Cell Stress & Chaperones最新文献_第5页

COL5A2-mediated endoplasmic reticulum stress promotes macrophage M2 polarization in lung adenocarcinoma col5a2介导的内质网应激促进肺腺癌中巨噬细胞M2极化。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-05-07 DOI: 10.1016/j.cstres.2025.100081

Gaozhong Sun , Yanzhe Wang , Kewei Ni , Jian Shen , Dongdong Liu , Haitao Wang

Collagen is a major component of the extracellular matrix. Type V collagen α2 (COL5A2), a common collagen subtype, plays a crucial role in immune regulation, angiogenesis, and tumor metastasis. It is highly expressed in various malignancies, but its mechanistic role in lung adenocarcinoma (LUAD) remains unclear. Therefore, this study aims to investigate the regulatory mechanism of COL5A2 in mediating macrophage M2 polarization in LUAD. We analyzed COL5A2 expression in LUAD samples from the TCGA-LUAD database. Using GSEA, we sought to identify the signaling pathways influenced by COL5A2 expression. mRNA levels of COL5A2, TGF-β, and IL-10 were quantified via qPCR analysis, and protein levels of COL5A2, PD-L1, and endoplasmic reticulum (ER) stress-related proteins (GRP78 and CHOP) were assessed using western blot. Immunofluorescence assay detected the fluorescence signal of CD206 in M2 macrophages, while flow cytometry assessed the M2 macrophage marker CD206, flow cytometry determined the positive rates for CD68 and CD206. Exosome uptake by macrophages was examined using confocal microscopy, and cell viability was measured with cell counting kit-8. KI-67 protein expression was analyzed by immunohistochemistry, and in vivo assays in animals verified our findings. The results showed that elevated COL5A2 levels in LUAD were found to correlate with a shift toward M2 macrophage polarization. Specifically, the overexpression of COL5A2 amplified ER stress, which led to an increase in PD-L1 exosome release and macrophage uptake of PD-L1, thus driving the M2 phenotype. In conclusion, COL5A2 in LUAD induces ER stress, which is associated with elevated PD-L1 exosome secretion and macrophage PD-L1 uptake, ramping up M2 polarization in macrophages.

背景：胶原蛋白是细胞外基质的主要成分。V型胶原α2 （COL5A2）是一种常见的胶原亚型，在免疫调节、血管生成和肿瘤转移中起重要作用。它在多种恶性肿瘤中高度表达，但其在肺腺癌（LUAD）中的机制作用尚不清楚。因此，本研究旨在探讨COL5A2在LUAD中介导巨噬细胞M2极化的调控机制。方法：从TCGA-LUAD数据库中分析COL5A2在LUAD样本中的表达。使用GSEA，我们试图确定受COL5A2表达影响的信号通路。采用qPCR法检测COL5A2、TGF-β、IL-10 mRNA表达水平，采用western blot法检测COL5A2、PD-L1、内质网（ER）应激相关蛋白（GRP78、CHOP）表达水平。免疫荧光法检测M2巨噬细胞中CD206的荧光信号，流式细胞术检测M2巨噬细胞标志物CD206，流式细胞术检测CD68和CD206的阳性率。用共聚焦显微镜检测巨噬细胞对外泌体的摄取，用细胞计数试剂盒-8检测细胞活力。免疫组织化学分析KI-67蛋白表达，动物体内实验证实了我们的发现。结果：LUAD中COL5A2水平升高与M2巨噬细胞极化相关。具体来说，COL5A2的过表达放大了内质网应激，导致PD-L1外泌体释放增加和巨噬细胞对PD-L1的摄取增加，从而驱动M2表型。结论：COL5A2在LUAD中诱导内质网应激，与PD-L1外泌体分泌升高和巨噬细胞PD-L1摄取增加有关，增强了巨噬细胞的M2极化。

