guodong Liu , Yuyang Zhang , Hui Gao , Xu Wu , Feng Li , Wei Zhang , Hui Jiang , Xiansheng Zhang

Aims

Artificial light exposure at night and irregular light schedules are increasingly prevalent environmental stressors in modern society and have been implicated in male reproductive disorders. This study aimed to determine how distinct patterns of circadian rhythm disruption differentially affect male reproductive function and to elucidate the underlying mechanisms.

Materials and methods

Three groups of male rats were subjected to standard 12-h light/12-h dark cycles (LD), fixed inverted light-dark cycles (DL), and a dynamic alternating light-dark-dark-light cycle (LDDL) designed to induce circadian rhythm instability. Reproductive outcomes including body weight, testicular index, serum testosterone levels, and sperm parameters were assessed. Testicular oxidative status was evaluated by measuring NOX4/5, HO-1, SOD, and MDA levels, while apoptosis was examined using Bax/Bcl-2 ratio, cleaved caspase-3 expression, and TUNEL staining.

Key findings

Male rats exposed to the LDDL cycle exhibited significant reproductive dysfunction, manifested as markedly reduced testicular index, decreased serum testosterone concentration, and impaired sperm motility. Mechanistically, LDDL conditions enhanced testicular oxidative stress, manifested by NOX4/5 upregulation and HO-1/SOD suppression. This redox imbalance was accompanied by germ cell apoptosis activation, evidenced by elevated Bax/Bcl-2 ratios, increased cleaved caspase-3 expression, and a higher proportion of TUNEL-positive cells. Notably, reproductive damage was more pronounced under dynamic circadian rhythm disruption than under fixed light-dark reversal conditions.

Significance

By linking dynamically light-induced circadian disruption to testicular oxidative stress and apoptotic signaling pathways, it elucidates potential mechanisms by which modern lighting environments impair male fertility and provides strategies for circadian rhythm intervention and environmental mitigation.

目的夜间人工光照和不规律光照是现代社会日益普遍的环境应激源，并与男性生殖障碍有关。本研究旨在确定昼夜节律中断的不同模式如何不同地影响男性生殖功能，并阐明潜在的机制。材料与方法将三组雄性大鼠分别置于标准的12-h光照/12-h黑暗周期（LD）、固定的倒置光照-黑暗周期（DL）和诱导昼夜节律不稳定的动态光-暗-暗交替周期（LDDL）。评估生殖结果，包括体重、睾丸指数、血清睾酮水平和精子参数。通过检测NOX4/5、HO-1、SOD和MDA水平评估睾丸氧化状态，通过Bax/Bcl-2比值、cleaved caspase-3表达和TUNEL染色检测细胞凋亡。主要发现暴露于LDDL周期的小鼠表现出明显的生殖功能障碍，表现为睾丸指数明显降低，血清睾酮浓度下降，精子活力受损。从机制上讲，ldl条件增强睾丸氧化应激，表现为NOX4/5上调和HO-1/SOD抑制。这种氧化还原失衡伴随着生殖细胞凋亡激活，表现为Bax/Bcl-2比值升高，cleaved caspase-3表达增加，tunel阳性细胞比例增加。值得注意的是，在动态昼夜节律中断条件下，生殖损伤比在固定的光暗反转条件下更为明显。通过将动态光诱导的昼夜节律中断与睾丸氧化应激和凋亡信号通路联系起来，该研究阐明了现代照明环境损害男性生育能力的潜在机制，并为昼夜节律干预和环境缓解提供了策略。

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引用次数: 0

The roles of extrachromosomal DNA in tumorigenesis and therapeutic resistance in cancer 染色体外DNA在肿瘤发生和肿瘤耐药中的作用。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-24 DOI: 10.1016/j.lfs.2026.124223

Yidan Zhang , Jiale Li , Hongbin Wang , Chang Xu , Qiang Liu

Extrachromosomal DNA (ecDNA) is a form of circular DNA that exists independently of chromosomes. Predominantly observed in tumor cells, ecDNA represents a key manifestation of genomic instability in cancer. In contrast to chromosomal DNA, ecDNA has a circular structure, often includes intact or fragmented gene sequences, and exhibits high copy number variation. Recent studies have shown that oncogene amplification on ecDNA is prevalent in many cancer types. This illustrates the significance of its role in the development and progression of cancer. Furthermore, ecDNA can induce drug resistance and adversely affect patient prognosis via various mechanisms, demonstrating considerable biological and potential therapeutic significance in preclinical investigations. This review outlines the key characteristics of ecDNA, analyzes its role in carcinogenesis and drug resistance, and evaluates current detection methods, aiming to explore its potential as a therapeutic target in cancer treatment.

