Cell Stress & Chaperones最新文献

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HSP mRNA sequences and their expression under different thermal oscillation patterns and heat stress in two populations of Nodipecten subnodosus 不同热振荡模式和热胁迫下两个种群的HSP mRNA序列及其表达。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-02-01 DOI: 10.1016/j.cstres.2024.12.002

Axel Bonesteve , Salvador E. Lluch-Cota , Maria Teresa Sicard , Ilie S. Racotta , Miguel A. Tripp-Valdez , Liliana Rojo-Arreola

Understanding the molecular mechanisms underlying thermal acclimation and heat shock responses in marine ectotherms is critical for assessing their adaptive capacity in the context of climate change and climate extremes. This study examines the expression dynamics of heat shock proteins (HSPs) in the scallop Nodipecten subnodosus, shedding light on their role in thermal adaptation. Our analysis revealed the presence of several conserved functional signatures in N. subnodosus HSPs deduced amino acid sequences. Comparative gene expression profiling between two populations of N. subnodosus, maintained for 15 days under constant and oscillatory thermal regimes and then exposed to acute heat stress, revealed conserved adaptive traits. The heat-inducible nature of N. subnodosus HSP70 (HSPA8) gene expression highlights its potential as a stress marker, in contrast to its human homolog, which is constitutively expressed. Furthermore, the identification of HSP90 (HSPC3) and its overexpression during acute heat stress underscores its critical role in initiating a protective stress response. Population-specific responses in the magnitude of gene expression were observed; however, both populations exhibited similar overall patterns of HSP induction, suggesting a shared adaptive response mechanism. This study also elucidated the diversity and expansion of members of the HSP70 family members, specifically the HSPA12 subfamily, in N. subnodosus. This characteristic, previously observed in other bivalves, underscores the role of HSPA12 in environmental adaptation, providing molecular plasticity to withstand varying environmental pressures. These findings offer valuable insights into the molecular basis of thermal adaptation in N. subnodosus, highlighting the importance of HSPs in coping with environmental stochasticity under climate change scenarios.

了解海洋变温动物热适应和热休克反应（HSR）的分子机制对于评估其在气候变化和极端气候背景下的适应能力至关重要。本研究研究了热休克蛋白（HSPs）在扇贝Nodipecten subnodosus中的表达动态，揭示了它们在热适应中的作用。我们的分析揭示了N. subnodosus热休克蛋白的氨基酸序列中存在几个保守的功能特征。在恒定和振荡热环境下维持15天，然后暴露于急性热应激下，两个亚结节棘豆种群的基因表达谱比较揭示了保守的适应特征。N. subnodosus HSP70 （HSPA8）基因表达的热诱导性质突出了其作为应激标记物的潜力，与其人类同源物相比，后者是组成性表达的。此外，HSP90 （hsp3）的鉴定及其在急性热应激中的过表达强调了它在启动保护性应激反应中的关键作用。观察到基因表达量的群体特异性反应；然而，这两个种群表现出相似的热休克诱导总体模式，表明具有共同的适应反应机制。本研究还阐明了HSP70家族成员（特别是HSPA12亚家族）在N. subnodosus中的多样性和扩展。这一特性，之前在其他双壳类动物中观察到，强调了HSPA12在环境适应中的作用，提供分子可塑性以承受不同的环境压力。这些发现为研究亚结节棘藓热适应的分子基础提供了有价值的见解，强调了热敏感蛋白在气候变化情景下应对环境随机性的重要性。

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引用次数: 0

Ceapin-A7 suppresses the protective effects of Octreotide in human and bovine lung endothelial cells Ceapin-A7抑制奥曲肽对人和牛肺内皮细胞的保护作用。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-02-01 DOI: 10.1016/j.cstres.2024.12.001

Saikat Fakir, Madan Sigdel, Md Matiur Rahman Sarker, Joy T. Folahan, Nektarios Barabutis

Endothelial injury can be the cause and consequence of severe inflammation and injury. Synthetic somatostatin analogs—which suppress Growth Hormone—are clinically-approved drugs associated with anti-inflammatory activities. In the present study, we suggest that the protective activities of Octreotide in human and bovine endothelial cells are mitigated by Ceapin-A7, which is an activating transcription factor 6 inhibitor. To study endothelial function, we assessed protein expression levels of key cytoskeletal proteins, as well as paracellular permeability. To evaluate inflammation, we measured factors that promote vascular leak, as well as reactive oxygen species generation. Collectively, our study supports the involvement of activating transcription factor 6 in the protective effects of Octreotide in endothelial barrier function.