{"title":"COL5A2-mediated endoplasmic reticulum stress promotes macrophage M2 polarization in lung adenocarcinoma","authors":"Gaozhong Sun , Yanzhe Wang , Kewei Ni , Jian Shen , Dongdong Liu , Haitao Wang","doi":"10.1016/j.cstres.2025.100081","DOIUrl":"10.1016/j.cstres.2025.100081","url":null,"abstract":"<div><div>Collagen is a major component of the extracellular matrix. Type V collagen α2 (COL5A2), a common collagen subtype, plays a crucial role in immune regulation, angiogenesis, and tumor metastasis. It is highly expressed in various malignancies, but its mechanistic role in lung adenocarcinoma (LUAD) remains unclear. Therefore, this study aims to investigate the regulatory mechanism of COL5A2 in mediating macrophage M2 polarization in LUAD. We analyzed COL5A2 expression in LUAD samples from the TCGA-LUAD database. Using GSEA, we sought to identify the signaling pathways influenced by COL5A2 expression. mRNA levels of COL5A2, TGF-β, and IL-10 were quantified via qPCR analysis, and protein levels of COL5A2, PD-L1, and endoplasmic reticulum (ER) stress-related proteins (GRP78 and CHOP) were assessed using western blot. Immunofluorescence assay detected the fluorescence signal of CD206 in M2 macrophages, while flow cytometry assessed the M2 macrophage marker CD206, flow cytometry determined the positive rates for CD68 and CD206. Exosome uptake by macrophages was examined using confocal microscopy, and cell viability was measured with cell counting kit-8. KI-67 protein expression was analyzed by immunohistochemistry, and in vivo assays in animals verified our findings. The results showed that elevated COL5A2 levels in LUAD were found to correlate with a shift toward M2 macrophage polarization. Specifically, the overexpression of COL5A2 amplified ER stress, which led to an increase in PD-L1 exosome release and macrophage uptake of PD-L1, thus driving the M2 phenotype. In conclusion, COL5A2 in LUAD induces ER stress, which is associated with elevated PD-L1 exosome secretion and macrophage PD-L1 uptake, ramping up M2 polarization in macrophages.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100081"},"PeriodicalIF":3.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965775","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

JNK signaling dominance in hyperthermia JNK信号在高温中的优势。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-05-06 DOI: 10.1016/j.cstres.2025.100080

Atsushi Enomoto , Takemichi Fukasawa

Hyperthermia is a promising anticancer treatment that induces heat stress, stimulating various signal transduction pathways to maintain cellular homeostasis. Mitogen-activated protein kinases (MAPKs) link various extracellular stimuli with cytoplasmic and nuclear mediators through a three-tiered cascade of kinases, including MAPKs, MAP2Ks, and MAP3Ks. In mammals, three major groups of MAPKs have been characterized: extracellular signal-regulated protein kinases (ERK), p38 MAPKs, and c-Jun NH₂-terminal kinases (JNK). Each group of MAPKs is heat-activated and exhibits distinct biological functions. However, the differences and advantages of the regulation of each MAPK with temperature changes remain unknown. Our results demonstrated that JNK was activated in a temperature-dependent manner, with degradation of the JNK phosphatases despite transient phosphorylation of ERK with induction of the ERK phosphatases. This brief insight deepens our current understanding of the deregulation of the ERK and JNK cascades in hyperthermia.

热疗是一种很有前途的抗癌治疗方法，它可以诱导热应激，刺激各种信号转导途径来维持细胞稳态。丝裂原活化蛋白激酶（MAPKs）通过包括MAPKs、map2k和map3k在内的三层激酶级联，将各种细胞外刺激与细胞质和核介质连接起来。在哺乳动物中，已经确定了三组主要的mapk：细胞外信号调节蛋白激酶（ERK）、p38 MAPKs和c-Jun nh2末端激酶（JNK）。每组mapk都是热激活的，并表现出不同的生物学功能。然而，每种MAPK随温度变化调控的差异和优势尚不清楚。我们的研究结果表明，尽管ERK通过诱导ERK磷酸酶进行短暂磷酸化，但JNK以温度依赖的方式被激活，JNK磷酸酶降解。这一简短的见解加深了我们目前对热疗中ERK和JNK级联解除管制的理解。

引用次数: 0

Editorial Board Members/Copyright 编辑委员会成员/版权

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-05-01 DOI: 10.1016/S1355-8145(25)00025-2

引用次数: 0

Cover and caption 封面及标题

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-05-01 DOI: 10.1016/S1355-8145(25)00024-0

引用次数: 0

HDAC1 is involved in the destabilization of the HSF2 protein under nonstress and stress conditions 在非应激和应激条件下，HDAC1参与HSF2蛋白的不稳定。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-05-01 DOI: 10.1016/j.cstres.2025.100079

Kevin Daupin , Véronique Dubreuil , Johanna K. Ahlskog , Annalisa Verrico , Lea Sistonen , Valérie Mezger , Aurélie de Thonel

