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Necroptosis in obesity: a complex cell death event. 肥胖的坏死性上睑下垂:一个复杂的细胞死亡事件。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-19 DOI: 10.1007/s10495-024-02055-z
Zunhai Liu, Simeng Wang, Wentao Wang, Rui Lv, Chao Sun

Obesity is an exceedingly prevalent and frequent health issue in today's society. Fat deposition is accompanied by low-grade inflammation in fat tissue and throughout the body, leading to metabolic disorders that ultimately promote the onset of obesity-related diseases. The development of obesity is accompanied by cell death events such as apoptosis as well as pyroptosis, however, the role of necroptosis in obesity has been widely reported in recent years. Necroptosis, a mode of cell death distinct from apoptosis and necrosis, is associated with developing many inflammatory conditions and their associated diseases. It also exhibits modulation of apoptosis and pyroptosis. It is morphologically similar to necroptosis, characterized by the inhibition of caspase-8, the formation of membrane pores, and the subsequent rupture of the plasma membrane. This paper focuses on the key pathways and molecules of necroptosis, exploring its connections with apoptosis and pyroptosis, and its implications in obesity. This paper posits that the modulation of necroptosis-related targets may represent a novel potential therapeutic avenue for the prevention and treatment of obesity-induced systemic inflammatory responses, and provides a synopsis of potential molecular targets that may prove beneficial in obesity-associated inflammatory diseases.

肥胖是当今社会一个非常普遍和频繁的健康问题。脂肪沉积伴随着脂肪组织和全身的低度炎症,导致代谢紊乱,最终促进肥胖相关疾病的发生。肥胖的发生伴随着细胞凋亡、焦亡等细胞死亡事件的发生,然而近年来,关于细胞坏死在肥胖中的作用已被广泛报道。坏死下垂是一种不同于细胞凋亡和坏死的细胞死亡模式,与许多炎症及其相关疾病的发生有关。它也表现出细胞凋亡和焦亡的调节。它在形态学上与坏死性上睑下垂相似,其特征是caspase-8的抑制,膜孔的形成,以及随后的质膜破裂。本文重点研究坏死下垂的关键通路和分子,探讨其与细胞凋亡和焦亡的联系及其在肥胖中的意义。本文认为,坏死相关靶点的调节可能代表了预防和治疗肥胖诱导的全身炎症反应的一种新的潜在治疗途径,并提供了可能证明对肥胖相关炎症性疾病有益的潜在分子靶点的概述。
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引用次数: 0
EFNA4-enhanced deubiquitination of SLC7A11 inhibits ferroptosis in hepatocellular carcinoma. efna4增强SLC7A11去泛素化抑制肝癌铁下垂。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-10 DOI: 10.1007/s10495-024-02042-4
Xingyi Zhong, Zhiqin Zhu, Yangfeng Du, Lingzhi Long, Ziping Xie, Yangfeng Zhang, Huijun Yao, Junhao Lin, Fengsheng Chen

EFNA4, a member of the Ephrin-A ligand family, may influence hepatocellular carcinoma cells through two distinct mechanisms: one reliant on specific Eph receptor binding and the other independent of receptor involvement. However, EFNA4's influence on HCC via non-Eph receptor pathways remains unclear. In this study, we aimed to investigate the role of EFNA4 in a receptor-independent environment. Firstly, we constructed an environment lacking Eph receptors via CRISPR/Cas9 and found that EFNA4 could still partially promote HCC proliferation and metastasis in vivo and in vitro. Further analyses of apoptosis, ROS, and GPX4 expression revealed that overexpression of EFNA4 would inhibit ferroptosis in HCC. Mechanistically, EFNA4 was positively correlated with SLC7A11 and directly interacted with SLC7A11 in HCC via bioinformatics analysis. We demonstrated that the structural domain (a.a. 161-201) of EFNA4 specifically binds to the domain (a.a. 222-501) of SLC7A11, which led to the deubiquitination of SLC7A11. Subsequently, we found that EFNA4 would recruit the deubiquitinase USP9X, resulting in inhibition of SLC7A11 degradation, which ultimately inhibits ferroptosis and enhances the proliferation and metastasis of HCC. In conclusion, we demonstrated that EFNA4 promotes the proliferation and metastasis of HCC independent of Eph receptors by inhibiting ferroptosis and advancing the deubiquitination of SLC7A11 by recruiting the deubiquitinase USP9X. This indicates that EFNA4 could act as a potential prognostic marker and a prospective therapeutic target in patients with HCC.