内皮损伤可能是严重炎症和损伤的原因和后果。合成的生长抑素类似物——抑制生长激素——是fda批准的具有抗炎活性的药物。在本研究中，我们认为奥曲肽对人和牛内皮细胞的保护作用被Ceapin-A7（一种激活转录因子6的抑制因子）所减弱。为了研究内皮功能，我们评估了关键细胞骨架蛋白的蛋白表达水平以及细胞旁通透性。为了评估炎症，我们测量了促进血管泄漏的因素，以及活性氧的产生。总的来说，我们的研究支持激活转录因子6参与奥曲肽对内皮屏障功能的保护作用。

引用次数: 0

FKBP51 overexpression in the corticolimbic system stabilizes circadian rhythms 皮质边缘系统中 FKBP51 的过度表达可稳定昼夜节律

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-02-01 DOI: 10.1016/j.cstres.2024.12.003

Niat T. Gebru , David Beaulieu-Abdelahad , Danielle Gulick , Laura J. Blair

Circadian rhythm disruptions have been associated with a wide range of health issues and complications, including an increased risk of circadian rhythm sleep disorders (CRSDs). CRSDs are common among individuals who have been through a traumatic event, particularly in those who have post-traumatic stress disorder (PTSD). Allelic variations in the gene encoding for FK506-binding protein 51 (FKBP51) can increase the susceptibility for PTSD and other stress-related disorders following trauma. At least one of these variants increases the levels of FKBP51 following stress through a glucocorticoid receptor-mediated process. Here, we used a mouse model that overexpresses human FKBP51 throughout the forebrain, rTgFKBP5, to investigate if elevated FKBP51 contributes to circadian rhythm disruption. Surprisingly, our findings indicate a greater rhythm amplitude and decreased rhythm fragmentation in rTgFKBP5 mice, particularly females, compared to controls. Female rTgFKBP5 mice also showed higher corticosterone levels basally and following stress exposure. Overall, this study associates FKBP51 overexpression with beneficial circadian rhythm outcomes.

昼夜节律紊乱与广泛的健康问题和并发症有关，包括昼夜节律睡眠障碍（crsd）的风险增加。crsd在经历过创伤性事件的个体中很常见，特别是在那些患有创伤后应激障碍（PTSD）的个体中。编码fk506结合蛋白51 （FKBP51）基因的等位基因变异可增加创伤后应激障碍和其他应激相关疾病的易感性。这些变体中至少有一种通过糖皮质激素受体介导的过程增加应激后FKBP51的水平。在这里，我们使用了一个在整个前脑过度表达人类FKBP51的小鼠模型，rTgFKBP5，来研究FKBP51的升高是否会导致昼夜节律紊乱。令人惊讶的是，我们的研究结果表明，与对照组相比，rTgFKBP5小鼠（尤其是雌性）的节律幅度更大，节律碎片化程度更低。雌性rTgFKBP5小鼠在应激暴露基础上和应激暴露后也表现出更高的皮质酮水平。总的来说，本研究将FKBP51过表达与有益的昼夜节律结果联系起来。

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引用次数: 0

Hsp90: Bringing it all together

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2025-02-01 DOI: 10.1016/j.cstres.2025.01.002