Heat shock transcription factors 1 and 2 (HSF1 and HSF2) are the major regulators of the cellular response to stressors, notably to heat shock and to oxidative stress. HSF1 and HSF2 are also important contributors in devastating human pathologies like cancer, neurodegenerative disorders, and neurodevelopmental disorders. Under physiological conditions, nuclear HSF2 is detected in only a few cell types in human adult healthy tissues. In contrast, HSF2 protein levels are elevated at some embryonic stages, but greatly vary among cell types and fluctuate during the cell cycle in diverse cell lines. HSF2 is a short-lived protein whose rapid turnover is controlled by the components of the ubiquitin-proteasome degradation pathway, and the stabilization of HSF2 constitutes an important step that regulates its DNA-binding activity and mediates its roles in nonstress, physiological processes. The control of HSF2 abundancy is therefore critical for its regulatory roles in stress responses as well as under physiological conditions. In this regard, the fetal brain cortex is a singular context where HSF2 is strikingly abundant, exhibits constitutive DNA-binding activity and, by controlling a specific repertoire of target genes that play important roles at multiple steps of neurodevelopment. Recently, we showed that the lysine-acetyl-transferases CBP and EP300 stabilize the HSF2 protein under both unstressed and stressed conditions and that the integrity of the CBP/EP300-HSF2 pathway is important for neurodevelopment. Here, we identify the lysine-deacetylase histone-deacetylase 1 (HDAC1) as a novel HSF2-interacting protein partner and regulator, in an unbiased manner, and show that HSF2 and HDAC1 localize in the same cells in the developing mouse cortex and human cerebral organoids. We also demonstrate that HDAC1, through its catalytic activity, destabilizes the HSF2 protein, through HSF2 poly-ubiquitination and proteasomal degradation, under both normal and stress conditions.

热休克转录因子1和2 （HSF1和HSF2）是细胞对应激源，特别是热休克和氧化应激反应的主要调节因子。HSF1和HSF2也是癌症、神经退行性疾病和神经发育障碍等毁灭性人类疾病的重要贡献者。在生理条件下，人类成人健康组织中仅在少数细胞类型中检测到核HSF2。相反，HSF2蛋白水平在某些胚胎阶段升高，但在不同的细胞类型中差异很大，在不同细胞系的细胞周期中波动。HSF2是一种短寿命蛋白，其快速更新受泛素-蛋白酶体降解途径组分的控制，HSF2的稳定是调节其dna结合活性和介导其在非应激生理过程中的作用的重要步骤。因此，HSF2丰度的控制对于其在应激反应和生理条件下的调节作用至关重要。在这方面，胎儿大脑皮层是一个独特的环境，其中HSF2显著丰富，表现出组成性dna结合活性，并通过控制在神经发育的多个步骤中发挥重要作用的特定靶基因库。最近，我们发现赖氨酸-乙酰基转移酶CBP和EP300在非应激和应激条件下都能稳定HSF2蛋白，并且CBP/EP300-HSF2通路的完整性对神经发育很重要。在这里，我们以无偏倚的方式确定了赖氨酸去乙酰化酶HDAC1是一种新的HSF2相互作用蛋白伴侣和调节剂，并表明HSF2和HDAC1定位于发育中的小鼠皮层和人脑类器官（hCOs）的相同细胞中。我们还证明，在正常和应激条件下，HDAC1通过其催化活性，通过HSF2多泛素化和蛋白酶体降解，使HSF2蛋白不稳定。

{"title":"HDAC1 is involved in the destabilization of the HSF2 protein under nonstress and stress conditions","authors":"Kevin Daupin , Véronique Dubreuil , Johanna K. Ahlskog , Annalisa Verrico , Lea Sistonen , Valérie Mezger , Aurélie de Thonel","doi":"10.1016/j.cstres.2025.100079","DOIUrl":"10.1016/j.cstres.2025.100079","url":null,"abstract":"<div><div>Heat shock transcription factors 1 and 2 (HSF1 and HSF2) are the major regulators of the cellular response to stressors, notably to heat shock and to oxidative stress. HSF1 and HSF2 are also important contributors in devastating human pathologies like cancer, neurodegenerative disorders, and neurodevelopmental disorders. Under physiological conditions, nuclear HSF2 is detected in only a few cell types in human adult healthy tissues. In contrast, HSF2 protein levels are elevated at some embryonic stages, but greatly vary among cell types and fluctuate during the cell cycle in diverse cell lines. HSF2 is a short-lived protein whose rapid turnover is controlled by the components of the ubiquitin-proteasome degradation pathway, and the stabilization of HSF2 constitutes an important step that regulates its DNA-binding activity and mediates its roles in nonstress, physiological processes. The control of HSF2 abundancy is therefore critical for its regulatory roles in stress responses as well as under physiological conditions. In this regard, the fetal brain cortex is a singular context where HSF2 is strikingly abundant, exhibits constitutive DNA-binding activity and, by controlling a specific repertoire of target genes that play important roles at multiple steps of neurodevelopment. Recently, we showed that the lysine-acetyl-transferases CBP and EP300 stabilize the HSF2 protein under both unstressed and stressed conditions and that the integrity of the CBP/EP300-HSF2 pathway is important for neurodevelopment. Here, we identify the lysine-deacetylase histone-deacetylase 1 (HDAC1) as a novel HSF2-interacting protein partner and regulator, in an unbiased manner, and show that HSF2 and HDAC1 localize in the same cells in the developing mouse cortex and human cerebral organoids. We also demonstrate that HDAC1, through its catalytic activity, destabilizes the HSF2 protein, through HSF2 poly-ubiquitination and proteasomal degradation, under both normal and stress conditions.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100079"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968527","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

