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The role and mechanism of fatty acid-binding protein 7 in spinal reactive astrocytes in prolonged postoperative pain induced by high-fat diet 脊髓反应性星形胶质细胞中脂肪酸结合蛋白7在高脂饮食术后延长疼痛中的作用及机制
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-26 DOI: 10.1016/j.yexcr.2025.114801
Han Zheng , Xiao Zhang , Mei Li , Yu Wang , Shufen Guo , Ming Jiang , Rui Xu , Yulin Huang , Zhengliang Ma
Obesity markedly exacerbates nociceptive sensitivity and substantially compromises the quality of life of affected people. Astrocytes orchestrate metabolic regulation and homeostatic maintenance in the central nervous system. Notably, fatty acid binding protein 7 (FABP7) is highly expressed in astrocytes that governs intracellular fatty acid uptake and transport. While systemic hyperlipidemia is pathognomonic of obesity, the mechanistic contribution of FABP7 in astrocytes to obesity-associated pain pathophysiology remains poorly characterized. The present study established a model of high-fat diet (HFD)-induced obesity combined with a standardized hind paw surgical incision paradigm, aiming to unveil the role of astrocytic FABP7 in HFD-induced chronic pain. Furthermore, an in vitro high-fat environment was induced by palmitic acid (PA),aiming to investigate the molecular mechanisms by which primary astrocytes were activated into the A1 phenotype to mediate neuroinflammation. FABP7 was overexpressed in the spinal dorsal of HFD mice. The activation of A1-type astrocytes and neuroinflammation cascades involving elevated iNOS eventually resulted in mechanical allodynia in HFD mice. Pharmacological inhibition of FABP7 via an intraperitoneal administration of SBFI-26 (20 mg/kg) significantly attenuated the paw withdrawal mechanical threshold and inhibited the A1-type astrocytes activation. PA-induced high-fat conditions promoted lipid droplet accumulation and upregulated FABP7 in astrocytes. Pharmacological inhibition of FABP7 using SBFI-26 (100 μmol/L) significantly suppressed the neurotoxic C3-positive A1 astrocyte phenotype, reduced intracellular lipid droplet accumulation, thereby inhibiting the activation of A1-type astrocytes and alleviating neuroinflammation. Overall, FABP7-mediated astrocytic reprogramming was a critical nexus bridging obesity with chronic pain. A1-astrocyte polarization initiated neuroinflammatory amplification, forming a feedforward loop perpetuating central sensitization. Our findings are expected to offer a viable target for metabolic pain management.
肥胖显著加剧了伤害敏感性,严重损害了患者的生活质量。星形胶质细胞在中枢神经系统中协调代谢调节和稳态维持。值得注意的是,脂肪酸结合蛋白7 (FABP7)在星形胶质细胞中高度表达,控制细胞内脂肪酸的摄取和运输。虽然全身性高脂血症是肥胖的病理特征,但星形胶质细胞中FABP7对肥胖相关疼痛病理生理的机制贡献仍不清楚。本研究建立高脂饮食(high-fat diet, HFD)诱导的肥胖模型,结合标准的后爪手术切口模式,旨在揭示星形胶质细胞FABP7在高脂饮食(high-fat diet, HFD)诱导的慢性疼痛中的作用。此外,我们采用棕榈酸(PA)诱导体外高脂环境,旨在探讨原代星形胶质细胞被激活为A1表型介导神经炎症的分子机制。FABP7在HFD小鼠脊髓背侧过表达。a1型星形胶质细胞的激活和涉及iNOS升高的神经炎症级联反应最终导致HFD小鼠的机械异常性疼痛。通过腹腔注射SBFI-26 (20 mg/kg)对FABP7进行药理抑制,可显著降低足跖退缩机械阈值,抑制a1型星形胶质细胞的激活。pa诱导的高脂状态促进了星形胶质细胞中脂滴的积累和FABP7的上调。SBFI-26 (100 μmol/L)药理抑制FABP7可显著抑制神经毒性c3阳性A1星形胶质细胞表型,减少细胞内脂滴积累,从而抑制A1型星形胶质细胞的活化,减轻神经炎症。总之,fabp7介导的星形细胞重编程是连接肥胖与慢性疼痛的关键纽带。a1 -星形胶质细胞极化引发神经炎症放大,形成一个前馈循环,使中枢致敏持续存在。我们的发现有望为代谢性疼痛管理提供一个可行的目标。
{"title":"The role and mechanism of fatty acid-binding protein 7 in spinal reactive astrocytes in prolonged postoperative pain induced by high-fat diet","authors":"Han Zheng ,&nbsp;Xiao Zhang ,&nbsp;Mei Li ,&nbsp;Yu Wang ,&nbsp;Shufen Guo ,&nbsp;Ming Jiang ,&nbsp;Rui Xu ,&nbsp;Yulin Huang ,&nbsp;Zhengliang Ma","doi":"10.1016/j.yexcr.2025.114801","DOIUrl":"10.1016/j.yexcr.2025.114801","url":null,"abstract":"<div><div>Obesity markedly exacerbates nociceptive sensitivity and substantially compromises the quality of life of affected people. Astrocytes orchestrate metabolic regulation and homeostatic maintenance in the central nervous system. Notably, fatty acid binding protein 7 (FABP7) is highly expressed in astrocytes that governs intracellular fatty acid uptake and transport. While systemic hyperlipidemia is pathognomonic of obesity, the mechanistic contribution of FABP7 in astrocytes to obesity-associated pain pathophysiology remains poorly characterized. The present study established a model of high-fat diet (HFD)-induced obesity combined with a standardized hind paw surgical incision paradigm, aiming to unveil the role of astrocytic FABP7 in HFD-induced chronic pain. Furthermore, an <em>in vitro</em> high-fat environment was induced by palmitic acid (PA),aiming to investigate the molecular mechanisms by which primary astrocytes were activated into the A1 phenotype to mediate neuroinflammation. FABP7 was overexpressed in the spinal dorsal of HFD mice. The activation of A1-type astrocytes and neuroinflammation cascades involving elevated iNOS eventually resulted in mechanical allodynia in HFD mice. Pharmacological inhibition of FABP7 <em>via</em> an intraperitoneal administration of SBFI-26 (20 mg/kg) significantly attenuated the paw withdrawal mechanical threshold and inhibited the A1-type astrocytes activation. PA-induced high-fat conditions promoted lipid droplet accumulation and upregulated FABP7 in astrocytes. Pharmacological inhibition of FABP7 using SBFI-26 (100 μmol/L) significantly suppressed the neurotoxic C3-positive A1 astrocyte phenotype, reduced intracellular lipid droplet accumulation, thereby inhibiting the activation of A1-type astrocytes and alleviating neuroinflammation. Overall, FABP7-mediated astrocytic reprogramming was a critical nexus bridging obesity with chronic pain. A1-astrocyte polarization initiated neuroinflammatory amplification, forming a feedforward loop perpetuating central sensitization. Our findings are expected to offer a viable target for metabolic pain management.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 2","pages":"Article 114801"},"PeriodicalIF":3.5,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145388196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effects of everolimus on circadian gene expression and cell fate in synchronized Caco-2 cells 依维莫司对同步Caco-2细胞昼夜节律基因表达和细胞命运的影响
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-25 DOI: 10.1016/j.yexcr.2025.114810
Dilek Ozturk Civelek , Beyza Goncu , Sadullah Goncu , Alper Okyar