Georgios Ioannis Karras , Giorgio Colombo , Andrea N. Kravats

Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation and function of Hsp90, which dwarfs most other machines in the cell in sophistication. Here, we propose four analogies to illustrate Hsp90’s sophistication: a multifunctional Swiss Army knife, an automobile engine and its controls, a switchboard acting as a hub and directing signals, and an orchestra conductor setting the tempo of a symphony. Although each of these analogies represents some key Hsp90 activities, none of them captures the entirety of Hsp90’s complexity. Together, these roles enable Hsp90 to support both homeostasis and differentiation, both cellular stability and adaptability. At the 11th International Conference on the Hsp90 Chaperone Machine, the consensus was that to understand this major guardian of proteostasis, we need to study how the many facets of Hsp90’s function influence each other. We hope that these analogies will help to conceptually integrate the many roles of Hsp90 in proteostasis and help the field develop the practical applications of Hsp90 modulators.

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引用次数: 0

Editorial Board Members/Copyright

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2024-12-01 DOI: 10.1016/S1355-8145(24)00137-8

引用次数: 0

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IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2024-12-01 DOI: 10.1016/S1355-8145(24)00136-6

引用次数: 0

Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: From molecular mechanisms to therapeutic applications 骨关节炎中内质网应激介导的细胞凋亡和自噬：从分子机制到治疗应用。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2024-12-01 DOI: 10.1016/j.cstres.2024.11.005

Yifan Lu , Jing Zhou , Hong Wang , Hua Gao , Eryu Ning , Zhiqiang Shao , Yuefeng Hao , Xing Yang

Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response, ER-associated degradation, and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy—key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.

骨关节炎（OA）的主要特征是关节软骨退化，发病率和致残率都很高。软骨细胞作为软骨内唯一的细胞类型，其功能表型对 OA 的发展至关重要。由于软骨的无血管性质及其有限的再生能力，损伤后的修复面临着巨大的挑战。各种细胞应激因素，包括缺氧、营养匮乏、氧化应激和胶原突变，都可能导致折叠错误的蛋白质在内质网（ER）中堆积，造成ER应激（ERS）。为了恢复ER的平衡以及细胞的活力和功能，一系列适应机制被触发，包括未折叠蛋白反应（UPR）、ER相关降解（ERAD）和ER吞噬。长期或严重的ERS可能会超出细胞的适应能力，导致细胞凋亡和自噬失调--这是导致软骨细胞损伤和OA进展的主要致病因素。本综述探讨了 OA 软骨细胞的 ERS 与细胞凋亡和自噬之间的关系，以确定预防和治疗 OA 的潜在治疗靶点和策略。

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引用次数: 0

The role of the FKBP51–Hsp90 complex in Alzheimer’s disease: An emerging new drug target FKBP51-Hsp90复合物在阿尔茨海默病中的作用：一个新兴的新药物靶点。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2024-12-01 DOI: 10.1016/j.cstres.2024.11.006

Xavier Jeanne , Zsolt Török , László Vigh , Chrisostomos Prodromou

With increasing age comes the inevitable decline in proteostasis, where chaperone and co-chaperone activity becomes imbalanced. These changes lead to global disturbances and pathogenic rewiring of the chaperone system into epichaperones consisting of protein networks that are ultimately dysfunctional. Such imbalances in proteostasis may favor mechanisms that can lead to neurological diseases, such as Alzheimer’s disease (AD). Consequently, there has been an increase in research activity toward finding small molecules that can re-balance the chaperone and co-chaperone machinery to counter the effects of disease resulting from old age. The Hsp90 co-chaperone FKBP51 has recently been identified as a protein whose induction not only increases with age but is elevated further in AD cells. Significantly, FKBP51 plays a role in the Hsp90-dependent isomerization of tau, which in turn influences its phosphorylation and susceptibility to aggregation. We hypothesize that FKBP51 is a major player that is able to elicit tauopathy in response to amyloid-beta senile plaques that damage the brain. We propose that elevated FKBP51 levels result in an abnormal FKBP51–Hsp90 activity that alters the normal processing of tau, which manifests as hyperphosphorylation and oligomerization of tau. Thus, the Hsp90–FKBP51 complex is emerging as a drug target against AD. In support of this idea, the structure of the FKBP51–Hsp90 complex was recently described, and significantly, the small-molecule dihydropyridine LA1011 was shown to be able to disrupt the Hsp90–FKBP51 complex. LA1011 was previously shown to effectively prevent neurodegeneration in the APPxPS1 AD transgenic mouse model. This review looks at the role of Hsp90 and its co-chaperones in AD with a focus on FKBP51.