The protective role of the IRE1α/XBP1 signaling cascade in autophagy during ischemic stress and acute kidney injury IRE1α/XBP1信号级联在缺血应激和急性肾损伤自噬中的保护作用

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-05-01 DOI: 10.1016/j.cstres.2025.02.004

Ting Liu , Lu Li , Meixia Meng , Ming Gao , Jinhua Zhang , Yuan Zhang , Yukun Gan , Yangjie Dang , Limin Liu

Acute kidney injury (AKI) is a common and serious complication resulting from ischemia and hypoxia, leading to significant morbidity and mortality. Autophagy, a cellular process for degrading damaged components, plays a crucial role in kidney protection. The unfolded protein response pathway, particularly the inositol-requiring enzyme 1 (IRE1α)/X-box binding protein 1 (XBP1) signaling cascade, is implicated in regulating autophagy during renal stress. To elucidate the role of the IRE1α/XBP1 pathway in autophagy during hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) injury, renal tubular epithelial cells (TECs) were subjected to H/R conditions, and I/R injury was induced in mice. The expression of autophagy-related and endoplasmic reticulum stress markers (IRE1α, XBP1, GRP78, Beclin1, LC3I/II, and P62) was assessed using immunoblotting and immunofluorescence. Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist), and STF083010 (IRE1α inhibitor) were evaluated on autophagy regulation. H/R injury significantly increased mitochondrial damage and the formation of autophagic vesicles in TECs. Key markers of autophagy were elevated in response to H/R and I/R injury, with activation of the IRE1α/XBP1 pathway enhancing autophagic processes. IXA6 treatment improved renal function and reduced injury in I/R models, while STF083010 exacerbated kidney damage. The IRE1α/XBP1 pathway is a critical regulator of autophagy in renal TECs during ischemic stress, suggesting that pharmacological modulation of this pathway may offer therapeutic avenues for preventing or mitigating AKI. Enhanced understanding of these mechanisms may lead to novel strategies for kidney disease management.

急性肾损伤（Acute kidney injury， AKI）是一种常见且严重的由缺血和缺氧引起的并发症，具有很高的发病率和死亡率。自噬是一种降解受损成分的细胞过程，在肾脏保护中起着至关重要的作用。未折叠蛋白反应（UPR）途径，特别是IRE1α/XBP1信号级联，参与调节肾应激过程中的自噬。为了阐明IRE1α/XBP1通路在缺氧/再氧化（H/R）和缺血/再灌注（I/R）损伤中自噬中的作用，我们将小鼠肾小管上皮细胞（tec）置于H/R条件下，并诱导其I/R损伤。采用免疫印迹法和免疫荧光法检测自噬相关和内质网应激标志物（IRE1α、XBP1、GRP78、Beclin1、LC3I/II和P62）的表达。此外，我们还评估了IRE1α过表达以及IRE1α激动剂IXA6和IRE1α抑制剂STF083010对自噬调节的影响。H/R损伤显著增加TECs线粒体损伤和自噬囊泡的形成。H/R和I/R损伤后，自噬的关键标志物升高，IRE1α/XBP1通路的激活增强了自噬过程。IXA6治疗改善了I/R模型的肾功能，减轻了损伤，而STF083010加重了肾损伤。IRE1α/XBP1通路是缺血应激期间肾tec自噬的关键调节因子，提示该通路的药理调节可能为预防或减轻AKI提供治疗途径。加强对这些机制的了解可能会导致新的肾脏疾病管理策略。

{"title":"The protective role of the IRE1α/XBP1 signaling cascade in autophagy during ischemic stress and acute kidney injury","authors":"Ting Liu , Lu Li , Meixia Meng , Ming Gao , Jinhua Zhang , Yuan Zhang , Yukun Gan , Yangjie Dang , Limin Liu","doi":"10.1016/j.cstres.2025.02.004","DOIUrl":"10.1016/j.cstres.2025.02.004","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a common and serious complication resulting from ischemia and hypoxia, leading to significant morbidity and mortality. Autophagy, a cellular process for degrading damaged components, plays a crucial role in kidney protection. The unfolded protein response pathway, particularly the inositol-requiring enzyme 1 (IRE1α)/X-box binding protein 1 (XBP1) signaling cascade, is implicated in regulating autophagy during renal stress. To elucidate the role of the IRE1α/XBP1 pathway in autophagy during hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) injury, renal tubular epithelial cells (TECs) were subjected to H/R conditions, and I/R injury was induced in mice. The expression of autophagy-related and endoplasmic reticulum stress markers (IRE1α, XBP1, GRP78, Beclin1, LC3I/II, and P62) was assessed using immunoblotting and immunofluorescence. Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist), and STF083010 (IRE1α inhibitor) were evaluated on autophagy regulation. H/R injury significantly increased mitochondrial damage and the formation of autophagic vesicles in TECs. Key markers of autophagy were elevated in response to H/R and I/R injury, with activation of the IRE1α/XBP1 pathway enhancing autophagic processes. IXA6 treatment improved renal function and reduced injury in I/R models, while STF083010 exacerbated kidney damage. The IRE1α/XBP1 pathway is a critical regulator of autophagy in renal TECs during ischemic stress, suggesting that pharmacological modulation of this pathway may offer therapeutic avenues for preventing or mitigating AKI. Enhanced understanding of these mechanisms may lead to novel strategies for kidney disease management.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 3","pages":"Pages 160-171"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472193","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