EFNA4是Ephrin-A配体家族的一员,可能通过两种不同的机制影响肝癌细胞:一种依赖于特定的Eph受体结合,另一种独立于受体参与。然而,EFNA4通过非eph受体途径对HCC的影响尚不清楚。在这项研究中,我们旨在研究EFNA4在不依赖受体的环境中的作用。首先,我们通过CRISPR/Cas9构建了缺乏Eph受体的环境,发现EFNA4在体内和体外仍能部分促进HCC的增殖和转移。进一步对细胞凋亡、ROS和GPX4表达的分析表明,过表达EFNA4可抑制HCC中的铁下垂。从机制上看,EFNA4与SLC7A11呈正相关,并通过生物信息学分析在HCC中与SLC7A11直接相互作用。我们证明了EFNA4的结构域(a.a. 161-201)特异性结合SLC7A11的结构域(a.a. 222-501),从而导致SLC7A11的去泛素化。随后,我们发现EFNA4会募集去泛素酶USP9X,从而抑制SLC7A11的降解,最终抑制铁下沉,促进HCC的增殖和转移。综上所述,我们证明EFNA4通过募集去泛素酶USP9X来抑制铁凋亡和促进SLC7A11的去泛素化,从而独立于Eph受体促进HCC的增殖和转移。这表明EFNA4可以作为HCC患者的潜在预后标志物和前瞻性治疗靶点。
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引用次数: 0
Microglia programmed cell death in neurodegenerative diseases and CNS injury. 神经退行性疾病和中枢神经系统损伤中的小胶质细胞程序性死亡。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-10 DOI: 10.1007/s10495-024-02041-5
Ling Cai, Qiuyue Fan, Rui Pang, Chen Chen, Yueman Zhang, Haiyi Xie, Jingyi Huang, Yu Wang, Peiying Li, Dan Huang, Xia Jin, Yuxi Zhou, Yan Li

Programmed cell death (PCD) has emerged as a critical regulatory mechanism in the initiation and progression of various pathological conditions. PCD in microglia, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, occurs in a variety of central nervous system (CNS) diseases. Dysregulation of microglia can lead to excessive tissue damage or neuronal death in CNS injury. Various injury stimuli trigger aberrant activation of the PCD pathway of microglia, which then further leads to inflammatory cascades that exacerbates CNS pathology in a vicious cycle. Therefore, targeting PCD in microglia is considered an important avenue for the treatment of various neurodegenerative diseases and CNS injury. In this review, we summarize the major and recent findings focusing on the mechanisms of PCD in microglia modulating functions in neurodegenerative diseases and CNS injury and provide a systematic overview of the current inhibitors targeting various PCD pathways, which may provide important therapeutic targets that merit further investigation.

程序性细胞死亡(PCD)已成为各种病理状况发生和发展的关键调控机制。小胶质细胞的PCD包括坏死性坏死、焦亡、凋亡、铁性坏死和自噬,发生在多种中枢神经系统疾病中。在中枢神经系统损伤中,小胶质细胞的失调可导致过度的组织损伤或神经元死亡。各种损伤刺激触发小胶质细胞PCD通路的异常激活,然后进一步导致炎症级联反应,从而加剧中枢神经系统病理,形成恶性循环。因此,在小胶质细胞中靶向PCD被认为是治疗各种神经退行性疾病和中枢神经系统损伤的重要途径。在这篇综述中,我们总结了PCD在神经退行性疾病和中枢神经系统损伤中对小胶质细胞调节功能机制的主要和最新发现,并系统概述了目前针对各种PCD途径的抑制剂,这些抑制剂可能提供值得进一步研究的重要治疗靶点。
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引用次数: 0
Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells. 线粒体CLPB是小鼠成髓细胞粒细胞分化开始时的促存活因子。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-07 DOI: 10.1007/s10495-024-02053-1
Tomasz Wenta, Guanpeng Wang, Tessa Van Buren, Michal Zolkiewski, Anna Zolkiewska