染色体外DNA （ecDNA）是一种独立于染色体存在的环状DNA。主要在肿瘤细胞中观察到，ecDNA代表了癌症基因组不稳定的关键表现。与染色体DNA相比，ecDNA具有环状结构，通常包括完整或片段化的基因序列，并表现出高拷贝数变异。最近的研究表明，在许多癌症类型中，ecDNA上的致癌基因扩增是普遍存在的。这说明了它在癌症发生和发展中的重要作用。此外，ecDNA可以通过多种机制诱导耐药并对患者预后产生不利影响，在临床前研究中显示出相当大的生物学和潜在的治疗意义。本文概述了ecDNA的主要特征，分析了其在肿瘤发生和耐药中的作用，并对现有的检测方法进行了评价，旨在探索其作为癌症治疗靶点的潜力。

引用次数: 0

Reversible ubiquitination regulates HSF1 phase separation in response to proteotoxic stress 可逆泛素化调节HSF1相分离响应蛋白毒性应激。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-22 DOI: 10.1016/j.lfs.2026.124224

Yue Zhu , Jianhua Wang , Shuhong Tang , Zhiqiang Li , Ruilin Wang , Peng Wang , Jiayu Li , Shaoxuan Cheng , Han Liu , Yingqiu Zhang , Zhaoxia Dai , Qitao Yan , Shuyan Liu

Aims

Heat shock factor 1 (HSF1) undergoes phase separation to form nuclear condensates in response to proteotoxic stress, which governs cell fate. Protein ubiquitination is a widely existed post-translational modification and closely participated in liquid-liquid phase separation. However, the exact roles of ubiquitination in HSF1 condensation remain obscure. Here, we aimed to investigate the regulation of HSF1 phase separation by ubiquitination in cells under proteotoxic conditions.

Materials and methods

Endogenous and exogenous HSF1 condensate formation was detected by immunofluorescence assays. HSF1 phase separation properties were analyzed by fluorescence recovery after photobleaching (FRAP) analysis. Western blotting, immunofluorescence, immunoprecipitation and co-transfection assays were performed to identify E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) regulating HSF1 phase separation. The influence of ubiquitination sites on HSF1 phase separation was investigated by site-directed mutagenesis.

Key findings

Proteasome inhibitor PS341 induced HSF1 to form nuclear phase-separated condensates in a time-dependent manner. E3 ubiquitin ligase STUB1 promoted the phase separation of HSF1 by enhancing HSF1 ubiquitination, while DUBs USP13 and ATXN3 negatively regulated HSF1 condensation. Mutations of all nine ubiquitination sites within HSF1 dramatically inhibited condensate formation, with single-site mutations also showing significantly attenuated phase separation.

Significance

Ubiquitination at multiple lysine residues jointly drives HSF1 phase separation in cells exposed to proteotoxic stress, which is coordinately regulated by E3 ubiquitin ligase STUB1 and DUBs including USP13 and ATXN3.

目的：热休克因子1 （HSF1）在蛋白毒性应激下发生相分离形成核凝析物，控制细胞命运。蛋白质泛素化是一种广泛存在的翻译后修饰，与液-液相分离密切相关。然而，泛素化在HSF1缩聚中的确切作用仍然不清楚。在此，我们旨在研究蛋白毒性条件下细胞中泛素化对HSF1相分离的调控。材料和方法：采用免疫荧光法检测内源性和外源性HSF1凝结物的形成。采用光漂白后荧光恢复法（FRAP）分析HSF1的相分离特性。采用Western blotting、免疫荧光、免疫沉淀和共转染等方法鉴定E3泛素连接酶和去泛素化酶（DUBs）对HSF1相分离的调节作用。通过位点定向诱变研究了泛素化位点对HSF1相分离的影响。主要发现：蛋白酶体抑制剂PS341诱导HSF1以时间依赖性的方式形成核相分离凝析物。E3泛素连接酶STUB1通过增强HSF1泛素化促进HSF1相分离，而DUBs USP13和ATXN3负调控HSF1缩聚。HSF1中所有9个泛素化位点的突变显著抑制凝析物的形成，单位点突变也显著减弱相分离。意义：多赖氨酸残基泛素化共同驱动蛋白毒性应激细胞HSF1相分离，这一过程由E3泛素连接酶STUB1和DUBs（包括USP13和ATXN3）协同调控。

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引用次数: 0

Targeting the lysine methyltransferase Suv39h1 in cardiac fibroblasts attenuates post-infarct myocardial fibrosis 靶向心肌成纤维细胞中的赖氨酸甲基转移酶Suv39h1可减轻梗死后心肌纤维化。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-22 DOI: 10.1016/j.lfs.2026.124221

Shuai Liu , Xiaoping Wu , Yujia Xue , Mengwen Qi , Tianfa Li , Yuanyuan Zhang , Mingming Fang

Aims

Adverse ventricular remodeling following myocardial infarction contributes to heart failure. Following cardiac injury, quiescent fibroblasts trans-differentiate into myofibroblasts and produce extracellular matrix proteins to initiate ventricular remodeling. We investigated the role of Suv39h1, a lysine methyltransferase, in this process.

Methods

Myocardial infarction was induced by permanent ligation of the left anterior descending (LAD) coronary artery.