Objectives

Circadian rhythms regulate key biological processes, including cell proliferation and metabolism, and their disruption is implicated in colorectal cancer (CRC). mTOR signaling interacts bidirectionally with the circadian clock, yet how mTOR inhibition modulates clock gene dynamics and cellular behavior in intestinal models remains unclear. This study aimed to investigate the effects of everolimus, an mTOR inhibitor, on circadian gene expression, cell viability, apoptosis, and cell cycle progression in synchronized Caco-2 cells, with consideration of cell confluency and Circadian Time (CT).

Methods

Caco-2 cells were synchronized using serum shock at 20 % and 70 % confluency. Time-series samples were collected across multiple CTs (CT6–CT60). Gene expression (BMAL1, PER2, mTOR) was assessed by qRT-PCR using ACTB and RPLP0 as reference genes. Rhythmicity was evaluated via Cosinor analysis. Cell viability, apoptosis, and cell cycle dynamics were analyzed using the Muse™ Cell Analyzer following everolimus treatment (1–50 μM).

Results

RPLP0 proved to be a more stable reference gene than ACTB. BMAL1 exhibited stronger rhythmic expression than PER2, particularly at 20 % confluency. Everolimus (50 μM) significantly reduced cell viability in a time-dependent manner, with the greatest effect at CT6 and CT18 (p < 0.0001). Apoptosis was markedly increased at CT6 (+38.5 %) and moderate at CT18, indicating circadian modulation of drug sensitivity. Serum shock alone shifted cell cycle distribution, decreasing G0/G1 and increasing G2/M phase populations (p < 0.01). Everolimus altered BMAL1 and PER2 expression rhythms and significantly reduced mTOR expression at CT30, where baseline mTOR levels were highest. Cosinor analysis confirmed rhythmicity in BMAL1/RPLP0 and mTOR/RPLP0 profiles under low confluency.