Loss-of-function mutations in the CLPB gene lead to congenital neutropenia due to impaired neutrophil differentiation. CLPB, a member of the AAA+ family of proteins, resides in the intermembrane space of mitochondria. The mechanism by which a loss of CLPB elicits defects in the differentiation program of neutrophil precursor cells is not understood. Here, we used 32D clone 3 (32Dcl3) cells, an interleukin-3 (IL-3)-dependent mouse myeloblastic cell line model, to investigate the effects of CLPB knockout on myeloblast-to-neutrophil differentiation in vitro. We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells. Despite those abnormalities, CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF). CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells. Moreover, we found that increased apoptosis of CLPB-deficient cells is linked to production of reactive oxygen species (ROS). N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation. The protective effect of citrate was abolished by inhibition of ATP-citrate lyase (ACLY), an enzyme that converts cytosolic citrate into acetyl-CoA, a substrate for protein acetylation. We propose that citrate supplementation may help mitigate the effects of CLPB loss by facilitating ACLY-dependent ROS detoxification in granulocytic precursor cells.

由于中性粒细胞分化受损,CLPB基因的功能缺失突变导致先天性中性粒细胞减少症。CLPB是AAA+蛋白家族的一员,存在于线粒体的膜间空间。CLPB缺失导致中性粒细胞前体细胞分化程序缺陷的机制尚不清楚。本研究采用白细胞介素-3 (IL-3)依赖性小鼠成髓细胞系模型32D克隆3 (32Dcl3)细胞,在体外研究敲除CLPB对成髓细胞向中性粒细胞分化的影响。我们发现,与对照细胞相比,缺乏clpb的32Dcl3细胞线粒体膜电位降低,线粒体中不溶性HAX1聚集物水平升高。尽管存在这些异常,但在IL-3存在的情况下,CLPB丢失不影响细胞增殖率,但在IL-3退出和粒细胞集落刺激因子(G-CSF)同时诱导细胞分化后,CLPB丢失增加了细胞凋亡。在IL-3戒断/G-CSF处理相关应激下存活的clpb缺陷细胞表达与对照细胞相同水平的分化标记。此外,我们发现clpb缺陷细胞的凋亡增加与活性氧(ROS)的产生有关。n -乙酰半胱氨酸、外源性游离脂肪酸或外源性柠檬酸可保护clpb缺陷32Dcl3细胞在分化开始时免于凋亡。柠檬酸盐的保护作用被atp -柠檬酸裂解酶(ACLY)的抑制所消除,ACLY是一种将细胞质柠檬酸转化为乙酰辅酶a(一种蛋白质乙酰化的底物)的酶。我们建议补充柠檬酸盐可以通过促进粒细胞前体细胞中acly依赖性ROS解毒来帮助减轻CLPB丢失的影响。
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引用次数: 0
GAS5 long non-coding RNA interacts with microRNA-205 to relieve fibroblast-like synoviocyte inflammation and ferroptosis in osteoarthritis. GAS5长链非编码RNA与microRNA-205相互作用,缓解成纤维细胞样滑膜细胞炎症和骨关节炎中的铁下垂。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-07 DOI: 10.1007/s10495-024-02051-3
Yanglin Gu, Guangchang Wang, Peng Chen

This study aimed to explore the role of the growth arrest-specific five gene (GAS5) long non-coding RNA (lncRNA) in fibroblast-like synoviocytes (FLSs) during the development of osteoarthritis (OA). A total of 25 OA synovial tissues and nine healthy control tissues were collected, and their GAS5 expression was compared. To confirm GAS5 expression in vitro, interleukin (IL)-1β was used to mimic a cellular OA model based on isolated FLSs. Quantitative polymerase chain reaction revealed higher expression levels of GAS5 in OA samples than in non-OA samples. In vitro, the stimulation of FLSs by IL-1β induced high GAS5 expression. The IL-1β-exposed cells exhibited impaired growth, viability, and antioxidant capacity, as well as increased cell death, production of cellular and lipid ROS, and inflammatory cytokine levels. The expression levels of ferroptosis-related proteins in FLSs were also altered in IL-1β-exposed cells. GAS5 was observed to directly target and inhibit micro-RNA 205, partially reversing the effect of GAS5 silencing on cell proliferation, cell death, oxidative stress, inflammation, and FLS ferroptosis. FLS ferroptosis is recognized to be involved in OA development, and the downregulation of the GAS5 lncRNA exhibits protective effects by suppressing ferroptosis and sponging miR-205 in FLSs in OA, thereby providing a novel strategy for the treatment of OA. The GAS5-miR-205 axis can regulate inflammation and oxidative stress in the FLSs of patients with OA.