Results

Suv39h1 expression was up-regulated in cardiac fibroblasts isolated from mice subjected to the LAD procedure compared to the sham procedure mirroring the induction of Periostin, a myofibroblast marker. Reporter assay and chromatin immunoprecipitation (ChIP) assay showed that C/EBPβ was recruited to the Suv39h1 promoter to mediate Suv39h1 trans-activation by pro-fibrogenic stimuli in fibroblasts. Genetic deletion of Suv39h1 from either quiescent fibroblasts or activated fibroblasts (myofibroblasts) in mice attenuated cardiac fibrosis and rescued the decline of heart function following myocardial infarction. Importantly, administration of a small-molecule Suv39h1 inhibitor F5446 ameliorated cardiac fibrosis and partially normalized heart function in mice following myocardial infarction. RNA-seq identified several potential Suv39h1 targets that might contribute to fibroblast-myofibroblast transition.

Significance

In conclusion, our data demonstrate that Suv39h1 might play an important role regulating ventricular remodeling in ischemic cardiomyopathy.

目的：心肌梗死后不良心室重构可导致心力衰竭。心脏损伤后，静止的成纤维细胞向肌成纤维细胞分化，产生细胞外基质蛋白，启动心室重构。我们研究了赖氨酸甲基转移酶Suv39h1在这一过程中的作用。方法：采用冠状动脉左前降支永久性结扎术诱导心肌梗死。结果：与肌成纤维细胞标志物Periostin的诱导相比，经LAD手术分离的小鼠心脏成纤维细胞中Suv39h1的表达上调。报告基因实验和染色质免疫沉淀（ChIP）实验表明，C/EBPβ被募集到Suv39h1启动子上，介导成纤维细胞中促纤维化刺激对Suv39h1反式激活。从小鼠静止的成纤维细胞或活化的成纤维细胞（肌成纤维细胞）中删除Suv39h1基因可减轻心肌纤维化并挽救心肌梗死后心功能的下降。重要的是，小分子Suv39h1抑制剂F5446改善了心肌梗死后小鼠的心脏纤维化和部分正常化的心脏功能。RNA-seq鉴定了几个潜在的Suv39h1靶点，这些靶点可能有助于成纤维细胞向肌成纤维细胞的转变。意义：综上所述，我们的数据表明Suv39h1可能在缺血性心肌病中发挥重要的调节心室重构的作用。

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引用次数: 0

Aerobic exercise stabilizes atherosclerotic plaques by suppressing miR-15a-5p-mediated repression of Semaphorin-3A in vascular smooth muscle cells 有氧运动通过抑制mir -15a-5p介导的血管平滑肌细胞中信号蛋白3a的抑制来稳定动脉粥样硬化斑块

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-22 DOI: 10.1016/j.lfs.2026.124226

Guomin Hu , Weijia Chen , Xiangyuan Zhou , Yueshen Wang , Na Feng , Wei Gao , Haiyi Yu

Aims

Aerobic exercise reduces cardiovascular events in atherosclerosis, but the causal roles of microRNAs (miRNAs) in mediating exercise-induced vascular smooth muscle cell (VSMC) phenotypic switching and plaque stabilization remains unclear. This study investigated whether aerobic exercise stabilizes atherosclerotic plaques by reprogramming VSMC miRNA expression, focusing on the miR-15a-5p/Semaphorin-3A (Sema3A) axis.

Materials and methods

High-fat diet-fed ApoE^−/− mice were assigned to sedentary or 12-week moderate-intensity treadmill exercise. Aortic miRNA profiles were analyzed by small RNA sequencing and integrated with exercise-responsive circulating miRNAs. Plaque burden and vulnerability were evaluated by histology and immunohistochemistry. Molecular mechanisms were validated in vitro and in vivo using luciferase reporter assays, qPCR, Western blotting, and VSMC-specific AAV9-mediated miR-15a-5p overexpression. miR-15a-5p and Sema3A expression were examined in human carotid atherosclerotic plaques.

Key findings

Exercise reduced plaque vulnerability, increased collagen content, reduced lipid content, and attenuated macrophage infiltration. Integrative miRNA profiling revealed that miR-15a-5p was markedly upregulated in atherosclerotic aortas but significantly suppressed by exercise locally and in circulation. In human carotid plaques, miR-15a-5p levels positively correlated with the plaque vulnerability index. Mechanistically, miR-15a-5p directly targeted the 3′-UTR of Sema3A, repressing its expression. VSMC-specific miR-15a-5p overexpression in vivo downregulated contractile markers, accelerated phenotypic switching, and destabilized plaques, such traits resembled those in cells from sedentary mice.

Significance

Aerobic exercise stabilizes plaques by downregulating miR-15a-5p, relieving Sema3A repression and preserving the contractile VSMC phenotype. The miR-15a-5p/Sema3A signaling axis mediates exercise-induced atheroprotection. Notably, elevated miR-15a-5p levels in human carotid plaques correlate positively with plaque vulnerability, supporting its potential as an atherosclerotic therapeutic target.