Conclusion

Our findings demonstrate that everolimus influences circadian gene expression and exerts time-dependent antiproliferative and pro-apoptotic effects in Caco-2 cells. These results support the potential of circadian timing as a strategy to enhance mTOR-targeted therapies in CRC.
昼夜节律调节关键的生物过程,包括细胞增殖和代谢,其破坏与结直肠癌(CRC)有关。mTOR信号与生物钟双向相互作用,但在肠道模型中,mTOR抑制如何调节生物钟基因动力学和细胞行为尚不清楚。本研究旨在探讨everolimus(一种mTOR抑制剂)对同步Caco-2细胞的昼夜节律基因表达、细胞活力、凋亡和细胞周期进展的影响,并考虑细胞融合度和昼夜节律时间(CT)。方法采用血清震荡法对scaco -2细胞在20%和70%的融合度下进行同步。在多个ct (CT6-CT60)中收集时间序列样本。以ACTB和RPLP0为内参基因,采用qRT-PCR法检测BMAL1、PER2、mTOR基因的表达。通过余弦分析评估节律性。依维莫司处理(1-50 μM)后,使用Muse™细胞分析仪分析细胞活力、凋亡和细胞周期动力学。结果rplp0是比ACTB更稳定的内参基因。BMAL1表现出比PER2更强的节奏性表达,特别是在20%的流畅性时。依维莫司(50 μM)以时间依赖性的方式显著降低细胞活力,在CT6和CT18时效果最大(p < 0.0001)。CT6时细胞凋亡明显增加(+ 38.5%),CT18时细胞凋亡减少,表明药物敏感性有昼夜调节。血清休克可改变细胞周期分布,降低G0/G1期,增加G2/M期细胞数量(p < 0.01)。依维莫司改变了BMAL1和PER2的表达节律,并显著降低了CT30时mTOR的表达,而CT30时mTOR的基线水平最高。余弦分析证实低合流状态下BMAL1/RPLP0和mTOR/RPLP0谱存在节律性。结论依维莫司影响Caco-2细胞的昼夜节律基因表达,并具有时间依赖性的抗增殖和促凋亡作用。这些结果支持了昼夜节律定时作为一种增强mtor靶向治疗CRC的策略的潜力。
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引用次数: 0
EIF4A3-mediated localization of circDNAJC16 sequesters miR-93-5p to suppress lung adenocarcinoma progression via CDKN1A-regulated cell cycle and EMT eif4a3介导的circDNAJC16的定位分离miR-93-5p,通过cdkn1a调节的细胞周期和EMT抑制肺腺癌的进展。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-24 DOI: 10.1016/j.yexcr.2025.114799
Liu Yang , Yaodong Fan , Yiyin Wang , Chuntao Yan , Zheng Guan , Yuan Li , Xiaosan Su , Xiaowei Huang
Lung adenocarcinoma (LUAD), the predominant non-small cell lung cancer subtype, exhibits high mortality due to metastasis and therapeutic resistance. While circular RNAs (circRNAs) are implicated in oncogenesis, their functional mechanisms and upstream regulation in LUAD remain incompletely characterized. This study identifies circDNAJC16 (hsa_circ_0000018) as significantly downregulated in advanced-stage LUAD (Stage III-IV vs. I-II, p = 0.001), where its low expression independently predicts poor survival (HR = 1.93, p = 0.043). Functional characterization demonstrates that circDNAJC16 overexpression suppresses in vivo tumor growth (volume reduction: 26.56 %, p < 0.001) through cytoplasmic sequestration of oncogenic miR-93-5p, thereby activating CDKN1A/p21 to induce G0/G1 cell cycle arrest and inhibit proliferation, while concurrently suppressing metastasis via epithelial-mesenchymal transition (EMT) regulation. Crucially, the RNA-binding protein eIF4A3 binds upstream flanking introns of the host DNAJC16 pre-mRNA, driving selective nuclear retention of circDNAJC16 and redirecting linear DNAJC16 mRNA to the cytoplasm – a bifurcation mechanism essential for tumor suppression. These findings identify circDNAJC16 downregulation as a negative prognostic indicator in LUAD and reveal its dual tumor-suppressive roles: cytoplasmic sequestration of miR-93-5p activating CDKN1A-mediated cell cycle arrest, coupled with eIF4A3-governed nuclear retention controlling functional subcellular localization. Significantly, this work is the first to demonstrate eIF4A3-mediated circRNA compartmentalization, establishing circDNAJC16 as a novel prognostic biomarker and therapeutic target for LUAD.
肺腺癌(LUAD)是主要的非小细胞肺癌亚型,由于转移和治疗抵抗而具有很高的死亡率。虽然环状rna (circRNAs)与肿瘤发生有关,但它们在LUAD中的功能机制和上游调控仍不完全清楚。本研究发现circDNAJC16 (hsa_circ_0000018)在晚期LUAD中显著下调(III-IV期vs. I-II期,p = 0.001),其低表达独立预测较差的生存率(HR = 1.93, p = 0.043)。功能表征表明,circDNAJC16过表达通过细胞质隔离致癌的miR-93-5p抑制体内肿瘤生长(体积减少26.56%,p < 0.001),从而激活CDKN1A/p21诱导G0/G1细胞周期阻滞和抑制增殖,同时通过上皮-间质转化(EMT)调节抑制肿瘤转移。至关重要的是,rna结合蛋白eIF4A3结合宿主DNAJC16前mRNA的上游侧翼内含子,驱动circDNAJC16的选择性核保留,并将线性DNAJC16 mRNA重定向到细胞质-这是肿瘤抑制所必需的分岔机制。这些发现确定circDNAJC16下调是LUAD的一个阴性预后指标,并揭示了其双重肿瘤抑制作用:细胞质隔离miR-93-5p激活cdkn1a介导的细胞周期阻滞,加上eif4a3控制的核保留控制功能亚细胞定位。值得注意的是,这项工作首次证明了eif4a3介导的circRNA区域化,建立了circDNAJC16作为LUAD的新型预后生物标志物和治疗靶点。
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引用次数: 0
A tRNA-derived fragment tiRNA-Met-CAT-002 induced by myocardial ischemia/reperfusion injury inhibits cardiomyocyte autophagy by regulating Bnip3 心肌缺血/再灌注损伤诱导的trna衍生片段tiRNA-Met-CAT-002通过调节Bnip3抑制心肌细胞自噬
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-22 DOI: 10.1016/j.yexcr.2025.114809
Lang Deng , Yawen Weng , Jiahui Lin , Lingfeng Zhong , Zhixuan Tang , Shuang Lin , Weijian Huang , Zhenfeng Cheng , Kongjie Lu , Bozhi Ye
Myocardial ischemia/reperfusion (I/R) injury is a significant contributor to the development of heart failure. This study investigates the differential expression of tRNA-derived small RNAs (tsRNAs) during I/R and explores their potential functional implications. Through tRF & tiRNA sequencing, we identified 115 tsRNAs exhibiting significant changes in expression following I/R. Notably, tiRNA-Met-CAT-002 was found to be upregulated via the hypoxia/hypoxia-inducible factor 1 subunit α (HIF1α)/angiogenin (ANG) signaling axis. Our findings suggest that Bnip3 represents a crucial target for tiRNA-Met-CAT-002. Mechanistically, mimics of tiRNA-Met-CAT-002 reduced Bnip3 protein expression by directly targeting the 3′ untranslated region (UTR) of its mRNA in a manner resembling microRNA activity. Furthermore, tiRNA-Met-CAT-002 was observed to decrease autophagy levels while enhancing cell viability under hypoxia/reoxygenation (H/R) conditions. In conclusion, this study underscores the substantial role of tsRNAs in the pathophysiology of I/R injury, with tiRNA-Met-CAT-002 potentially serving as a protective factor by attenuating autophagy levels.
