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Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures 通过对免疫细胞、细胞因子和症状措施进行全系统分析,从海湾战争疾病中析出创伤后应激障碍对男性退伍军人的影响
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2024-01-02 DOI: 10.1186/s40779-023-00505-4
Esha Sultana, Nandan Shastry, Rishabh Kasarla, Jacob Hardy, Fanny Collado, Kristina Aenlle, Maria Abreu, Emily Sisson, Kimberly Sullivan, Nancy Klimas, Travis J. A. Craddock
One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI. Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine & cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWIH) and GWI with low probability of PTSD symptoms (GWIL). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWIH, GWIL, and healthy control groups. GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWIL subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWIL subgroup was found to be delineated from both GWIH and HC on measures of IL-15 across an exercise challenge (ANOVA F > 3.75, P < 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms. We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.
从 1990-1991 年海湾战争中归来的退伍军人中,有三分之一的人报告出现了认知功能障碍、皮疹、肌肉骨骼不适和疲劳等多种症状。这种症状群现在被称为海湾战争病(GWI)。由于海湾战争综合症的内在机制尚未完全阐明,因此诊断和治疗都以症状表现为基础。与该疾病相关的一个干扰因素是创伤后应激障碍(PTSD)的高发病率。以往的研究表明,GWI 和创伤后应激障碍都与免疫功能紊乱有关。因此,本研究旨在深入探讨 GWI 症状、细胞因子存在和免疫细胞群之间的复杂关系,以确定创伤后应激障碍对 GWI 中这些指标的影响。症状测量通过多维疲劳量表(MFI)和36项简表健康调查(SF-36)量表收集,生物测量通过细胞因子和细胞测量分析获得。使用戴维森创伤量表评分和《精神障碍诊断与统计手册》(DSM)-5结构化临床访谈进行了分组,分为创伤后应激障碍症状可能性高的 GWI(GWIH)和创伤后应激障碍症状可能性低的 GWI(GWIL)。数据分析采用方差分析(ANOVA)统计分析和相关图分析。我们绘制了免疫细胞和细胞因子信号转导指标、激素和 GWI 症状指标之间的相关图,以确定 GWIH、GWIL 和健康对照组之间的调节模式。与健康对照组(HC)和 GWIL 亚组相比,伴有创伤后应激障碍症状的 GWI 患者的健康状况较差。无论是否合并有创伤后应激障碍症状,在运动高峰期,GWI 与 HC 的嗜碱性粒细胞水平都存在显著差异(方差分析 F = 4.7,P = 0.01),这表明它有可能被用作一般 GWI 与对照组的生物标志物。虽然 GWI 与创伤后应激障碍症状的独特识别不那么明确,但发现 GWIL 亚组与 GWIH 和 HC 在运动挑战中的 IL-15 测量值上有明显区别(方差分析 F > 3.75,P < 0.03)。自然杀伤(NK)细胞数量和功能的其他差异突出表明,在没有创伤后应激障碍症状的情况下,IL-15 是 GWI 的潜在生物标志物。我们的结论是,通过定义基于创伤的亚组将 GWI 和创伤后应激障碍区分开来,可能有助于识别独特的 GWI 生物特征,从而有助于改进 GWI 的诊断和更有效的针对性治疗。
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引用次数: 0
Elevated FBXL6 activates both wild-type KRAS and mutant KRASG12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice 升高的 FBXL6 可激活野生型 KRAS 和突变型 KRASG12D,并通过 ERK/mTOR/PRELID2/ROS 轴驱动小鼠发生 HCC 肿瘤
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-20 DOI: 10.1186/s40779-023-00501-8
Hao-Jun Xiong, Hong-Qiang Yu, Jie Zhang, Lei Fang, Di Wu, Xiao-Tong Lin, Chuan-Ming Xie
Kirsten rat sarcoma (KRAS) and mutant KRASG12D have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRASG12D activity in hepatocellular carcinoma (HCC). We constructed transgenic mouse strains LC (LSL-Fbxl6KI/+;Alb-Cre, n = 13), KC (LSL-KrasG12D/+;Alb-Cre, n = 10) and KLC (LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d. Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation. Co‑immunoprecipitation (Co-IP), Western blotting, ubiquitination assay and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS. The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2 (PRELID2) axis was evaluated in 129 paired samples from HCC patients. FBXL6 is highly expressed in HCC as well as other human cancers (P < 0.001). Interestingly, FBXL6 drives HCC in transgenic mice. Mechanistically, elevated FBXL6 promotes the polyubiquitination of both wild-type KRAS and KRASG12D at lysine 128, leading to the activation of both KRAS and KRASG12D and promoting their binding to the serine/threonine-protein kinase RAF, which is followed by the activation of mitogen-activated protein kinase kinase (MEK)/ERK/mTOR signaling. The oncogenic activity of the MEK/ERK/mTOR axis relies on PRELID2, which induces reactive oxygen species (ROS) generation. Furthermore, hepatic FBXL6 upregulation facilitates KRASG12D to induce more severe hepatocarcinogenesis and lung metastasis via the MEK/ERK/mTOR/PRELID2/ROS axis. Dual inhibition of MEK and mTOR effectively suppresses tumor growth and metastasis in this subtype of cancer in vivo. In clinical samples, FBXL6 expression positively correlates with p-ERK (χ2 = 85.067, P < 0.001), p-mTOR (χ2 = 66.919, P < 0.001) and PRELID2 (χ2 = 20.891, P < 0.001). The Kaplan–Meier survival analyses suggested that HCC patients with high FBXL6/p-ERK levels predicted worse overall survival (log‑rank P < 0.001). FBXL6 activates KRAS or KRASG12D via ubiquitination at the site K128, leading to activation of the ERK/mTOR/PRELID2/ROS axis and tumorigenesis. Dual inhibition of MEK and mTOR effectively protects against FBXL6- and KRASG12D-induced tumorigenesis, providing a potential therapeutic strategy to treat this aggressive subtype of liver cancer.
克氏大鼠肉瘤(KRAS)和突变体 KRASG12D 与人类癌症有牵连,但它们的激活是否需要泛素化仍不清楚。本研究旨在探讨 F-box and leucine-rich repeat 6 (FBXL6) 是否以及如何调节肝细胞癌(HCC)中 KRAS 和 KRASG12D 的活性。我们构建了转基因小鼠品系 LC(LSL-Fbxl6KI/+;Alb-Cre,n = 13)、KC(LSL-KrasG12D/+;Alb-Cre,n = 10)和 KLC(LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre,n = 12),然后监测 HCC 320 d。研究还采用了共免疫沉淀(Co-IP)、Western印迹、泛素化检测和RAS活性检测等方法来研究FBXL6激活KRAS的分子机制。在 129 例配对的 HCC 患者样本中评估了 FBXL6/KRAS/细胞外信号调节激酶(ERK)/哺乳动物雷帕霉素靶标(mTOR)/相关进化和淋巴兴趣域 2 蛋白(PRELID2)轴的病理相关性。FBXL6 在 HCC 及其他人类癌症中高表达(P < 0.001)。有趣的是,FBXL6 在转基因小鼠中可驱动 HCC。从机理上讲,升高的 FBXL6 会促进野生型 KRAS 和 KRASG12D 在赖氨酸 128 处发生多泛素化,从而导致 KRAS 和 KRASG12D 被激活,并促进它们与丝氨酸/苏氨酸蛋白激酶 RAF 结合,继而激活丝裂原活化蛋白激酶(MEK)/ERK/mTOR 信号转导。MEK/ERK/mTOR轴的致癌活性依赖于PRELID2,而PRELID2会诱导活性氧(ROS)的产生。此外,肝脏 FBXL6 上调有助于 KRASG12D 通过 MEK/ERK/mTOR/PRELID2/ROS 轴诱导更严重的肝癌发生和肺转移。对 MEK 和 mTOR 的双重抑制可有效抑制该亚型癌症的体内肿瘤生长和转移。在临床样本中,FBXL6的表达与p-ERK(χ2 = 85.067,P < 0.001)、p-mTOR(χ2 = 66.919,P < 0.001)和PRELID2(χ2 = 20.891,P < 0.001)呈正相关。Kaplan-Meier生存分析表明,FBXL6/p-ERK水平高的HCC患者总生存率较低(log-rank P < 0.001)。FBXL6通过在K128位点泛素化激活KRAS或KRASG12D,导致ERK/mTOR/PRELID2/ROS轴激活和肿瘤发生。对MEK和mTOR的双重抑制能有效防止FBXL6和KRASG12D诱导的肿瘤发生,为治疗这种侵袭性亚型肝癌提供了一种潜在的治疗策略。