Melatonin ameliorates heat stress-induced oxidative apoptosis in mouse spermatocytes via autophagy and ferroptosis pathways 褪黑素通过自噬和铁下垂途径改善热应激诱导的小鼠精细胞氧化凋亡

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-04-20 DOI: 10.1016/j.cstres.2025.100078

Yi-Ping Lei, Jia Wang, Peng-Luo Yin, Hua Jia, Wen-Zhi Ma

Testicular heat stress is a critical factor contributing to male infertility, with spermatocytes exhibiting heightened sensitivity to temperature elevation. This study systematically elucidates the protective mechanisms of melatonin against heat stress-induced spermatocyte injury. In a murine heat stress model, melatonin intervention significantly reduced testicular accumulation of malondialdehyde (MDA) induced by heat stress, enhanced the activities of catalase (CAT) and superoxide dismutase (SOD), and suppressed germ cell apoptosis by downregulating the pro-apoptotic protein Bax and upregulating GPX4 expression. Sycp3 immunohistochemistry demonstrated that melatonin significantly improved spermatocyte structural integrity. In the GC-2spd (ts) spermatocyte cell line model, melatonin treatment markedly reduced MDA levels and alleviated heat stress-induced oxidative apoptosis and proliferation inhibition by downregulating key apoptotic proteins (Bax, Caspase-3, and cleaved-Caspase-3). Mechanistic studies revealed that melatonin restores autophagic balance by modulating the expression of autophagy-related proteins LC3-I, LC3-II, and P62. Concurrently, melatonin downregulated ferroptosis markers P53 and COX2, inhibiting ferroptosis by blocking DNA damage response and inflammatory amplification pathways. Melatonin synergistically maintained cellular redox homeostasis by downregulating the NRF2/HO-1 pathway and upregulating GPX4 expression, significantly reducing Fe²⁺ accumulation and ameliorating iron metabolism dysregulation. This study unveils the molecular mechanisms by which melatonin mitigates testicular heat stress injury through a multitarget regulatory network, providing novel therapeutic strategies for clinical intervention in heat stress-associated infertility.

睾丸热应激是导致男性不育的一个关键因素，精子细胞对温度升高表现出更高的敏感性。本研究系统地阐明了褪黑素对热应激诱导的精母细胞损伤的保护机制。在小鼠热应激模型中，褪黑激素干预可显著降低热应激诱导的睾丸丙二醛（MDA）积累，增强过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性，并通过下调促凋亡蛋白Bax和上调GPX4表达抑制生殖细胞凋亡。Sycp3免疫组化显示褪黑素显著改善精母细胞结构完整性。在GC-2spd （ts）精细胞系模型中，褪黑素处理通过下调关键凋亡蛋白（Bax、Caspase-3和cleaved-Caspase-3），显著降低MDA水平，减轻热应激诱导的氧化性凋亡和增殖抑制。机制研究表明，褪黑素通过调节自噬相关蛋白LC3-I、LC3-II和P62的表达来恢复自噬平衡。同时，褪黑素下调铁下垂标志物P53和COX2，通过阻断DNA损伤反应和炎症扩增途径抑制铁下垂。褪黑素通过下调NRF2/HO-1通路和上调GPX4表达，协同维持细胞氧化还原稳态，显著减少Fe +积累，改善铁代谢失调。本研究揭示了褪黑素通过多靶点调控网络减轻睾丸热应激损伤的分子机制，为临床干预热应激相关性不孕提供了新的治疗策略。