有氧运动可减少动脉粥样硬化中的心血管事件，但microrna （mirna）在介导运动诱导的血管平滑肌细胞（VSMC）表型转换和斑块稳定中的因果作用尚不清楚。本研究研究了有氧运动是否通过重编程VSMC miRNA表达来稳定动脉粥样硬化斑块，重点关注miR-15a-5p/ Sema3A （Sema3A）轴。材料和方法高脂肪饮食喂养的ApoE - / -小鼠被分配为久坐或12周的中等强度跑步机运动。通过小RNA测序分析主动脉miRNA谱，并与运动反应性循环miRNA相结合。通过组织学和免疫组织化学评估斑块负担和易损性。通过荧光素酶报告基因检测、qPCR、Western blotting和vsmc特异性aav9介导的miR-15a-5p过表达，验证了体外和体内的分子机制。检测miR-15a-5p和Sema3A在人颈动脉粥样硬化斑块中的表达。主要发现：运动降低斑块易损性，增加胶原蛋白含量，降低脂质含量，并减弱巨噬细胞浸润。综合miRNA分析显示，miR-15a-5p在动脉粥样硬化主动脉中显着上调，但在局部和循环中被运动显著抑制。在人颈动脉斑块中，miR-15a-5p水平与斑块易损指数呈正相关。在机制上，miR-15a-5p直接靶向Sema3A的3 ' -UTR，抑制其表达。体内vsmc特异性miR-15a-5p过表达下调收缩标记物，加速表型转换和破坏斑块，这些特征与久坐小鼠细胞中的特征相似。有氧运动通过下调miR-15a-5p、缓解Sema3A抑制和保持收缩性VSMC表型来稳定斑块。miR-15a-5p/Sema3A信号轴介导运动诱导的动脉粥样硬化保护。值得注意的是，人颈动脉斑块中miR-15a-5p水平升高与斑块易感性呈正相关，支持其作为动脉粥样硬化治疗靶点的潜力。

{"title":"Aerobic exercise stabilizes atherosclerotic plaques by suppressing miR-15a-5p-mediated repression of Semaphorin-3A in vascular smooth muscle cells","authors":"Guomin Hu , Weijia Chen , Xiangyuan Zhou , Yueshen Wang , Na Feng , Wei Gao , Haiyi Yu","doi":"10.1016/j.lfs.2026.124226","DOIUrl":"10.1016/j.lfs.2026.124226","url":null,"abstract":"<div><h3>Aims</h3><div>Aerobic exercise reduces cardiovascular events in atherosclerosis, but the causal roles of microRNAs (miRNAs) in mediating exercise-induced vascular smooth muscle cell (VSMC) phenotypic switching and plaque stabilization remains unclear. This study investigated whether aerobic exercise stabilizes atherosclerotic plaques by reprogramming VSMC miRNA expression, focusing on the miR-15a-5p/Semaphorin-3A (Sema3A) axis.</div></div><div><h3>Materials and methods</h3><div>High-fat diet-fed <em>ApoE</em><sup><em>−/−</em></sup> mice were assigned to sedentary or 12-week moderate-intensity treadmill exercise. Aortic miRNA profiles were analyzed by small RNA sequencing and integrated with exercise-responsive circulating miRNAs. Plaque burden and vulnerability were evaluated by histology and immunohistochemistry. Molecular mechanisms were validated in vitro and in vivo using luciferase reporter assays, qPCR, Western blotting, and VSMC-specific AAV9-mediated miR-15a-5p overexpression. miR-15a-5p and Sema3A expression were examined in human carotid atherosclerotic plaques.</div></div><div><h3>Key findings</h3><div>Exercise reduced plaque vulnerability, increased collagen content, reduced lipid content, and attenuated macrophage infiltration. Integrative miRNA profiling revealed that miR-15a-5p was markedly upregulated in atherosclerotic aortas but significantly suppressed by exercise locally and in circulation. In human carotid plaques, miR-15a-5p levels positively correlated with the plaque vulnerability index. Mechanistically, miR-15a-5p directly targeted the 3′-UTR of Sema3A, repressing its expression. VSMC-specific miR-15a-5p overexpression in vivo downregulated contractile markers, accelerated phenotypic switching, and destabilized plaques, such traits resembled those in cells from sedentary mice.</div></div><div><h3>Significance</h3><div>Aerobic exercise stabilizes plaques by downregulating miR-15a-5p, relieving Sema3A repression and preserving the contractile VSMC phenotype. The miR-15a-5p/Sema3A signaling axis mediates exercise-induced atheroprotection. Notably, elevated miR-15a-5p levels in human carotid plaques correlate positively with plaque vulnerability, supporting its potential as an atherosclerotic therapeutic target.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124226"},"PeriodicalIF":5.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of miR-338-3p and miR-378a-3p as regulators in Crohn's disease pathogenesis: Potential therapeutic implications in inflammatory bowel disease miR-338-3p和miR-378a-3p作为调节因子在克罗恩病发病机制中的作用：炎症性肠病的潜在治疗意义

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-21 DOI: 10.1016/j.lfs.2026.124217

Ki-Uk Kim , Jung Min Moon , Eunsu Lim , Kang-Bin Dan , Jeongkuk Seo , Kyuwon Kim , Seung Yong Shin , Hyeyoung Min , Chang Hwan Choi

Aims

Epithelial cell-derived microRNAs (miRNAs) are increasingly recognized as contributors to inflammatory bowel disease (IBD) through altered epithelial permeability and inflammatory cytokine production. This prospective study compared epithelial miRNA expression in Crohn's disease (CD) patients and healthy controls, and investigated their immunoregulatory role in experimental IBD models