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引用次数: 0
Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury 抗凋亡巨核细胞在辐射损伤时产生大量高反应性血小板
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-19 DOI: 10.1186/s40779-023-00499-z
Chang-Hong Du, Yi-Ding Wu, Ke Yang, Wei-Nian Liao, Li Ran, Chao-Nan Liu, Shu-Zhen Zhang, Kuan Yu, Jun Chen, Yong Quan, Mo Chen, Ming-Qiang Shen, Hong Tang, Shi-Lei Chen, Song Wang, Jing-Hong Zhao, Tian-Min Cheng, Jun-Ping Wang
The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
血小板在血栓形成中的重要作用已得到公认。令人意想不到的是,在生物、物理和化学源性细胞毒性诱发的血小板减少症中,血栓形成非常普遍,在化学、生物、放射性和核事件中,军事人员和平民都可能遭遇这种情况。特别是,血栓形成被认为是辐射损伤诱发的血小板减少症致死的主要原因,但其潜在的致病机制仍未确定。通过将小鼠暴露于亚致死剂量的电离辐射(IR),建立了辐射损伤诱发血小板减少症的小鼠模型。通过流式细胞术、流式细胞室、组织病理学、Western 印迹和染色质免疫沉淀等一系列体内外检测方法,并结合转录组学分析,确定了血小板和巨核细胞(MKs)的表型和功能变化。对分子机制进行了体外和体内研究,并利用 MK 特异性基因敲除小鼠进行了巩固。利用人类 MK 细胞系和几种药理抑制剂对其转化潜力进行了评估。与原始 MKs 不同的是,成熟 MKs(mMKs)是通过重新编程 Bcl-xL-BAX/BAK 轴来抗凋亡的。有趣的是,mMKs 在红外线照射后会发生少数线粒体外膜通透(MOMP),从而通过释放线粒体 DNA 激活环 GMP-AMP 合成酶-IFN 基因刺激因子(cGAS-STING)通路。随后,mMKs 中的干扰素-β(IFN-β)反应会上调 GTPase 鸟苷酸结合蛋白 2 (GBP2),从而产生有利于血栓形成的大量高反应性血小板。此外,我们还揭示了自噬可抑制IR后mMKs中的少数MOMP。我们的研究发现,巨核细胞线粒体-cGAS/STING-IFN-β-GBP2轴是一个基本的检查点,在辐射损伤后指示血小板的大小和功能,并可用于治疗血小板病变。
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引用次数: 0
The applied principles of EEG analysis methods in neuroscience and clinical neurology 脑电图分析方法在神经科学和临床神经学中的应用原理
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-19 DOI: 10.1186/s40779-023-00502-7
Hao Zhang, Qing-Qi Zhou, He Chen, Xiao-Qing Hu, Wei-Guang Li, Yang Bai, Jun-Xia Han, Yao Wang, Zhen-Hu Liang, Dan Chen, Feng-Yu Cong, Jia-Qing Yan, Xiao-Li Li
Electroencephalography (EEG) is a non-invasive measurement method for brain activity. Due to its safety, high resolution, and hypersensitivity to dynamic changes in brain neural signals, EEG has aroused much interest in scientific research and medical fields. This article reviews the types of EEG signals, multiple EEG signal analysis methods, and the application of relevant methods in the neuroscience field and for diagnosing neurological diseases. First, three types of EEG signals, including time-invariant EEG, accurate event-related EEG, and random event-related EEG, are introduced. Second, five main directions for the methods of EEG analysis, including power spectrum analysis, time–frequency analysis, connectivity analysis, source localization methods, and machine learning methods, are described in the main section, along with different sub-methods and effect evaluations for solving the same problem. Finally, the application scenarios of different EEG analysis methods are emphasized, and the advantages and disadvantages of similar methods are distinguished. This article is expected to assist researchers in selecting suitable EEG analysis methods based on their research objectives, provide references for subsequent research, and summarize current issues and prospects for the future.