本研究旨在探讨生长阻滞特异性五基因(GAS5)长链非编码RNA (lncRNA)在成纤维细胞样滑膜细胞(FLSs)中在骨关节炎(OA)发展过程中的作用。共收集25例OA滑膜组织和9例健康对照组织,比较其GAS5表达情况。为了证实GAS5在体外的表达,我们利用白细胞介素(IL)-1β模拟了基于分离FLSs的细胞OA模型。定量聚合酶链反应显示OA样品中GAS5的表达水平高于非OA样品。在体外,IL-1β刺激FLSs可诱导GAS5高表达。暴露于il -1β的细胞表现出生长、活力和抗氧化能力受损,以及细胞死亡、细胞和脂质ROS产生和炎症细胞因子水平增加。在il -1β暴露的细胞中,FLSs中铁中毒相关蛋白的表达水平也发生了变化。GAS5直接靶向并抑制了微rna 205,部分逆转了GAS5沉默对细胞增殖、细胞死亡、氧化应激、炎症和FLS铁凋亡的影响。FLS铁下垂被认为参与OA的发展,GAS5 lncRNA的下调通过抑制OA中FLS中的铁下垂和海绵miR-205表现出保护作用,从而为OA的治疗提供了一种新的策略。GAS5-miR-205轴可以调节OA患者fls的炎症和氧化应激。
{"title":"GAS5 long non-coding RNA interacts with microRNA-205 to relieve fibroblast-like synoviocyte inflammation and ferroptosis in osteoarthritis.","authors":"Yanglin Gu, Guangchang Wang, Peng Chen","doi":"10.1007/s10495-024-02051-3","DOIUrl":"https://doi.org/10.1007/s10495-024-02051-3","url":null,"abstract":"<p><p>This study aimed to explore the role of the growth arrest-specific five gene (GAS5) long non-coding RNA (lncRNA) in fibroblast-like synoviocytes (FLSs) during the development of osteoarthritis (OA). A total of 25 OA synovial tissues and nine healthy control tissues were collected, and their GAS5 expression was compared. To confirm GAS5 expression in vitro, interleukin (IL)-1β was used to mimic a cellular OA model based on isolated FLSs. Quantitative polymerase chain reaction revealed higher expression levels of GAS5 in OA samples than in non-OA samples. In vitro, the stimulation of FLSs by IL-1β induced high GAS5 expression. The IL-1β-exposed cells exhibited impaired growth, viability, and antioxidant capacity, as well as increased cell death, production of cellular and lipid ROS, and inflammatory cytokine levels. The expression levels of ferroptosis-related proteins in FLSs were also altered in IL-1β-exposed cells. GAS5 was observed to directly target and inhibit micro-RNA 205, partially reversing the effect of GAS5 silencing on cell proliferation, cell death, oxidative stress, inflammation, and FLS ferroptosis. FLS ferroptosis is recognized to be involved in OA development, and the downregulation of the GAS5 lncRNA exhibits protective effects by suppressing ferroptosis and sponging miR-205 in FLSs in OA, thereby providing a novel strategy for the treatment of OA. The GAS5-miR-205 axis can regulate inflammation and oxidative stress in the FLSs of patients with OA.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
HIG-2 promotes glioma stemness and radioresistance mediated by IGFBP2-rich microparticles in hypoxia. high -2促进缺氧条件下富含igfbp2微粒介导的胶质瘤干性和辐射抗性。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s10495-024-02045-1
Ying Yang, Ting Sun, Xuefei Xue, Huiling Tan, Yanyan Li, Wei Yang