心肌缺血/再灌注(I/R)损伤是心衰发生的重要因素。本研究研究了trna衍生的小rna (tsrna)在I/R过程中的差异表达,并探讨了其潜在的功能意义。通过tRF &; tiRNA测序,我们鉴定出115种tsrna在I/R后表现出显著的表达变化。值得注意的是,tiRNA-Met-CAT-002通过缺氧/缺氧诱导因子1亚单位α (HIF1α)/血管生成素(ANG)信号轴被发现上调。我们的研究结果表明Bnip3是tiRNA-Met-CAT-002的关键靶点。在机制上,模拟tiRNA-Met-CAT-002通过直接靶向其mRNA的3 '非翻译区(UTR),以类似于microRNA活性的方式降低Bnip3蛋白的表达。此外,在缺氧/再氧化(H/R)条件下,观察到tiRNA-Met-CAT-002可以降低自噬水平,同时提高细胞活力。总之,本研究强调了tsRNAs在I/R损伤病理生理中的重要作用,其中tiRNA-Met-CAT-002可能通过降低自噬水平作为一种保护因子。
{"title":"A tRNA-derived fragment tiRNA-Met-CAT-002 induced by myocardial ischemia/reperfusion injury inhibits cardiomyocyte autophagy by regulating Bnip3","authors":"Lang Deng ,&nbsp;Yawen Weng ,&nbsp;Jiahui Lin ,&nbsp;Lingfeng Zhong ,&nbsp;Zhixuan Tang ,&nbsp;Shuang Lin ,&nbsp;Weijian Huang ,&nbsp;Zhenfeng Cheng ,&nbsp;Kongjie Lu ,&nbsp;Bozhi Ye","doi":"10.1016/j.yexcr.2025.114809","DOIUrl":"10.1016/j.yexcr.2025.114809","url":null,"abstract":"<div><div>Myocardial ischemia/reperfusion (I/R) injury is a significant contributor to the development of heart failure. This study investigates the differential expression of tRNA-derived small RNAs (tsRNAs) during I/R and explores their potential functional implications. Through tRF &amp; tiRNA sequencing, we identified 115 tsRNAs exhibiting significant changes in expression following I/R. Notably, tiRNA-Met-CAT-002 was found to be upregulated via the hypoxia/hypoxia-inducible factor 1 subunit α (HIF1α)/angiogenin (ANG) signaling axis. Our findings suggest that Bnip3 represents a crucial target for tiRNA-Met-CAT-002. Mechanistically, mimics of tiRNA-Met-CAT-002 reduced Bnip3 protein expression by directly targeting the 3′ untranslated region (UTR) of its mRNA in a manner resembling microRNA activity. Furthermore, tiRNA-Met-CAT-002 was observed to decrease autophagy levels while enhancing cell viability under hypoxia/reoxygenation (H/R) conditions. In conclusion, this study underscores the substantial role of tsRNAs in the pathophysiology of I/R injury, with tiRNA-Met-CAT-002 potentially serving as a protective factor by attenuating autophagy levels.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 2","pages":"Article 114809"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Developmental delay in DCP2l(3)tb of Drosophila melanogaster is due to disruption in the regulation of ecdysone signaling 黑腹果蝇dcp21 (3)tb的发育延迟是由于蜕皮激素信号调节的中断。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-22 DOI: 10.1016/j.yexcr.2025.114808
Govind R. Chaudhary, Vaishali Yadav, Jagat Kumar Roy
The balance between mRNA synthesis and degradation plays an important role in gene regulation, their perturbation can lead to deleterious consequences to the cell. In eukaryotes, mRNA is degraded by a decapping protein-2 (DCP2). A hypomorph mutant allele of DCP2, DCP2l(3)tb, identified in our lab, shows delayed moulting, pupariation and absolute lethality in pupal stages. In Drosophila, moulting and pupariation are primarily regulated by ecdysone which is modulated by a few regulators synthesized by the larval brain, some are stimulatory such as Prothoracicotropic hormone (PTTH) and Drosophila insulin-like peptides (Dilps); whereas some are inhibitory, such as Lgr3-expressing neurons. We aimed to investigate the cause of the delay in moulting and pupariation in DCP2l(3)tb homozygous mutants. Through our RNA Seq data, we found downregulated expression of brain-derived neuropeptides such as PTTH and Dilps which were further confirmed and validated through qRT-PCR and semiquantitative PCR. Furthermore, we assessed the mRNA level of Lgr3 which was found to be upregulated in the larval CNS of DCP2l(3)tb homozygotes suggesting insufficient production of stimulatory modulators. Further, providing 20H-ecdysone exogenously through diet, curtailed the extended larval life. We propose that the larval CNS of DCP2l(3)tb homozygotes produces insufficient brain-derived neuropeptides to stimulate the prothoracic gland to synthesize the ecdysone required for moulting and metamorphosis.
mRNA合成和降解之间的平衡在基因调控中起着重要作用,它们的干扰可能导致对细胞有害的后果。在真核生物中,mRNA被脱帽蛋白-2 (DCP2)降解。在我们的实验室中发现了DCP2的一个低变形突变等位基因DCP2l(3)tb,该等位基因在蛹期表现出蜕皮和羽化延迟和绝对致命性。在果蝇中,蜕皮和化蛹主要受蜕皮激素的调控,蜕皮激素由幼虫大脑合成的少数调节因子调节,其中一些是刺激性的,如促胸激素(pth)和果蝇胰岛素样肽(Dilps);而有些是抑制性的,比如表达lgr3的神经元。我们的目的是研究纯合突变体dcp21(3)的蜕皮和羽化延迟的原因。通过RNA Seq数据,我们发现PTTH和Dilps等脑源性神经肽的表达下调,并通过qRT-PCR和半定量PCR进一步证实和验证。此外,我们评估了Lgr3的mRNA水平,发现Lgr3在dcp21(3)的幼虫中枢神经系统中通过纯合子上调,表明刺激调节剂的产生不足。此外,通过饮食外源性提供20h -蜕皮激素,减少了延长的幼虫寿命。我们认为,DCP2l(3)tb纯合子的幼虫中枢神经系统产生的脑源神经肽不足以刺激前胸腺合成蜕皮和变态所需的蜕皮素。