Materials and methods

Terminal ileum samples were collected via ileocolonoscopy from healthy controls and CD patients (remission and active state). Small-RNA sequencing identified unique miRNA profiles, including miR-338-3p and miR-378a-3p, validated by qRT-PCR. In dextran sodium sulfate-induced colitis mice, mimics were administered, and disease severity, gene expression, and immune cell infiltration were assessed by clinical, histological, and molecular assays

Key findings

miR-338-3p/miR-378a-3p mimics reduced disease activity scores, attenuated colon shortening, and decreased Th17 cell infiltration in colonic tissues. Histological and immunohistochemical analyses confirmed improved tissue integrity and reduced macrophage/T-cell infiltration in the colon. Mechanistically, miR-338-3p targeted MACC1, while miR-378a-3p suppressed IL33, a proinflammatory cytokine linked to CD pathogenesis.

Significance

The results underscore the distinct features of miR-338-3p and miR-378a-3p in CD mucosa and suggest their therapeutic potential for modulating immune responses in CD

目的：上皮细胞来源的microRNAs （miRNAs）越来越多地被认为是炎症性肠病（IBD）的贡献者，通过改变上皮通透性和炎症细胞因子的产生。这项前瞻性研究比较了克罗恩病（CD）患者和健康对照者上皮miRNA的表达，并研究了它们在实验性IBD模型中的免疫调节作用材料和方法：通过回肠结肠镜检查从健康对照者和CD患者（缓解状态和活跃状态）收集回肠末样本。经qRT-PCR验证，小rna测序鉴定出独特的miRNA谱，包括miR-338-3p和miR-378a-3p。在葡聚糖硫酸钠诱导的结肠炎小鼠中，给予模拟物，通过临床、组织学和分子分析评估疾病严重程度、基因表达和免疫细胞浸润。关键发现：miR-338-3p/miR-378a-3p模拟物降低了疾病活度评分，减轻了结肠缩短，减少了结肠组织中的Th17细胞浸润。组织学和免疫组织化学分析证实，结肠组织完整性改善，巨噬细胞/ t细胞浸润减少。在机制上，miR-338-3p靶向MACC1，而miR-378a-3p抑制与CD发病相关的促炎细胞因子IL33。意义：这些结果强调了miR-338-3p和miR-378a-3p在CD粘膜中的独特特征，并提示它们在调节CD免疫反应方面的治疗潜力。

{"title":"Role of miR-338-3p and miR-378a-3p as regulators in Crohn's disease pathogenesis: Potential therapeutic implications in inflammatory bowel disease","authors":"Ki-Uk Kim , Jung Min Moon , Eunsu Lim , Kang-Bin Dan , Jeongkuk Seo , Kyuwon Kim , Seung Yong Shin , Hyeyoung Min , Chang Hwan Choi","doi":"10.1016/j.lfs.2026.124217","DOIUrl":"10.1016/j.lfs.2026.124217","url":null,"abstract":"<div><h3>Aims</h3><div>Epithelial cell-derived microRNAs (miRNAs) are increasingly recognized as contributors to inflammatory bowel disease (IBD) through altered epithelial permeability and inflammatory cytokine production. This prospective study compared epithelial miRNA expression in Crohn's disease (CD) patients and healthy controls, and investigated their immunoregulatory role in experimental IBD models</div></div><div><h3>Materials and methods</h3><div>Terminal ileum samples were collected via ileocolonoscopy from healthy controls and CD patients (remission and active state). Small-RNA sequencing identified unique miRNA profiles, including miR-338-3p and miR-378a-3p, validated by qRT-PCR. In dextran sodium sulfate-induced colitis mice, mimics were administered, and disease severity, gene expression, and immune cell infiltration were assessed by clinical, histological, and molecular assays</div></div><div><h3>Key findings</h3><div>miR-338-3p/miR-378a-3p mimics reduced disease activity scores, attenuated colon shortening, and decreased Th17 cell infiltration in colonic tissues. Histological and immunohistochemical analyses confirmed improved tissue integrity and reduced macrophage/T-cell infiltration in the colon. Mechanistically, miR-338-3p targeted <em>MACC1</em>, while miR-378a-3p suppressed <em>IL33</em>, a proinflammatory cytokine linked to CD pathogenesis.</div></div><div><h3>Significance</h3><div>The results underscore the distinct features of miR-338-3p and miR-378a-3p in CD mucosa and suggest their therapeutic potential for modulating immune responses in CD</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124217"},"PeriodicalIF":5.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Amniotic fluid stem cell-derived extracellular vesicles enhance functional recovery of neurogenic bladder and neurovascular plasticity after cerebral ischemia in rats 羊水干细胞源性细胞外囊泡促进脑缺血大鼠神经源性膀胱功能恢复和神经血管可塑性

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-21 DOI: 10.1016/j.lfs.2026.124225

Ching-Chung Liang , Steven W. Shaw , Hsien-Ming Wu , Yi-Haou Lin , Tzu-Hsiang Hsieh , Yung-Hsin Huang , Tsong-Hai Lee

Background

Post-stroke neurogenic bladder dysfunction impairs patients' quality of life, yet current treatments offer limited effectiveness. This study investigated the therapeutic effects and underlying mechanisms of human amniotic fluid stem cell-derived extracellular vesicle (hAFSC-EV) on bladder dysfunction and neurovascular plasticity after cerebral ischemia.