Hypoxia can weaken the efficacy of radiotherapy and decrease tumor immunogenicity leading to immune escape. Thus, a thorough understanding of the key signaling pathways regulated by hypoxia is vitally important to enhance the radiosensitivity and improve immunosuppressive microenvironment of glioma. In this study, we verified the crucial role of hypoxia-inducible gene 2 (HIG-2) in lipid droplet (LD) accumulation and demonstrated that HIG-2 binding to frizzled class receptor 10 (FZD10) activated Wnt/β-catenin signaling pathway and increased its downstream insulin-like growth factor binding protein 2 (IGFBP2) level in microparticles (MPs) derived from glioma stem cells (GSCs), leading to decreased radiosensitivity and immunogenicity of MPs-receiving cells via the cross-talk between GSCs and non-stem glioma cells (GCs). These findings suggest that HIG-2 may be a promising target in glioma radiotherapy and/or immunotherapy.

缺氧可削弱放疗效果,降低肿瘤免疫原性,导致免疫逃逸。因此,深入了解缺氧调控的关键信号通路对于增强胶质瘤的放射敏感性和改善免疫抑制微环境至关重要。在本研究中,我们验证了缺氧诱导基因2 (high -2)在脂滴(LD)积累中的关键作用,并证明high -2与卷曲类受体10 (FZD10)的结合激活了Wnt/β-catenin信号通路,并增加了其下游胰岛素样生长因子结合蛋白2 (IGFBP2)在胶质瘤干细胞(GSCs)衍生的微颗粒(MPs)中的水平。通过GSCs和非干细胞胶质瘤细胞(GCs)之间的串扰,导致mp接收细胞的放射敏感性和免疫原性降低。这些发现表明high -2可能是胶质瘤放疗和/或免疫治疗的一个有希望的靶点。
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引用次数: 0
Probiotic DNA regulates intestinal Th2 polarization by inducing epithelial cells to produce PD-L1. 益生菌DNA通过诱导上皮细胞产生PD-L1调节肠道Th2极化。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s10495-024-02043-3
Shuo Song, Hanqing Zhang, Le Liu, Minyao Li, Xiangyu Wang, Haotao Zeng, Miao Zhao, Pixin Ran, Qing Shu, Pingchang Yang

Th2 polarization is a characteristic feature of many immune diseases; its pathogenesis is still being elucidated. Probiotics have immune regulatory effects. This study is aimed at testing the impact of Lactobacillus rhamnosus (LR) DNA on regulating Th2 polarization and elucidating its underlying mechanism. In this study, ovalbumin plus alum protocol was used to establish the Th2 polarization status in the mouse intestine. Mice received LR-DNA gavage daily for five days. The expression of programmed cell death ligand-1 (PD-L1) in intestinal epithelial cells was assessed using RT-qPCR, enzyme-linked immunosorbent assay, and immunohistochemistry. The results showed that the expression of PD-L1 was detected in mouse intestinal epithelial cells, which was up regulated by LR-DNA gavage daily for 5 days. The expression of PD-L1 was also detected in T84 cells, which could be increased by exposing them to LR-DNA in culture. RNA sequencing results showed that the gene activities of Kdm5a, foxo1 and Pdl1 could be upregulated by LR-DNA in mouse intestinal epithelial cells. The epithelial cell-derived PD-L1 induced the activated Th2 cell apoptosis by interacting with programmed cell death protein-1 (PD-1). Administration of LR-DNA, but not live probiotics, alleviated experimental Th2 polarization in a food allergy mouse model. In conclusion, LR-DNA induces intestinal epithelial cells to produce PD-L1, which induces the activated Th2 cell apoptosis. Administration of LR-DNA mitigated experimental Th2 polarization in the intestine.