脑电图(EEG)是一种非侵入性的大脑活动测量方法。由于其安全性、高分辨率以及对脑神经信号动态变化的高敏感性,脑电图在科学研究和医学领域引起了广泛关注。本文综述了脑电信号的类型、多种脑电信号分析方法以及相关方法在神经科学领域和神经疾病诊断中的应用。首先,介绍了三类脑电信号,包括时间不变脑电信号、精确事件相关脑电信号和随机事件相关脑电信号。其次,在主要部分介绍了脑电图分析方法的五个主要方向,包括功率谱分析、时频分析、连通性分析、源定位方法和机器学习方法,以及解决同一问题的不同子方法和效果评估。最后,强调了不同脑电图分析方法的应用场景,并区分了同类方法的优缺点。本文希望能帮助研究人员根据自己的研究目标选择合适的脑电图分析方法,为后续研究提供参考,并总结当前的问题和展望未来。
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引用次数: 1
Pre-hospital application of REBOA for life-threatening hemorrhage 院前应用 REBOA 治疗危及生命的大出血
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-13 DOI: 10.1186/s40779-023-00504-5
Xiao-Mei Tian, Wei Hu, Feng-Yong Liu

Dear Editor,

Most battlefield casualties occur prior to the arrival of medical facilities. Uncontrollable hemorrhage accounts for more than 90% of those potentially survivable battlefield casualties [1]. In both military and civilian conditions, non-compressible torso hemorrhage always caused rapid exsanguination and high mortality rates before definitive treatment [2]. More than half of the deaths due to non-compressible torso hemorrhage occur before hospital care can be provided [2]. Therefore, early and rapid pre-hospital hemorrhage control is essential to reduce mortality.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a life-saving procedure for patients with non-compressible hemorrhage and severe hemorrhagic shock [3]. In addition to in-hospital REBOA, urgent REBOA can be rapidly completed in grim pre-hospital situations for patients [4]. Thus, pre-hospital REBOA application for the treatment of life-threatening hemorrhages has attracted increasing attention. In patients who receive timely pre-hospital REBOA treatment, the mortality can be reduced to less than 40% [5]. In this letter, we focus on the pre-hospital application of REBOA for managing life-threatening traumatic hemorrhages in both military and civilian settings.

REBOA was first introduced by the US Army in the Korean War to treat intraabdominal hemorrhages. With significant improvements in endovascular equipment and techniques, pre-hospital REBOA has attracted renewed clinical interest. Recently, the US Army reported the use of pre-hospital REBOA in treating modern combat casualties [6]. After pre-hospital REBOA treatment, the patients were finally hemodynamically stabilized and safely evacuated without any apparent complications. Furthermore, the Russian Army have also validated the effectiveness of pre-hospital REBOA on the battlefield [7]. When combined with other resuscitation strategies like blood transfusion, pre-hospital REBOA can further enhance survival rates. Therefore, it is evident that pre-hospital REBOA is an effective method for acute care of massive hemorrhage and can be safely performed in the battlefield setting as an emergency treatment option for individuals at risk of cardiovascular failure due to injuries sustained in combat situations. On the battlefield, frontline implementation of REBOA allows temporary hemorrhage control and facilitates timely evacuation to the hospital, thereby reducing mortality rate and improving overall treatment outcomes, simultaneously saving lives among military personnel. This technology is of great significance for military applications and may become an essential skill for military training programs and medical practices in the future.