{"title":"Melatonin ameliorates heat stress-induced oxidative apoptosis in mouse spermatocytes via autophagy and ferroptosis pathways","authors":"Yi-Ping Lei, Jia Wang, Peng-Luo Yin, Hua Jia, Wen-Zhi Ma","doi":"10.1016/j.cstres.2025.100078","DOIUrl":"10.1016/j.cstres.2025.100078","url":null,"abstract":"<div><div>Testicular heat stress is a critical factor contributing to male infertility, with spermatocytes exhibiting heightened sensitivity to temperature elevation. This study systematically elucidates the protective mechanisms of melatonin against heat stress-induced spermatocyte injury. In a murine heat stress model, melatonin intervention significantly reduced testicular accumulation of malondialdehyde (MDA) induced by heat stress, enhanced the activities of catalase (CAT) and superoxide dismutase (SOD), and suppressed germ cell apoptosis by downregulating the pro-apoptotic protein Bax and upregulating GPX4 expression. Sycp3 immunohistochemistry demonstrated that melatonin significantly improved spermatocyte structural integrity. In the GC-2spd (ts) spermatocyte cell line model, melatonin treatment markedly reduced MDA levels and alleviated heat stress-induced oxidative apoptosis and proliferation inhibition by downregulating key apoptotic proteins (Bax, Caspase-3, and cleaved-Caspase-3). Mechanistic studies revealed that melatonin restores autophagic balance by modulating the expression of autophagy-related proteins LC3-I, LC3-II, and P62. Concurrently, melatonin downregulated ferroptosis markers P53 and COX2, inhibiting ferroptosis by blocking DNA damage response and inflammatory amplification pathways. Melatonin synergistically maintained cellular redox homeostasis by downregulating the NRF2/HO-1 pathway and upregulating GPX4 expression, significantly reducing Fe²⁺ accumulation and ameliorating iron metabolism dysregulation. This study unveils the molecular mechanisms by which melatonin mitigates testicular heat stress injury through a multitarget regulatory network, providing novel therapeutic strategies for clinical intervention in heat stress-associated infertility.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100078"},"PeriodicalIF":3.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922054","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

Amyloidogenesis promotes HSF1 activity enhancing cell survival during breast cancer metastatic colonization 淀粉样蛋白形成促进HSF1活性，增强乳腺癌转移定殖过程中的细胞存活。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-03-25 DOI: 10.1016/j.cstres.2025.03.003

Natasha Hockaden , Gabi Leriger , John Wang , Haimanti Ray , Sunandan Chakrabarti , Nicholas Downing , Jacob Desmond , David Williams , Peter C. Hollenhorst , Gregory Longmore , Richard L. Carpenter

Breast cancer is the most commonly diagnosed cancer among women and the second leading cause of cancer deaths in women. A majority of these breast cancer deaths are due to metastasis, which occurs when primary tumor cells invade into the blood stream to travel and colonize at distant organ sites. Metastatic colonization is the rate-limiting step of metastasis. Heat shock factor 1 (HSF1) is a transcription factor that has been shown to be involved in promoting malignancy with a function in metastatic dissemination due to its contribution to promoting epithelial-to-mesenchymal transition. The role of HSF1 in colonization is unclear. In this study, we observed that HSF1 was essential for metastatic colonization. Consistent with these findings, we also observed that HSF1 was more active in human metastatic tumors compared to primary tumors. HSF1 was also seen to be activated during in vitro colony formation, which was accompanied by increases in amyloid beta (Aβ) fibrils, which was also observed in human metastatic tumors. Aβ fibrils led to HSF1 activation and depletion or inhibition of HSF1 led to increases in Aβ fibrils. HSF1 inhibition with small molecule inhibitors suppressed in vitro colony formation and mammosphere growth of metastatic breast cancer cells. These results suggest that colonization increases Aβ fibril formation that subsequently activates HSF1 as a cell survival mechanism that is essential for metastatic initiation and outgrowth.

乳腺癌是妇女中最常见的癌症，也是妇女癌症死亡的第二大原因。大多数乳腺癌死亡是由于转移，当原发肿瘤细胞侵入血流并迁移到远处的器官部位时就会发生转移。转移定殖是转移的限速步骤。热休克因子1 （HSF1）是一种转录因子，由于其促进上皮-间质转化（EMT）的作用，已被证明参与促进恶性肿瘤的转移传播。HSF1在定植中的作用尚不清楚。在这项研究中，我们观察到HSF1在转移性定植中是必不可少的。与这些发现一致，我们还观察到HSF1在人类转移性肿瘤中比原发肿瘤更活跃。HSF1在体外集落形成过程中也被激活，这伴随着淀粉样蛋白（Aβ）原纤维的增加，这在人类转移性肿瘤中也被观察到。β原纤维导致HSF1激活，而HSF1的消耗或抑制导致β原纤维的增加。用小分子抑制剂抑制HSF1抑制转移性乳腺癌细胞体外集落形成和乳腺球生长。这些结果表明，定殖增加了a β纤维的形成，随后激活HSF1，这是转移起始和生长所必需的细胞存活机制。