Th2极化是许多免疫疾病的特征;其发病机制尚不清楚。益生菌具有免疫调节作用。本研究旨在检测鼠李糖乳杆菌(Lactobacillus rhamnosus, LR) DNA对Th2极化的调控作用,并阐明其潜在机制。本研究采用卵清蛋白加明矾方案建立小鼠肠道中Th2极化状态。小鼠每天灌胃LR-DNA,连续5天。采用RT-qPCR、酶联免疫吸附法和免疫组织化学检测肠上皮细胞中程序性细胞死亡配体-1 (PD-L1)的表达。结果表明,小鼠肠上皮细胞中检测到PD-L1的表达,每天灌胃5 d后PD-L1表达上调。在T84细胞中也检测到PD-L1的表达,将其暴露于培养的LR-DNA中可以增加PD-L1的表达。RNA测序结果显示,LR-DNA可上调小鼠肠上皮细胞中Kdm5a、foxo1和Pdl1的基因活性。上皮细胞源性PD-L1通过与程序性细胞死亡蛋白-1 (PD-1)相互作用诱导活化的Th2细胞凋亡。在食物过敏小鼠模型中,给予LR-DNA而非活益生菌可减轻实验性Th2极化。综上所述,LR-DNA诱导肠上皮细胞产生PD-L1, PD-L1诱导活化的Th2细胞凋亡。给药LR-DNA减轻了实验性肠内Th2极化。
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引用次数: 0
Machine learning-based analysis of programmed cell death types and key genes in intervertebral disc degeneration. 基于机器学习的椎间盘退变中程序性细胞死亡类型和关键基因分析。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s10495-024-02047-z
Yigang Lv, Jiawei Du, Haoning Xiong, Lei Feng, Di Zhang, Hengxing Zhou, Shiqing Feng

Intervertebral disc degeneration (IVDD) is intricately associated with various forms of programmed cell death (PCD). Identifying key PCD types and associated genes is essential for understanding the molecular mechanisms underlying IVDD and discovering potential therapeutic targets. This study aimed to elucidate core PCD types, related genes, and potential drug interactions in IVDD using comprehensive bioinformatic and experimental approaches. Using datasets GSE167199, GSE176205, GSE34095, GSE56081, and GSE70362, relevant gene expression and clinical data were analyzed. Differential expression gene (DEG) analysis identified upregulated genes linked to 15 PCD types. Gene Set Variation Analysis (GSVA) was employed to pinpoint key PCD types contributing to disc degeneration. Core genes were identified through machine learning techniques, while immune infiltration and single-cell analysis helped identify apoptosis-related cell types. Molecular docking, along with in vivo and in vitro experiments using a murine IVDD model, validated potential drug interactions. The results identified apoptosis, autophagy, ferroptosis, and necroptosis as key PCD types in IVDD. A gene module associated with apoptosis showed a strong correlation with the severity of disc degeneration, revealing 34 central genes in the gene network. Drug screening identified Glibenclamide as effectively interacting with PDCD6 and UBE2K. Subsequent in vitro and in vivo experiments demonstrated that Glibenclamide reduced apoptosis and delayed disc degeneration progression. This study provides a comprehensive bioinformatics analysis of PCD in IVDD, identifying four primary PCD types contributing to the disease's progression. The findings offer novel insights into the molecular pathology of disc degeneration and suggest promising therapeutic strategies for future treatment development.

椎间盘退变(IVDD)与多种形式的程序性细胞死亡(PCD)有着复杂的关系。确定关键的PCD类型和相关基因对于理解IVDD的分子机制和发现潜在的治疗靶点至关重要。本研究旨在利用综合生物信息学和实验方法阐明IVDD的核心PCD类型、相关基因和潜在的药物相互作用。使用GSE167199、GSE176205、GSE34095、GSE56081和GSE70362数据集分析相关基因表达和临床数据。差异表达基因(DEG)分析发现了与15种PCD类型相关的上调基因。基因集变异分析(GSVA)用于确定导致椎间盘退变的关键PCD类型。通过机器学习技术鉴定核心基因,而免疫浸润和单细胞分析有助于鉴定与凋亡相关的细胞类型。分子对接,以及使用小鼠IVDD模型的体内和体外实验,验证了潜在的药物相互作用。结果发现凋亡、自噬、铁下垂和坏死下垂是IVDD的主要PCD类型。一个与细胞凋亡相关的基因模块显示与椎间盘退变的严重程度密切相关,揭示了基因网络中的34个中心基因。药物筛选证实格列本脲可与PDCD6和UBE2K有效相互作用。随后的体外和体内实验表明,格列本脲可减少细胞凋亡并延缓椎间盘退变的进展。本研究提供了IVDD中PCD的全面生物信息学分析,确定了四种主要的PCD类型对疾病进展的影响。这些发现为椎间盘退变的分子病理学提供了新的见解,并为未来的治疗发展提出了有希望的治疗策略。
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引用次数: 0
Melatonin ameliorates inflammation and improves outcomes of ischemia/reperfusion injury in patients undergoing coronary artery bypass grafting surgery: a randomized placebo-controlled study. 褪黑素可改善冠状动脉搭桥术患者的炎症并改善缺血/再灌注损伤的预后:一项随机安慰剂对照研究。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s10495-024-02040-6
Eman Ahmed Casper, Lamia El Wakeel, Nagwa A Sabri, Ramy Khorshid, Mohamed A Gamal, Sarah F Fahmy