随着年龄的增长，蛋白质平衡不可避免地下降，伴侣和共同伴侣的活动变得不平衡。这些变化导致伴侣系统的全局干扰和致病性重新布线，使之成为由蛋白质网络组成的表伴侣体，最终功能失调。蛋白质平衡的这种不平衡可能有利于导致神经系统疾病的机制，如阿尔茨海默病（AD）。因此，在寻找小分子方面的研究活动有所增加，这些小分子可以重新平衡伴侣和共同伴侣机制，以对抗老年引起的疾病的影响。Hsp90的共同伴侣FKBP51最近被确定为一种蛋白质，其诱导不仅随着年龄的增长而增加，而且在AD细胞中进一步升高。值得注意的是，FKBP51在依赖Hsp90的tau异构化中发挥作用，进而影响其磷酸化和对聚集的易感性。我们假设FKBP51是一个主要的参与者，能够引起对淀粉样- β老年斑损伤大脑的反应。我们提出FKBP51水平升高导致FKBP51- hsp90活性异常，从而改变tau的正常加工，表现为tau的过度磷酸化和低聚化。因此，Hsp90-FKBP51复合物正成为治疗AD的药物靶点。为了支持这一观点，最近对FKBP51-Hsp90复合物的结构进行了描述，值得注意的是，小分子二氢吡啶LA1011被证明能够破坏Hsp90-FKBP51复合物。LA1011先前在APPxPS1 AD转基因小鼠模型中被证明能有效预防神经退行性变。本综述着眼于Hsp90及其伴蛋白在AD中的作用，重点关注FKBP51。

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引用次数: 0

Pyrotinib induces cell death in HER2-positive breast cancer via triggering HSP90-dependent HER2 degradation and ROS/HSF-1-dependent oxidative DNA damage 派罗替尼通过引发依赖HSP90的HER2降解和依赖ROS/HSF-1的氧化性DNA损伤，诱导HER2阳性乳腺癌细胞死亡。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2024-12-01 DOI: 10.1016/j.cstres.2024.11.004

Xiaomin Gao , Xu Guo , Wenbo Yuan , Sunmin Jiang , Zihong Lu , Qing Luo , Yuan Zha , Ling Wang , Shu Li , Ke Wang , Xue Zhu , Ying Yao

HER2-positive breast cancer (HER2+ BC) is distinguished by its poor prognosis, propensity for early onset, and high risk of recurrence and metastasis. Consequently, anti-HER2-targeted therapy has emerged as a principal strategy in the treatment of this form of breast cancer. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor, has brought fresh hope to patients with advanced HER2+ breast cancer. In this study, we conducted a comprehensive exploration of pyrotinib’s antitumor mechanism. The in vitro results showed that pyrotinib significantly inhibited SKBR3 cells viability and induced apoptosis by promoting HER2 endocytosis and ubiquitylation, leading to HER2 degradation through the displacement of HSP90 from HER2. Beyond targeting the HER2 signaling pathway, pyrotinib also induced DNA damage, which was mediated by the activation of the reactive oxygen species/heat shock factor 1 signaling pathway and the downregulation of proliferating cell nuclear antigen expression. Furthermore, the in vivo results demonstrated a pronounced anticancer effect of pyrotinib in the SKBR3 xenograft mouse model, concomitant with a reduction in HER2 expression. In summary, our findings provide novel insights into the mechanism of pyrotinib in the treatment of HER2+ BC.