{"title":"Developmental delay in DCP2l(3)tb of Drosophila melanogaster is due to disruption in the regulation of ecdysone signaling","authors":"Govind R. Chaudhary,&nbsp;Vaishali Yadav,&nbsp;Jagat Kumar Roy","doi":"10.1016/j.yexcr.2025.114808","DOIUrl":"10.1016/j.yexcr.2025.114808","url":null,"abstract":"<div><div>The balance between mRNA synthesis and degradation plays an important role in gene regulation, their perturbation can lead to deleterious consequences to the cell. In eukaryotes, mRNA is degraded by a decapping protein-2 (DCP2). A hypomorph mutant allele of DCP2, <em>DCP2</em><sup><em>l(3)tb</em></sup>, identified in our lab, shows delayed moulting, pupariation and absolute lethality in pupal stages. In <em>Drosophila</em>, moulting and pupariation are primarily regulated by ecdysone which is modulated by a few regulators synthesized by the larval brain, some are stimulatory such as Prothoracicotropic hormone (PTTH) and <em>Drosophila</em> insulin-like peptides (Dilps); whereas some are inhibitory, such as Lgr3-expressing neurons. We aimed to investigate the cause of the delay in moulting and pupariation in <em>DCP2</em><sup><em>l(3)tb</em></sup> homozygous mutants. Through our RNA Seq data, we found downregulated expression of brain-derived neuropeptides such as <em>PTTH</em> and <em>Dilps</em> which were further confirmed and validated through qRT-PCR and semiquantitative PCR. Furthermore, we assessed the mRNA level of <em>Lgr3</em> which was found to be upregulated in the larval CNS of <em>DCP2</em><sup><em>l(3)tb</em></sup> homozygotes suggesting insufficient production of stimulatory modulators. Further, providing 20H-ecdysone exogenously through diet, curtailed the extended larval life. We propose that the larval CNS of <em>DCP2</em><sup><em>l(3)tb</em></sup> homozygotes produces insufficient brain-derived neuropeptides to stimulate the prothoracic gland to synthesize the ecdysone required for moulting and metamorphosis.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 2","pages":"Article 114808"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular mechanisms of cuproptosis in osteoarthritis: Pathways, crosstalk, and therapeutic opportunities 骨关节炎中铜骨畸形的分子机制:途径、串扰和治疗机会。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-20 DOI: 10.1016/j.yexcr.2025.114800
Yanyang Shen , Mingdong Liu , Benson O.A. Botchway , Yong Zhang , Xuehong Liu
Osteoarthritis (OA), the most prevalent degenerative joint disorder worldwide, continues to impose significant personal and societal burdens due to the absence of effective disease-modifying therapies. Recent advances in metallobiology have identified cuproptosis, a copper (Cu)-dependent regulated cell death pathway, as a potential driver of OA pathogenesis. In OA, dysregulated Cu homeostasis has been linked to oxidative stress, inflammatory signalling activation, mitochondrial dysfunction, and direct chondrocyte injury. Mechanistically, Cu2+ overload promotes aggregation of lipoylated tricarboxylic acid (TCA) cycle enzymes and destabilisation of iron–sulfur clusters, thereby impairing mitochondrial integrity and cellular metabolism. Emerging evidence also highlights extensive crosstalk between cuproptosis and ferroptosis, mediated largely by glutathione depletion and glutathione peroxidase 4 (GPX4) dysfunction, which amplifies oxidative damage in joint tissues. This review synthesises current evidence on Cu metabolism, the regulation and function of cuproptosis-related genes (CRGs), and their roles in immune infiltration, inflammatory signalling, and cartilage degeneration in OA. We further examine the interplay between cuproptosis and ferroptosis, and critically evaluate therapeutic strategies, including Cu chelation, antioxidant reinforcement, and pathway modulation, that may offer disease-modifying potential. By integrating these mechanistic insights, we aim to define new translational opportunities for OA management and outline priority areas for future research.
骨关节炎(OA)是世界上最常见的退行性关节疾病,由于缺乏有效的疾病改善治疗,它继续给个人和社会带来重大负担。金属生物学的最新进展已经确定了铜增生,一种依赖铜(Cu)调节的细胞死亡途径,是OA发病的潜在驱动因素。在骨性关节炎中,铜稳态失调与氧化应激、炎症信号激活、线粒体功能障碍和直接软骨细胞损伤有关。机制上,Cu2+超载促进脂酰化三羧酸(TCA)循环酶的聚集和铁硫簇的不稳定,从而损害线粒体的完整性和细胞代谢。新出现的证据也强调了铜下垂和铁下垂之间广泛的串扰,主要是由谷胱甘肽消耗和谷胱甘肽过氧化物酶4 (GPX4)功能障碍介导的,这加剧了关节组织的氧化损伤。本文综述了目前关于骨关节炎中铜代谢、铜中毒相关基因(CRGs)的调控和功能,以及它们在免疫浸润、炎症信号传导和软骨退行性变中的作用。我们进一步研究了铜下垂和铁下垂之间的相互作用,并批判性地评估了治疗策略,包括铜螯合、抗氧化强化和途径调节,这些可能提供疾病改善的潜力。通过整合这些机制的见解,我们的目标是为OA管理定义新的转化机会,并概述未来研究的优先领域。
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引用次数: 0
Corrigendum to ‘Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway’ [Exp Cell Res. 2018 Jan 15;362(2):362–369] “辛伐他汀通过增加PTEN-PI3K/AKT通路的放射敏感性和逆转EMT过程来抑制放射耐药食管癌细胞的发展”的更正[Exp Cell Res. 2018 1月15日;362(2):362-369]。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-16 DOI: 10.1016/j.yexcr.2025.114792
Yingying Jin, Kun Xu, Qingjuan Chen, Baofeng Wang, Jiyuan Pan, Shan Huang, Yang Wei, Hongbing Ma
{"title":"Corrigendum to ‘Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway’ [Exp Cell Res. 2018 Jan 15;362(2):362–369]","authors":"Yingying Jin,&nbsp;Kun Xu,&nbsp;Qingjuan Chen,&nbsp;Baofeng Wang,&nbsp;Jiyuan Pan,&nbsp;Shan Huang,&nbsp;Yang Wei,&nbsp;Hongbing Ma","doi":"10.1016/j.yexcr.2025.114792","DOIUrl":"10.1016/j.yexcr.2025.114792","url":null,"abstract":"","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 1","pages":"Article 114792"},"PeriodicalIF":3.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Maternal protein restriction promotes cardiac disorders by disrupting heart developmental morphophysiology in young male offspring rats 母体蛋白限制通过破坏年轻雄性后代大鼠心脏发育形态生理促进心脏疾病。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-15 DOI: 10.1016/j.yexcr.2025.114795