{"title":"Amyloidogenesis promotes HSF1 activity enhancing cell survival during breast cancer metastatic colonization","authors":"Natasha Hockaden , Gabi Leriger , John Wang , Haimanti Ray , Sunandan Chakrabarti , Nicholas Downing , Jacob Desmond , David Williams , Peter C. Hollenhorst , Gregory Longmore , Richard L. Carpenter","doi":"10.1016/j.cstres.2025.03.003","DOIUrl":"10.1016/j.cstres.2025.03.003","url":null,"abstract":"<div><div>Breast cancer is the most commonly diagnosed cancer among women and the second leading cause of cancer deaths in women. A majority of these breast cancer deaths are due to metastasis, which occurs when primary tumor cells invade into the blood stream to travel and colonize at distant organ sites. Metastatic colonization is the rate-limiting step of metastasis. Heat shock factor 1 (HSF1) is a transcription factor that has been shown to be involved in promoting malignancy with a function in metastatic dissemination due to its contribution to promoting epithelial-to-mesenchymal transition. The role of HSF1 in colonization is unclear. In this study, we observed that HSF1 was essential for metastatic colonization. Consistent with these findings, we also observed that HSF1 was more active in human metastatic tumors compared to primary tumors. HSF1 was also seen to be activated during <em>in vitro</em> colony formation, which was accompanied by increases in amyloid beta (Aβ) fibrils, which was also observed in human metastatic tumors. Aβ fibrils led to HSF1 activation and depletion or inhibition of HSF1 led to increases in Aβ fibrils. HSF1 inhibition with small molecule inhibitors suppressed <em>in vitro</em> colony formation and mammosphere growth of metastatic breast cancer cells. These results suggest that colonization increases Aβ fibril formation that subsequently activates HSF1 as a cell survival mechanism that is essential for metastatic initiation and outgrowth.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 3","pages":"Pages 143-159"},"PeriodicalIF":3.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lycium barbarum polysaccharide alleviates H2O2-induced premature senescence by downregulating miRNA-34a-5p in ARPE-19 cells 枸杞多糖通过下调ARPE-19细胞中的miRNA-34a-5p，缓解H2O2诱导的早衰。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-03-18 DOI: 10.1016/j.cstres.2025.03.002

Meng Kong , Jingwen Li , Rong Jin , Yi Zhang , Jia You , Nan Wang , Nianting Tong

The premature senescence of retinal pigment epithelium (RPE) plays a significant role in the development of age-related macular degeneration. This study aimed to investigate the potential protective effect of Lycium barbarum polysaccharide (LBP) against H₂O₂-induced premature senescence and to elucidate the underlying mechanisms. The ARPE-19 cell line was subjected to H₂O₂ exposure to create a model of premature senescence. The modulation of microRNA-34a-5p expression was accomplished using antagomir and agomir, as assessed by quantitative real-time polymerase chain reaction. The senescence model was successfully established by treating cells with 200 μM H₂O₂ for 2 hours daily over a span of three consecutive days. This oxidative stress resulted in a notable increase in the proportion of senescence-associated beta-galactosidase-positive cells, reaching 33.5%, without significant alterations in cell viability or apoptosis. In the ARPE-19 cells undergoing premature senescence, there was a marked increase in reactive oxygen species (ROS) production and malondialdehyde levels, coupled with a significant decrease in the activity of total superoxide dismutase, glutathione peroxidase, and catalase. Additionally, microRNA-34a-5p was found to be overexpressed in these cells. Treatment with LBP alleviated H₂O₂-induced premature senescence, diminished the overexpression of microRNA-34a-5p, and suppressed ROS production. Moreover, the incubation with ago-34a reversed the protective effect of LBP in ARPE-19 cells. In conclusion, the overexpression of microRNA-34a-5p contributes to the H₂O₂-induced premature senescence of ARPE-19 cells. LBP appears to mitigate this premature senescence, at least in part, by downregulating microRNA-34a-5p expression and reducing oxidative stress.

背景：视网膜色素上皮（RPE）的过早衰老在老年性黄斑变性的发生中起着重要作用。本研究旨在探讨枸杞多糖（LBP）对H2O2诱导的过早衰老的保护作用，并阐明其潜在机制：方法：将ARPE-19细胞系置于H2O2暴露下，建立早衰模型。方法：ARPE-19 细胞系暴露于 H2O2，以建立早衰模型。模型建立后，细胞在枸杞多糖存在或不存在的情况下维持。使用 antagomir 和 agomir 对 microRNA（miRNA）-34a-5p 的表达进行调节，并通过定量实时聚合酶链反应进行评估：连续三天每天用 200μM H2O2 处理细胞 2 小时，成功建立了衰老模型。这种氧化应激导致衰老相关的 beta-半乳糖苷酶阳性细胞比例明显增加，达到 33.5%，但细胞活力和凋亡没有明显变化。在过早衰老的 ARPE-19 细胞中，活性氧（ROS）生成和丙二醛（MDA）水平明显增加，同时总超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH px）和过氧化氢酶（CAT）的活性显著下降。此外，还发现 miRNA-34a-5p 在这些细胞中过度表达。用枸杞多糖处理可缓解 H2O2 诱导的早衰，减少 miRNA-34a-5p 的过表达，并抑制 ROS 的产生。此外，与 ago-34a 一起孵育可逆转枸杞多糖对 ARPE-19 细胞的保护作用：结论：miRNA-34a-5p的过表达是H2O2诱导ARPE-19细胞早衰的原因之一。枸杞多糖似乎可以通过下调 miRNA-34a-5p 的表达和减少氧化应激来缓解这种过早衰老，至少部分是这样。