In addition to the battlefield environment, pre-hospital REBOA is also suitable for trauma patients in civilian conditions. Uncontrolled hemorrhagic shock or cardiac arrest accounts for a significant percentage of trauma patients. Some of these pa

亲爱的编辑,大多数战场伤亡都发生在医疗设施到达之前。无法控制的大出血占战场上可能存活的伤亡人数的 90% 以上[1]。在军用和民用条件下,不可压缩的躯干大出血总是会导致快速失血,并在最终治疗前造成高死亡率[2]。超过一半的非可压缩性躯干大出血导致的死亡发生在医院救治之前[2]。因此,早期、快速的院前出血控制对于降低死亡率至关重要。主动脉血管内球囊闭塞复苏术(REBOA)是针对不可压缩性出血和严重失血性休克患者的一种挽救生命的手术[3]。除院内 REBOA 外,紧急 REBOA 也可在严峻的院前情况下为患者快速完成 [4]。因此,应用院前 REBOA 治疗危及生命的大出血越来越受到关注。及时接受院前 REBOA 治疗的患者,死亡率可降至 40% 以下[5]。在这封信中,我们重点讨论了在院前应用 REBOA 治疗危及生命的创伤性大出血在军事和民用环境中的应用。REBOA 由美国陆军在朝鲜战争中首次引入,用于治疗腹腔内出血。随着血管内设备和技术的重大改进,院前 REBOA 再次引起临床关注。最近,美国陆军报道了使用院前 REBOA 治疗现代作战伤员的情况[6]。经过院前 REBOA 治疗,患者最终血流动力学稳定并安全撤离,没有出现任何明显的并发症。此外,俄罗斯军队也验证了院前 REBOA 在战场上的有效性[7]。如果与输血等其他复苏策略相结合,院前 REBOA 还能进一步提高存活率。因此,院前 REBOA 显然是急性救治大出血的有效方法,可以在战场环境中安全实施,作为在战斗中受伤而面临心血管衰竭风险的人员的紧急治疗选择。在战场上,前线实施 REBOA 可暂时控制出血,便于及时送往医院,从而降低死亡率,改善整体治疗效果,同时挽救军人的生命。除了战场环境,院前 REBOA 也适用于民用环境下的创伤患者。无法控制的失血性休克或心脏骤停在创伤患者中占很大比例。其中一些患者可受益于院前 REBOA。对于因高空坠落而严重受伤的患者,REBOA 是一种安全有效的外科技术,可减少失血,稳定患者的血流动力学状态,延长转运时间,并提供明确止血的机会[8]。院前 REBOA 使用便携式球囊导管装置在现场进行紧急止血,可迅速控制出血、维持血流动力学稳定并提供复苏支持,避免因失血性休克而死亡。下肢缺血、器官缺血再灌注损伤、主动脉夹层等术后并发症发生率较低。与院内条件不同,在严峻的院前环境中实施 REBOA 需要一个协调的急诊医疗系统,以及一支训练有素、装备精良的护理团队。鉴于战场或院前伤员通常需要后送,确保建立动脉通路和成功放置动脉鞘至关重要。有报道称在旋转翼平台上可成功置入 REBOA [4]。因此,建议在后送期间及时后送符合条件的患者,同时在途中实施 REBOA。在创伤性出血的院前处理中,及时实施 REBOA 至关重要,强调了快速外科干预的必要性。以前,在启动 REBOA 之前,应进行超声波或数字减影血管造影。随着导管设备和技术的改进,盲法操作的能力和成功率显著提高,尤其是在接受了全面的 REBOA 培训之后。
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引用次数: 0
ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression ADP 依赖性葡萄糖激酶控制前列腺癌进展过程中的代谢适应性
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-12 DOI: 10.1186/s40779-023-00500-9
Hang Xu, Yi-Fan Li, Xian-Yan-Ling Yi, Xiao-Nan Zheng, Yang Yang, Yan Wang, Da-Zhou Liao, Jia-Peng Zhang, Ping Tan, Xing-Yu Xiong, Xi Jin, Li-Na Gong, Shi Qiu, De-Hong Cao, Hong Li, Qiang Wei, Lu Yang, Jian-Zhong Ai
Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment. The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays. ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa. In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.