To investigate the protective role of high dose melatonin concerning myocardial I/R injury and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG) surgery by evaluating IR/inflammatory biomarkers and clinical outcomes. This was a prospective; randomized; single-blinded placebo-controlled study conducted at cardio-thoracic surgery department of the Academy of the Cardiovascular and Thoracic Surgery, Ain Shams University. Eligible patients were randomly allocated to; melatonin-treated group (MTG) or placebo-treated group (PTG). The MTG (n = 17) received 60 mg/day melatonin capsules daily starting 5 days before surgery in addition to the standard of care. PTG (n = 17) received placebo also 5 days before surgery plus standard of care. The levels of nuclear factor kappa beta (NF-κb) (primary outcome), tumor necrosis factor (TNF-α), cardiac troponins I, and IL-6 levels were all assessed for both groups at five time points: baseline before melatonin or placebo administration (T0), before cross-clamp application(T1), 5 min after cross-clamp removal(T2), 6 h after cross-clamp removal(T3) and 24 h after cross-clamp removal(T4). Blood pressure was assessed at baseline, pre-operative and 24-hours post-operative. The Quality of recovery-40 score (QOR-40) was assessed for both groups on day 4 after surgery. TNF-α levels decreased in the MTG at T1(p = 0.034) versus PTG. At T2(p = 0.005), and T3(p = 0.04), TNF-α significantly increased in PTG versus MTG. Troponins significantly increased in PTG at T3 (p = 0.04) versus MTG. NF-κB levels declined at T1 (p = 0.013) and T2 (p = 0.0001) in MTG compared to PTG. IL-6 significantly increased in PTG versus MTG at T3 (p = 0.04). The QOR-40 score significantly decreased in MTG versus PTG. MTG had statistically significant decrease in DBP compared to the placebo group (p = 0.024). MTG had a statistically significant shorter intubation time than did the placebo group (p = 0.03). Melatonin 60 mg was well-tolerated without any reported side effects. Our findings suggested that melatonin could ameliorate myocardial I/R injury after on-pump CABG and that this outcome was essentially correlated to its antiapoptotic and anti-inflammatory effects. Trial registration: ClinicalTrials.gov registration number NCT05552586, 9/2022.

通过评估IR/炎症生物标志物和临床结果,探讨大剂量褪黑素对无泵冠状动脉旁路移植术(CABG)患者心肌I/R损伤和炎症的保护作用。这是一种前景;随机的;在艾因沙姆斯大学心血管胸外科学院心胸外科进行的单盲安慰剂对照研究。符合条件的患者被随机分配到;褪黑激素治疗组(MTG)或安慰剂治疗组(PTG)。MTG (n = 17)除标准护理外,在手术前5天开始每天接受60mg /天褪黑激素胶囊。PTG (n = 17)在手术前5天接受安慰剂加标准护理。在5个时间点评估两组患者的核因子κb (NF-κb)(主要结局)、肿瘤坏死因子(TNF-α)、心肌肌钙蛋白I和IL-6水平:褪黑素或安慰剂给药前基线(T0)、交叉钳应用前(T1)、交叉钳去除后5分钟(T2)、交叉钳去除后6小时(T3)和交叉钳去除后24小时(T4)。在基线、术前和术后24小时评估血压。术后第4天评估两组患者的恢复质量-40评分(QOR-40)。与PTG相比,MTG在T1时TNF-α水平降低(p = 0.034)。在T2(p = 0.005)和T3(p = 0.04)时,PTG与MTG相比,TNF-α显著升高,肌钙蛋白显著升高(p = 0.04), NF-κB水平在T1 (p = 0.013)和T2(p = 0.0001)时下降。T3时PTG组IL-6明显高于MTG组(p = 0.04)。与PTG相比,MTG组QOR-40评分显著降低。与安慰剂组相比,MTG组DBP有统计学意义的降低(p = 0.024)。MTG组插管时间短于安慰剂组,差异有统计学意义(p = 0.03)。褪黑素60毫克耐受性良好,无任何副作用报道。我们的研究结果表明,褪黑素可以改善无泵CABG后心肌I/R损伤,这一结果本质上与其抗凋亡和抗炎作用相关。试验注册:ClinicalTrials.gov注册号NCT05552586, 9/2022。
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引用次数: 0
Single-cell RNA sequencing analysis reveals the dynamic changes in the tumor microenvironment during NMIBC recurrence. 单细胞RNA测序分析揭示了NMIBC复发过程中肿瘤微环境的动态变化。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s10495-024-02044-2
Ziang Chen, Tianxiang Zhang, Weijian Li, Jia Hu, Yuxi Ou, Fangdie Ye, Jinhao Zhang, Haowen Jiang, Shenghua Liu