{"title":"Lycium barbarum polysaccharide alleviates H2O2-induced premature senescence by downregulating miRNA-34a-5p in ARPE-19 cells","authors":"Meng Kong , Jingwen Li , Rong Jin , Yi Zhang , Jia You , Nan Wang , Nianting Tong","doi":"10.1016/j.cstres.2025.03.002","DOIUrl":"10.1016/j.cstres.2025.03.002","url":null,"abstract":"<div><div>The premature senescence of retinal pigment epithelium (RPE) plays a significant role in the development of age-related macular degeneration. This study aimed to investigate the potential protective effect of <em>Lycium barbarum</em> polysaccharide (LBP) against H<sub>2</sub>O<sub>2</sub>-induced premature senescence and to elucidate the underlying mechanisms. The ARPE-19 cell line was subjected to H<sub>2</sub>O<sub>2</sub> exposure to create a model of premature senescence. The modulation of microRNA-34a-5p expression was accomplished using antagomir and agomir, as assessed by quantitative real-time polymerase chain reaction. The senescence model was successfully established by treating cells with 200 μM H<sub>2</sub>O<sub>2</sub> for 2 hours daily over a span of three consecutive days. This oxidative stress resulted in a notable increase in the proportion of senescence-associated beta-galactosidase-positive cells, reaching 33.5%, without significant alterations in cell viability or apoptosis. In the ARPE-19 cells undergoing premature senescence, there was a marked increase in reactive oxygen species (ROS) production and malondialdehyde levels, coupled with a significant decrease in the activity of total superoxide dismutase, glutathione peroxidase, and catalase. Additionally, microRNA-34a-5p was found to be overexpressed in these cells. Treatment with LBP alleviated H<sub>2</sub>O<sub>2</sub>-induced premature senescence, diminished the overexpression of microRNA-34a-5p, and suppressed ROS production. Moreover, the incubation with ago-34a reversed the protective effect of LBP in ARPE-19 cells. In conclusion, the overexpression of microRNA-34a-5p contributes to the H<sub>2</sub>O<sub>2</sub>-induced premature senescence of ARPE-19 cells. LBP appears to mitigate this premature senescence, at least in part, by downregulating microRNA-34a-5p expression and reducing oxidative stress.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 3","pages":"Pages 130-142"},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endoplasmic reticulum stress in acute pancreatitis: Exploring the molecular mechanisms and therapeutic targets 内质网应激在急性胰腺炎：探索分子机制和治疗靶点。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-03-17 DOI: 10.1016/j.cstres.2025.03.001

Xiaoliang Zhang , Chenchen Xu , LiJuan Ji , Haiwei Zhang

Acute pancreatitis (AP) is associated with multiple cellular mechanisms that trigger and or are triggered by the inflammatory injury and death of the acinar cells. One of the key mechanisms is the endoplasmic reticulum (ER) stress, which manifests as an accumulation of misfolded proteins within ER, an event that has proinflammatory and proapoptotic consequences. Hence, the degree of cell insult during AP could considerably depend on the signaling pathways that are upregulated during ER stress and its resulting dyshomeostasis such as C/EBP homologous protein (CHOP), cJUN NH2-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome. Exploring these molecular pathways is an interesting area for translational medicine as it may lead to identifying new therapeutic targets in AP. This review of the literature aims to shed light on the different roles of ER stress in the etiopathogenesis and pathogenesis of AP. Then, it specifically focuses on the therapeutic implications of ER stress in this context.

急性胰腺炎（AP）与多种细胞机制有关，这些细胞机制触发或由腺泡细胞的炎症损伤和死亡触发。其中一个关键机制是内质网应激，其表现为内质网内错误折叠蛋白的积累，这一事件具有促炎症和促凋亡的后果。因此，AP过程中细胞损伤的程度可能在很大程度上取决于内质网应激过程中上调的信号通路及其导致的失衡，如C/EBP同源蛋白（CHOP）、cJUN nh2末端激酶（JNK）、核因子κB （NF-κB）和nod样受体蛋白3 （NLRP3）炎性体。对于转化医学来说，探索这些分子通路是一个有趣的领域，因为它可能导致发现新的AP治疗靶点。本文综述的目的是阐明内质网应激在AP的发病机制和发病机制中的不同作用。然后，它特别关注内质网应激在这种情况下的治疗意义。

引用次数: 0