Methods

Thirty-six female rats underwent bilateral ovariectomy and were assigned to sham-operated or 90-min middle cerebral artery occlusion (MCAO) groups, with or without a single injection of hAFSC-EVs. Magnetic resonance imaging (MRI), cystometry, blood-brain barrier (BBB) permeability, and markers of neurogenesis and angiogenesis in ischemic brain were assessed. Bladder levels of brain-derived neurotrophic factor (BDNF), β3-adrenoceptor, adenylate cyclase, and M2- and M3-muscarinic receptors were evaluated at 7 and 28 days post-MCAO or sham-operation.

Results

Compared with untreated rats, hAFSC-EV treatment significantly reduced cerebral infarct volume and BBB leakage, and enhanced microvessel and vascular density, along with angiogenesis. Neural markers such as BDNF, nestin, and doublecortin were significantly upregulated at 7 and/or 28 days post-MCAO. hAFSC-EV treatment ameliorated MCAO-induced bladder dysfunction by reducing peak voided volume, intercontraction interval, and bladder capacity, along with improving residual urine volume. hAFSC-EV treatment significantly increased bladder expression of BDNF and M3-muscarinic receptors, and recovers the expressions of M2, β3-adrenoceptor, and adenylate cyclase to near control levels at 7 and 28 days post-MCAO.

Conclusion

hAFSC-EV treatment improves neurogenic bladder dysfunction and cerebral ischemia post-MCAO, potentially through reducing infarct volume and BBB disruption, enhancing neurogenesis and angiogenesis in the ischemic brain, and modulating the expression of bladder BDNF, β3-adrenoceptor, adenylate cyclase and muscarinic receptors.

脑卒中后神经源性膀胱功能障碍会损害患者的生活质量，但目前的治疗效果有限。本研究探讨了人羊水干细胞源性细胞外囊泡（hAFSC-EV）对脑缺血后膀胱功能障碍和神经血管可塑性的治疗作用及其机制。方法36只雌性大鼠行双侧卵巢切除术，分为假手术组和90 min大脑中动脉闭塞组（MCAO），单次注射hafsc - ev或不注射hafsc - ev。评估脑缺血磁共振成像（MRI）、膀胱术、血脑屏障（BBB）通透性、神经新生和血管新生标志物。在mcao或假手术后7天和28天，评估膀胱脑源性神经营养因子（BDNF）、β3-肾上腺素能素、腺苷酸环化酶和M2-和m3 -毒蕈碱受体的水平。结果与未处理大鼠相比，hAFSC-EV处理显著减少脑梗死体积和血脑屏障渗漏，增强微血管和血管密度，促进血管生成。神经标志物如BDNF、巢蛋白和双皮质素在mcao后7天和/或28天显著上调。hAFSC-EV治疗通过减少峰值排尿量、收缩间期和膀胱容量以及改善剩余尿量来改善mcao诱导的膀胱功能障碍。hAFSC-EV治疗可显著提高膀胱BDNF和m3 -毒碱受体的表达，M2、β3-肾上腺素受体和腺苷酸环化酶的表达在mcao后7天和28天恢复到接近对照水平。结论hafsc - ev治疗可改善mcao后神经源性膀胱功能障碍和脑缺血，其机制可能是通过减少梗死面积和血脑屏障破坏，促进缺血脑的神经发生和血管生成，调节膀胱BDNF、β3-肾上腺素受体、腺苷酸环化酶和毒碱受体的表达。

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引用次数: 0

Exogenous hydrogen sulphide alleviates diabetes-associated cognitive decline by inhibiting ferroptosis through Nrf2/GPX4 signalling pathway 外源性硫化氢通过Nrf2/GPX4信号通路抑制铁下垂，减轻糖尿病相关认知能力下降

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-21 DOI: 10.1016/j.lfs.2026.124220

Wei Hua , Yilei Sun , Mingze Sun , Yiying Liu , Hongxue Sun , Huinan Chen , Shuainan Ma

Aims

Neuronal ferroptosis affects the pathogenesis of diabetes-associated cognitive decline (DACD). Exogenous hydrogen sulphide (H₂S) treatment ameliorates cognitive deficits in diabetic mice. This study aimed to explore whether H₂S exerts neuroprotective effects by suppressing ferroptosis through activation of Nrf2/GPX4 signalling pathway.

Materials and methods

STZ-induced diabetic mice received NaHS or NaHS combined with the Nrf2 inhibitor ML385, after which cognitive functions were evaluated using the Morris water maze test. Hippocampal neuronal damage and mitochondrial morphological changes were identified using transmission electron microscopy, haematoxylin and eosin (H&E) staining, Nissl staining, and immunofluorescence staining. The expression levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and iron were determined using assay kits. Western blotting was performed to evaluate the expression of the Nrf2/GPX4 axis, iron transport-related proteins, and GSH synthesis enzymes.