Lucas Sobrinho Lemos , Matheus Naia Fioretto , Isabelle Tenori Ribeiro , Luísa Annibal Barata , Flávia Alessandra Maciel , Felipe Leonardo Fagundes , Renato Mattos , Luiz Marcos Frediani Portela , João Miguel Barboza , Beatriz Souza de Oliveira , Keila Emílio de Almeida , Sérgio Alexandre Alcantara dos Santos , Clélia Akiko Hiruma Lima , José Ricardo de Arruda Miranda , Elena Zambrano , Luis Antonio Justulin
In recent years, cardiovascular diseases have been one of the leading causes of death worldwide. Epidemiological and experimental studies have linked adverse intrauterine conditions with an susceptibility to cardiovascular and metabolic diseases in subsequent generations, a concept related to the Developmental Origins of Health and Disease (DOHaD). Here, we evaluated the maternal protein restriction (MPR), and its harmful effects on the cardiac morphophysiology of offspring in early life. During gestation and lactation, the pregnant rats were divided into two groups: Control (CTR), which received a normoprotein diet (17 % protein), and Gestational and Lactational Low-Protein (GLLP), which received a hypoprotein diet (6 % protein). At postnatal day 21, the offspring were euthanized. There was a decrease in serum levels of IGF1, an increase in testosterone, and a decrease in several phenotypic parameters in the heart, such as the size of cardiomyocytes and their nuclei, collagen, reticular and elastic fibers, and mast cells in the GLLP group. We observed that MPR led to electrical disorders in the heart (bradycardia), in addition to impacting angiogenic proteins (high Aquaporin1 and PECAM-1), and proteins associated with the antioxidant system (low Peroxiredoxin 4 and high GSTpi expressions) in the GLLP group. These adverse effects early in life increase the risk of pathophysiological remodeling of the heart, with the potential for hypertension, hypertrophy, and cardiovascular disease later in life.
近年来,心血管疾病已成为世界范围内死亡的主要原因之一。流行病学和实验研究已将宫内不良状况与后代易患心血管和代谢性疾病联系起来,这一概念与健康和疾病的发育起源有关。在此,我们评估了母体蛋白限制(MPR)及其对后代早期心脏形态生理的有害影响。在妊娠和哺乳期,将妊娠大鼠分为两组:对照组(CTR)给予正常蛋白饮食(17%蛋白),妊娠和哺乳期低蛋白饮食(GLLP)给予低蛋白饮食(6%蛋白)。在出生后第21天,对后代实施安乐死。GLLP组血清IGF1水平降低,睾酮水平升高,心脏的一些表型参数减少,如心肌细胞及其细胞核的大小、胶原蛋白、网状纤维和弹性纤维以及肥大细胞。我们观察到,在GLLP组中,MPR除了影响血管生成蛋白(高水通道蛋白1和PECAM-1)和与抗氧化系统相关的蛋白(低过氧化氧还蛋白4和高GSTpi表达)外,还导致心脏电障碍(心动过缓)。生命早期的这些不良影响增加了心脏病理生理重塑的风险,并有可能在以后的生活中发生高血压、肥厚和心血管疾病。
{"title":"Maternal protein restriction promotes cardiac disorders by disrupting heart developmental morphophysiology in young male offspring rats","authors":"Lucas Sobrinho Lemos ,&nbsp;Matheus Naia Fioretto ,&nbsp;Isabelle Tenori Ribeiro ,&nbsp;Luísa Annibal Barata ,&nbsp;Flávia Alessandra Maciel ,&nbsp;Felipe Leonardo Fagundes ,&nbsp;Renato Mattos ,&nbsp;Luiz Marcos Frediani Portela ,&nbsp;João Miguel Barboza ,&nbsp;Beatriz Souza de Oliveira ,&nbsp;Keila Emílio de Almeida ,&nbsp;Sérgio Alexandre Alcantara dos Santos ,&nbsp;Clélia Akiko Hiruma Lima ,&nbsp;José Ricardo de Arruda Miranda ,&nbsp;Elena Zambrano ,&nbsp;Luis Antonio Justulin","doi":"10.1016/j.yexcr.2025.114795","DOIUrl":"10.1016/j.yexcr.2025.114795","url":null,"abstract":"<div><div>In recent years, cardiovascular diseases have been one of the leading causes of death worldwide. Epidemiological and experimental studies have linked adverse intrauterine conditions with an susceptibility to cardiovascular and metabolic diseases in subsequent generations, a concept related to the Developmental Origins of Health and Disease (DOHaD). Here, we evaluated the maternal protein restriction (MPR), and its harmful effects on the cardiac morphophysiology of offspring in early life. During gestation and lactation, the pregnant rats were divided into two groups: Control (CTR), which received a normoprotein diet (17 % protein), and Gestational and Lactational Low-Protein (GLLP), which received a hypoprotein diet (6 % protein). At postnatal day 21, the offspring were euthanized. There was a decrease in serum levels of IGF1, an increase in testosterone, and a decrease in several phenotypic parameters in the heart, such as the size of cardiomyocytes and their nuclei, collagen, reticular and elastic fibers, and mast cells in the GLLP group. We observed that MPR led to electrical disorders in the heart (bradycardia), in addition to impacting angiogenic proteins (high Aquaporin1 and PECAM-1), and proteins associated with the antioxidant system (low Peroxiredoxin 4 and high GSTpi expressions) in the GLLP group. These adverse effects early in life increase the risk of pathophysiological remodeling of the heart, with the potential for hypertension, hypertrophy, and cardiovascular disease later in life.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 1","pages":"Article 114795"},"PeriodicalIF":3.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bone marrow mesenchymal stem cell-derived exosomes HADH alleviate vitiligo by activating the Nrf2/HO-1 pathway 骨髓间充质干细胞来源的外泌体HADH通过激活Nrf2/HO-1途径缓解白癜风。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-15 DOI: 10.1016/j.yexcr.2025.114798
Shiyang Tang , Xin Li , Jianyuan Xi