Background: Due to the clinical characteristic of frequent recurrence in urothelial bladder cancer (UBC), patients face significant health impacts and economic burdens. Therefore, understanding the molecular mechanisms involved in UBC recurrence is crucial for reducing its recurrence rate. The aim of our study is to help urologists and clinical researchers gain a deeper understanding of the changes in the tumor microenvironment (TME) during UBC recurrence.

Methods: We collected 10 samples from primary and recurrent non-muscle-invasive bladder cancer (NMIBC) and performed single-cell RNA sequencing. By distinguishing and annotating cell subpopulations, we identified tissue preferences of some novel cell subgroups. Next, pseudotime trajectory analysis, cell-cell communication analysis, and function enrichment analysis were applied to evaluate the dynamic changes in the TME and biological functions. Finally, we validated the distribution of some of these cell subgroups using multiplex immunofluorescence experiments.

Results: We identified a tumor-associated fibroblast (CAF) subtype with high COL18A1 expression that is highly expressed in recurrent NMIBC, suggesting that the stromal component of the tumor may play a crucial role in the recurrence process. Additionally, pseudotime trajectory analysis revealed a macrophage subtype with high IL-6 expression at the terminal stage of macrophage differentiation, exhibiting significant immunosuppressive features. This indicated the presence of immune exhaustion during NMIBC recurrence. Lastly, we found an upregulation of estrogen in recurrent urothelial cancer cells, which may partially explain the gender disparity observed in UBC.

Conclusion: This study identified several cell subpopulations influencing NMIBC recurrence, which were heavily infiltrated in the TME of recurrent NMIBC. Additionally, the enrichment of estrogen in urothelial cancer cells from various sources suggested a role of sex hormones in NMIBC recurrence.

背景:由于尿路上皮性膀胱癌(UBC)的临床特点,患者面临着显著的健康影响和经济负担。因此,了解UBC复发的分子机制对于降低其复发率至关重要。我们的研究目的是帮助泌尿科医生和临床研究人员更深入地了解UBC复发期间肿瘤微环境(TME)的变化。方法:我们收集了10例原发性和复发性非肌浸润性膀胱癌(NMIBC)样本,并进行了单细胞RNA测序。通过区分和注释细胞亚群,我们确定了一些新的细胞亚群的组织偏好。接下来,利用伪时间轨迹分析、细胞间通讯分析和功能富集分析来评估TME和生物学功能的动态变化。最后,我们利用多重免疫荧光实验验证了其中一些细胞亚群的分布。结果:我们发现了一种COL18A1高表达的肿瘤相关成纤维细胞(CAF)亚型,该亚型在复发性NMIBC中高表达,表明肿瘤的基质成分可能在复发过程中发挥关键作用。此外,伪时间轨迹分析显示巨噬细胞亚型在巨噬细胞分化末期具有高IL-6表达,表现出明显的免疫抑制特征。这表明在NMIBC复发期间存在免疫衰竭。最后,我们在复发性尿路上皮癌细胞中发现雌激素上调,这可能部分解释了UBC中观察到的性别差异。结论:本研究确定了影响NMIBC复发的几个细胞亚群,这些细胞亚群在复发性NMIBC的TME中大量浸润。此外,各种来源的尿路上皮癌细胞中雌激素的富集表明性激素在NMIBC复发中的作用。
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Apoptosis
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