Key findings

Exogenous H₂S treatment ameliorated cognitive deficits by mitigating hippocampal neuronal loss and improving synaptic ultrastructural integrity. The levels of ROS, MDA, and iron were reduced, whereas SOD, GSH, and Nrf2/GPX4 expression were increased following NaHS administration. Exogenous H₂S also ameliorated mitochondrial impairment and suppressed ferroptosis in the hippocampal neurones. However, these neuroprotective effects were abolished by ML385. Diabetic mice cotreated with ML385 and NaHS exhibited prolonged escape latency and reduced time in the target quadrant. Additionally, ML385 co-administration with NaHS exacerbated neuronal damage, oxidative stress, synaptic ultrastructural abnormalities, and iron dysregulation, while downregulating Nrf2/GPX4 expression and inhibiting ferroptosis suppression.

Significance

Exogenous H₂S treatment alleviates DACD by suppressing ferroptosis via activation of the Nrf2/GPX4 signalling pathway.

目的神经元铁下垂影响糖尿病相关认知能力下降（daca）的发病机制。外源性硫化氢（H2S）治疗可改善糖尿病小鼠的认知缺陷。本研究旨在探讨H2S是否通过激活Nrf2/GPX4信号通路抑制铁下沉，从而发挥神经保护作用。材料与方法stz诱导的糖尿病小鼠分别给予NaHS或NaHS联合Nrf2抑制剂ML385治疗后，采用Morris水迷宫实验评估认知功能。采用透射电镜、血红素和伊红（H&；E）染色、尼氏染色和免疫荧光染色检测海马神经元损伤和线粒体形态学改变。采用检测试剂盒检测活性氧（ROS）、丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、铁的表达水平。Western blotting检测Nrf2/GPX4轴、铁转运相关蛋白和谷胱甘肽合成酶的表达。主要发现：同质H2S治疗通过减轻海马神经元丢失和改善突触超微结构完整性来改善认知缺陷。给予NaHS后，ROS、MDA和铁水平降低，SOD、GSH和Nrf2/GPX4表达升高。外源性H2S还可以改善线粒体损伤并抑制海马神经元的铁下垂。然而，这些神经保护作用被ML385所消除。与ML385和NaHS共处理的糖尿病小鼠表现出逃避潜伏期延长和靶象限时间缩短。此外，ML385与NaHS共给药加重了神经元损伤、氧化应激、突触超微结构异常和铁调节异常，同时下调Nrf2/GPX4表达，抑制铁下沉。外源性H2S处理通过激活Nrf2/GPX4信号通路抑制铁下垂来缓解ddad。

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引用次数: 0

LEAP2 acts in hepatocytes and at central level, alleviates steatosis and inflammation but resistance in obese and aging LEAP2在肝细胞和中枢水平起作用，减轻脂肪变性和炎症，但对肥胖和衰老有抵抗作用

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-20 DOI: 10.1016/j.lfs.2026.124219

Marta V. Miguéns , Carmen Quintela-Vilariño , Sabela Casado , Tadeu de Oliveira-Diz , Timo D. Müller , Rubén Nogueiras , Carlos Diéguez , Sulay Tovar

Scope

Global increase in obesity and metabolic syndrome has led to a marked rise in comorbidities, with liver disease emerging as a major concern. Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over 30% of the population, making it the most prevalent liver disorder worldwide. Hepatic steatosis, hallmark of MAFLD, can progress to inflammation, fibrosis, steatohepatitis, and cirrhosis. Despite advances in elucidating its mechanisms, no effective pharmacological therapy exists to reverse disease progression. Ghrelin signaling axis has been implicated in energy and lipid homeostasis, and the recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous ghrelin receptor antagonist and inverse agonist has generated interest in its potential role in liver metabolism. The primary objective of this study was to evaluate LEAP2 on hepatocyte lipid metabolism and determine its capacity to prevent diet- and age-induced steatosis in vivo.

Methods and results

We investigated LEAP2 actions on hepatocyte lipid metabolism using human and mouse hepatocyte cultures, also we did in vivo studies in mice with chronic central LEAP2 administration in models of diet-induced and age-related steatosis.

LEAP2 inhibited lipid accumulation in hepatocytes and reduced hepatic lipid deposition in mice fed a standard diet. However, LEAP2 did not prevent high-fat diet–induced steatosis in young mice although it attenuated hepatic inflammation. In aged animals, LEAP2 failed to suppress age-associated inflammation and steatosis.

Conclusion

LEAP2 has been identified as a novel regulator of hepatic lipid metabolism with the potential to counteract inflammation-associated steatosis, although its effects on age-related steatosis appear limited. Targeting the LEAP2–ghrelin axis may represent a promising therapeutic strategy; however, further studies are required to determine its efficacy in diet-induced hepatic disease.