HER2阳性乳腺癌（HER2+ BC）的特点是预后差、发病早、复发和转移风险高。因此，抗HER2靶向治疗已成为治疗这种乳腺癌的主要策略。派罗替尼是一种新型不可逆的泛HER2酪氨酸激酶抑制剂，为晚期HER2+乳腺癌患者带来了新的希望。在这项研究中，我们对派罗替尼的抗肿瘤机制进行了全面探索。体外实验结果表明，吡罗替尼通过促进HER2的内吞和泛素化，使HSP90从HER2上移位，导致HER2降解，从而显著抑制SKBR3细胞的活力并诱导其凋亡。除了靶向HER2信号通路外，吡罗替尼还能诱导DNA损伤，而DNA损伤是通过激活ROS/HSF-1信号通路和下调PCNA表达介导的。此外，体内研究结果表明，在SKBR3异种移植小鼠模型中，在降低HER2表达的同时，吡罗替尼具有明显的抗癌作用。总之，我们的研究结果为吡罗替尼治疗HER2+ BC的机制提供了新的见解。

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引用次数: 0

Protective role of short-chain fatty acids on intestinal oxidative stress induced by TNF-α 短链脂肪酸对 TNF-α 诱导的肠道氧化应激的保护作用

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Cell Stress & Chaperones

Pub Date : 2024-12-01 DOI: 10.1016/j.cstres.2024.11.002

Miguel Ferrer , Berta Buey , Laura Grasa , Jose Emilio Mesonero , Eva Latorre

Inflammatory bowel diseases (IBDs) are driven by an exaggerated inflammatory response, which leads to a marked increase in oxidative stress. This, in turn, exacerbates the inflammatory process and causes significant cellular and tissue damage. Intestinal dysbiosis, a common observation in IBD patients, alters the production of bacterial metabolites, including short-chain fatty acids (SCFAs), which are key by-products of dietary fiber fermentation. While the role of SCFAs in intestinal physiology is still being elucidated, this study aimed to investigate their effects on intestinal oxidative stress, particularly under inflammatory conditions induced by the proinflammatory mediator tumor necrosis factor alpha (TNF-α). The Caco-2/TC7 cell line was employed as an in vitro model of the intestinal epithelium, and the cells were treated with a range of SCFAs, including acetate, propionate, and butyrate. The levels of protein and lipid oxidation were quantified, as well as the activity of antioxidant enzymes. Our findings demonstrate that microbiota-derived SCFAs can effectively mitigate TNF-α-induced oxidative stress by modulating antioxidant enzyme activity. The proinflammatory mediator TNF-α induces lipid peroxidation by inhibiting catalase and glutathione peroxidase activities. SCFAs are able to upregulate antioxidant enzyme activity to restore lipid oxidative levels. These results underscore the critical role of the gut microbiota in maintaining intestinal homeostasis and highlight the therapeutic potential of SCFAs in managing oxidative stress-related pathologies.

炎症性肠病（IBD）是由夸张的炎症反应引起的，它会导致氧化应激明显增加。这反过来又加剧了炎症过程，造成严重的细胞和组织损伤。肠道菌群失调是 IBD 患者的常见症状，它会改变细菌代谢产物的产生，包括膳食纤维发酵的主要副产品短链脂肪酸 (SCFA)。虽然 SCFAs 在肠道生理学中的作用仍有待阐明，但本研究旨在调查它们对肠道氧化应激的影响，尤其是在促炎介质肿瘤坏死因子α（TNF-α）诱导的炎症条件下。我们采用 Caco-2/TC7 细胞系作为肠上皮细胞的体外模型，并用一系列 SCFAs（包括乙酸盐、丙酸盐和丁酸盐）对细胞进行处理。对蛋白质和脂质氧化水平以及抗氧化酶的活性进行了量化。我们的研究结果表明，微生物群衍生的 SCFAs 可通过调节抗氧化酶的活性，有效缓解 TNF-α 诱导的氧化应激。促炎介质 TNF-α 通过抑制过氧化氢酶和谷胱甘肽过氧化物酶的活性来诱导脂质过氧化。SCFAs 能够上调抗氧化酶的活性，从而恢复脂质氧化水平。这些结果强调了肠道微生物群在维持肠道平衡中的关键作用，并突出了 SCFAs 在控制氧化应激相关病症方面的治疗潜力。

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