Background

Vitiligo is a chronic skin disorder that significantly impairs patients' quality of life. Exosomes (Exos) have been reported to hold therapeutic promise for vitiligo. This study aimed to investigate the molecular mechanism by which bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) ameliorate vitiligo.

Methods

In vitro vitiligo cell model was established by hydrogen peroxide (H2O2)-induced melanocytes. A mouse model of vitiligo was also established. Immunofluorescence, cell counting kit-8, 2′,7′-dichlorofluorescein diacetate, enzyme linked immunosorbent assay, flow cytometry, real-time quantitative PCR, western blotting, hematoxylin-eosin, Masson-Fontana, and immunohistochemistry staining experiments were elucidated to explore the molecular mechanism of BMSC-Exos in relieving vitiligo.

Results

H2O2 treatment reduce the cell viability, superoxide dismutase and catalase activities, and promote reactive oxygen species production, pyroptosis, the expression of NLRP3, ASC, IL-1β and IL-18 proteins in melanocytes. BMSC-Exos treatment effectively counteracted these detrimental effects. Knockdown of exosomal HADH derived from BMSC enhanced H2O2-induced oxidative stress and pyroptosis in melanocytes. Mechanistically, BMSC-Exos attenuated H2O2-induced oxidative stress and pyroptosis by mediating HADH delivery to activate the Nrf2/HO-1 pathway. Moreover, these results were further confirmed by experiments in a mouse model of vitiligo.