全球肥胖和代谢综合征的增加导致合并症的显著增加，肝脏疾病成为一个主要问题。代谢功能障碍相关脂肪性肝病（MAFLD）影响超过30%的人口，使其成为世界上最普遍的肝脏疾病。肝脂肪变性是mald的标志，可发展为炎症、纤维化、脂肪性肝炎和肝硬化。尽管在阐明其机制方面取得了进展，但没有有效的药物治疗方法可以逆转疾病的进展。胃饥饿素信号轴与能量和脂质稳态有关，最近肝脏表达的抗菌肽2 （LEAP2）作为内源性胃饥饿素受体拮抗剂和逆激动剂的鉴定引起了人们对其在肝脏代谢中的潜在作用的兴趣。本研究的主要目的是评估LEAP2对肝细胞脂质代谢的影响，并确定其在体内预防饮食和年龄诱导的脂肪变性的能力。方法和结果我们通过人和小鼠肝细胞培养研究了LEAP2对肝细胞脂质代谢的作用，并在饮食诱导和年龄相关脂肪变性模型中对慢性中央给药的小鼠进行了体内研究。LEAP2抑制小鼠肝细胞脂质积累，减少小鼠肝脏脂质沉积。然而，LEAP2虽然减轻了肝脏炎症，但并不能预防年轻小鼠的高脂肪饮食诱导的脂肪变性。在老年动物中，LEAP2未能抑制与年龄相关的炎症和脂肪变性。结论leap2已被确定为一种新的肝脂质代谢调节剂，具有对抗炎症相关脂肪变性的潜力，尽管其对年龄相关脂肪变性的影响有限。靶向LEAP2-ghrelin轴可能是一种很有前途的治疗策略；然而，需要进一步的研究来确定其对饮食性肝病的疗效。

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引用次数: 0

Endostar overcomes Osimertinib-resistance mediated EGFR-activation mutation, T790M and cis-C797S triple mutations via enhancing the binding of Osimertinib to EGFR protein 恩度通过增强奥西替尼与EGFR蛋白的结合，克服了奥西替尼耐药介导的EGFR激活突变、T790M和顺式- c797s三重突变。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-20 DOI: 10.1016/j.lfs.2026.124218

Zhongquan Song , Yanmei Zhu , Surong Fang , Shuhua Han

Aims

The EGFR-C797S mutation is the main cause of Osimertinib resistance. No effective treatment regimen is currently available for patients harboring EGFR-activation mutation/T790M/cis-C797S triple mutations.

Materials and methods

Nine patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activation mutation/T790M/cis-C797S mutation were investigated. After Osimertinib resistance, these patients were treated with Endostar combination with Osimertinib. Network pharmacology and molecular dynamics simulations were used to clarify active sites of Endostar and the effect on protein conformation. In vivo and in vitro, EGFR L858R-T790M-C797S/H1975 cells were used to investigate the efficacy of co-treatment.

Key findings

Two patients achieved partial response (PR), six achieved stable disease (SD) and one had progressive disease (PD) at the 6-month efficacy assessment of co-treatment, resulting in an objective response rate (ORR) of 66.7% and a disease control rate (DCR) of 88.9%. These patients achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 18.5 months, and no patients experienced grade III or IV adverse events. Endostatin, the active ingredient of Endostar, bound EGFR to “pseudo” mediate EGFR signaling pathway, and the introduction of Endostar enhanced the binding of Osimertinib to EGFR L858R/T790M/C797S protein. In vitro and in vivo experiments have found the co-treatment restored sensitivity to Osimertinib. Moreover, the combination therapy significantly inhibited the activation of the EGFR signaling pathway and tumor neovascularization.

Significance

This work demonstrated for the first time that Endostar enhanced the antitumor efficacy of Osimertinib, offering a potential therapeutic approach for patients harboring triple mutations.

目的：EGFR-C797S突变是奥西替尼耐药的主要原因。对于egfr激活突变/T790M/cis-C797S三重突变的患者，目前尚无有效的治疗方案。材料与方法：对9例携带egfr激活突变/T790M/cis-C797S突变的晚期非小细胞肺癌（NSCLC）患者进行研究。在对奥西替尼耐药后，这些患者接受恩度联合奥西替尼治疗。网络药理学和分子动力学模拟阐明了恩度的活性位点及其对蛋白质构象的影响。在体内和体外，采用EGFR L858R-T790M-C797S/H1975细胞研究共处理的效果。主要发现：联合治疗6个月疗效评估时，2例患者部分缓解（PR）， 6例患者病情稳定（SD）， 1例患者病情进展（PD），客观缓解率（ORR）为66.7%，疾病控制率（DCR）为88.9%。这些患者的中位无进展生存期（PFS）为8.9 个月，中位总生存期（OS）为18.5 个月，没有患者发生III级或IV级不良事件。恩度的活性成分内皮抑素与EGFR结合，“伪”介导EGFR信号通路，恩度的引入增强了奥西替尼与EGFR L858R/T790M/C797S蛋白的结合。体外和体内实验发现，联合治疗恢复了对奥西替尼的敏感性。此外，联合治疗可显著抑制EGFR信号通路的激活和肿瘤新生血管的形成。意义：本工作首次证明恩度可增强奥西替尼的抗肿瘤疗效，为三突变患者提供了一种潜在的治疗途径。

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引用次数: 0