Conclusion

BMSC-Exos can alleviate vitiligo by delivering HADH to activate the Nrf2/HO-1 pathway. This study provides insights for exploring new treatments for vitiligo.
背景:白癜风是一种慢性皮肤病,严重影响患者的生活质量。外泌体(Exos)已被报道为白癜风的治疗前景。本研究旨在探讨骨髓间充质干细胞衍生外泌体(BMSC-Exos)改善白癜风的分子机制。方法:采用过氧化氢(H2O2)诱导黑色素细胞建立体外白癜风细胞模型。建立了白癜风小鼠模型。通过免疫荧光、细胞计数试剂盒- 8,2′,7′-二氯荧光素双醋酸酯、酶联免疫吸附、流式细胞术、实时定量PCR、western blotting、苏木精-伊红、Masson-Fontana、免疫组织化学染色等实验,探讨BMSC-Exos缓解白癜风的分子机制。结果:H2O2处理降低了黑素细胞的细胞活力、超氧化物歧化酶和过氧化氢酶活性,促进了活性氧的产生和焦亡,促进了NLRP3、ASC、IL-1β和IL-18蛋白的表达。BMSC-Exos治疗有效地抵消了这些有害影响。BMSC来源的外泌体HADH的敲除增强了h2o2诱导的黑素细胞氧化应激和焦亡。在机制上,BMSC-Exos通过介导HADH传递激活Nrf2/HO-1途径来减弱h2o2诱导的氧化应激和焦亡。此外,这些结果在白癜风小鼠模型的实验中得到进一步证实。结论:BMSC-Exos可通过传递HADH激活Nrf2/HO-1通路缓解白癜风。本研究为探索白癜风的新治疗方法提供了见解。
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引用次数: 0
Integrative multi-omics analysis identifies mitochondria- and ferroptosis-related prognostic genes in cervical cancer 综合多组学分析确定了宫颈癌中线粒体和铁凋亡相关的预后基因。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-15 DOI: 10.1016/j.yexcr.2025.114796
Linlin Jia , Xinyu Cui , Xiaoting Li , Rui Li

Background

Mitochondria and ferroptosis are crucial in tumorigenesis. However, their specific role in cervical cancer (CC) remains unclear. This study aimed to identify and validate prognostic genes linked to mitochondrial function and ferroptosis in CC.

Methods

Publicly available datasets were analyzed, including 306 CC tumor samples from The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC), with survival data for 293 samples, a training set of 24 normal and 33 tumor tissues (GSE9750), and a validation set of 300 tumor tissues (GSE44001). Prognostic genes associated with mitochondria-related genes (MRGs) and ferroptosis-related genes (FRGs) were identified through machine learning, univariate Cox regression, Weighted Gene Co-expression Network Analysis (WGCNA), Mendelian randomization (MR), differential expression analysis, and multivariate Cox analysis. A risk model was constructed and validated, with the High-Risk Group (HRG) and Low-Risk Group (LRG) defined by optimal risk score thresholds. Independent prognostic analysis, functional enrichment, immune infiltration profiling, and single-cell resolution studies were conducted to explore the underlying molecular mechanisms. Additionally, gene expression was validated in five paired clinical samples (5 tumor/5 normal tissues) using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

Results

HSDL2, AMACR, and CBR3 were identified as prognostic genes. The risk model indicated significantly poorer survival rates in HRG patients (P < 0.05). It demonstrated strong predictive performance, with area under the curve (AUC) values exceeding 0.7 in both the training and validation sets. The risk score, tumor (T) stage, and lymph node (N) stage were identified as independent prognostic factors for a nomogram model (hazard ratio (HR ≠ 1, P < 0.5). Pathways co-enriched by these markers, such as allograft rejection, were investigated. Immune infiltration analysis revealed significant differences between HRG and LRG in M0 macrophages and resting myeloid dendritic cells (mDCs) (P < 0.5). Macrophages and epithelial/cancer cells were identified as key contributors to CC progression, exhibiting 13 and 7 distinct differentiation states, respectively, in pseudo-time analysis. Notably, HSDL2 and CBR3 expression levels were significantly different between normal and CC samples (P < 0.05).

Conclusion

HSDL2, AMACR, and CBR3 were established as prognostic biomarkers for CC. The risk model demonstrated robust predictive accuracy, offering a scientific foundation for clinical prognosis prediction in CC.
背景:线粒体和铁下垂在肿瘤发生中起关键作用。然而,它们在宫颈癌(CC)中的具体作用尚不清楚。方法:对来自Cancer Genome - cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC)的306例CC肿瘤样本、293例样本的生存数据、24例正常组织(GSE9750)和33例肿瘤组织(GSE44001)的训练组和300例肿瘤组织的验证组进行分析。通过机器学习、单因素Cox回归、加权基因共表达网络分析(WGCNA)、孟德尔随机化(MR)、差异表达分析和多因素Cox分析,鉴定与线粒体相关基因(MRGs)和凋亡相关基因(FRGs)相关的预后基因。构建风险模型并进行验证,以最优风险评分阈值定义高风险组(HRG)和低风险组(LRG)。通过独立的预后分析、功能富集、免疫浸润谱和单细胞分辨率研究来探索潜在的分子机制。此外,利用逆转录-定量聚合酶链反应(RT-qPCR)在5个配对的临床样本(5个肿瘤/5个正常组织)中验证基因表达。结果:HSDL2、AMACR和CBR3被确定为预后基因。风险模型显示HRG患者生存率明显较低(P < 0.05)。它表现出很强的预测性能,在训练集和验证集中,曲线下面积(AUC)值都超过0.7。风险评分、肿瘤(T)分期和淋巴结(N)分期被确定为nomogram模型的独立预后因素(风险比(HR≠1,P < 0.5)。研究了这些标记共同富集的途径,如同种异体移植排斥反应。免疫浸润分析显示,M0巨噬细胞和静息髓样树突状细胞(mDCs) HRG和LRG差异有统计学意义(P < 0.5)。在伪时间分析中,巨噬细胞和上皮/癌细胞被确定为CC进展的关键贡献者,分别表现出13种和7种不同的分化状态。值得注意的是,HSDL2和CBR3的表达水平在正常和CC样本中有显著差异(P < 0.05)。结论:HSDL2、AMACR、CBR3可作为CC的预后生物标志物,该风险模型具有较强的预测准确性,为CC的临床预后预测提供了科学依据。
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引用次数: 0
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Experimental cell research
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