细胞新陈代谢在肿瘤进展中起着关键作用,针对癌症的新陈代谢可能会有效杀死癌细胞。我们旨在研究六磷酸酶在前列腺癌(PCa)中的作用,并确定治疗PCa的关键靶点。我们利用癌症基因组图谱(TCGA)数据库、在线工具和临床样本来评估ADP依赖性葡萄糖激酶(ADPGK)在PCa中的表达和预后作用。ADPGK的表达对PCa细胞恶性表型的影响已在体外和体内得到验证。研究人员进行了定量蛋白质组学、代谢组学、细胞外酸化率(ECAR)和耗氧量(OCR)测试,以评估ADPGK对PCa代谢的影响。研究人员通过ADPGK过表达和敲除、共免疫沉淀(Co-IP)、ECAR分析和细胞计数试剂盒-8(CCK-8)检测等方法探讨了其潜在机制。在前列腺癌(PRAD)中,ADPGK是唯一一种既上调又能预测总生存期(OS)恶化的葡萄糖激酶。临床样本分析表明,与非前列腺癌组织相比,ADPGK在前列腺癌组织中明显上调。ADPGK 的高表达预示着更差的生存结果,并且 ADPGK 是生化复发的独立因素。体外和体内实验表明,ADPGK过表达可促进PCa细胞的增殖和迁移,而抑制ADPGK可抑制恶性表型。代谢组学、蛋白质组学以及ECAR和OCR测试表明,ADPGK能显著加速PCa中的糖酵解。从机理上讲,ADPGK与醛缩酶C(ALDOC)结合,通过AMP激活蛋白激酶(AMPK)磷酸化促进糖酵解。ALDOC与ADPGK呈正相关,而ALDOC的高表达与PCa的生存预后较差有关。总之,ADPGK是PCa进展的驱动因素,其高表达导致PCa患者预后不良。ADPGK通过激活ALDOC-AMPK信号转导加速PCa糖酵解和进展,这表明ADPGK可能是PCa治疗和预后评估的有效靶点和标志物。
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引用次数: 0
Targeting NR1D1 in organ injury: challenges and prospects 在器官损伤中靶向 NR1D1:挑战与前景
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-11 DOI: 10.1186/s40779-023-00495-3
Zi-Yin Zhang-sun, Xue-Zeng Xu, Germaine Escames, Wang-Rui Lei, Lin Zhao, Ya-Zhe Zhou, Ye Tian, Ya-Nan Ren, Darío Acuña-Castroviejo, Yang Yang
Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα) belongs to the nuclear receptor (NR) family, and is a heme-binding component of the circadian clock that consolidates circadian oscillators. In addition to repressing the transcription of multiple clock genes associated with circadian rhythms, NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes, including autophagy, immunity, inflammation, metabolism and aging in multiple organs. This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network, with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands. NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases. Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.
核受体亚家族 1,D 组,成员 1(NR1D1,又称 REV-ERBα)属于核受体(NR)家族,是昼夜节律钟的血红素结合成分,能巩固昼夜节律振荡器。除了抑制与昼夜节律相关的多个时钟基因的转录外,NR1D1 还具有广泛的下游靶基因,这些靶基因密切参与许多生理病理过程,包括多个器官的自噬、免疫、炎症、代谢和衰老。这篇综述重点探讨了 NR1D1 作为关键转录因子在基因调控网络中的关键作用,特别强调了最新发现的 NR1D1 配体的里程碑意义。NR1D1 被认为是治疗各种疾病的有希望的药物靶点,并可能有助于器官损伤相关疾病的创新生物标志物和治疗靶点的研究。在前瞻性人体试验中对 NR1D1 配体的进一步研究可能会为它们在许多器官损伤相关疾病中的临床应用铺平道路。
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引用次数: 0
Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy Adipsin 可抑制 Irak2 线粒体转位并改善脂肪酸 β 氧化,从而缓解糖尿病心肌病变
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-11 DOI: 10.1186/s40779-023-00493-5
Meng-Yuan Jiang, Wan-Rong Man, Xue-Bin Zhang, Xiao-Hua Zhang, Yu Duan, Jie Lin, Yan Zhang, Yang Cao, De-Xi Wu, Xiao-Fei Shu, Lei Xin, Hao Wang, Xiao Zhang, Cong-Ye Li, Xiao-Ming Gu, Xuan Zhang, Dong-Dong Sun
Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism. A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC–MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator. The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC–MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin. Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.
糖尿病心肌病(DCM)会导致心肌依赖脂肪酸的β-氧化作用来获取能量。细胞内脂类和脂肪酸在心肌中的积累通常会导致脂毒性,从而损害心肌功能。Adipsin 可能在 DCM 的发病机制中发挥重要的保护作用。本研究旨在探讨 Adipsin 对 DCM 脂肪毒性的调节作用及其分子机制。在脂肪组织特异性过表达 Adipsin(Adipsin-Tg)的小鼠中构建了高脂饮食(HFD)诱导的 2 型糖尿病模型。采用液相色谱-串联质谱(LC-MS/MS)、谷胱甘肽-转移酶(GST)下拉技术、共免疫沉淀(Co-IP)和免疫荧光共定位分析等方法研究了能与Adipsin直接相互作用的分子。免疫胶体金法也用于检测 Adipsin 与其下游调节剂之间的相互作用。在高密度脂蛋白诱导的 DCM 模型中,Adipsin 的表达明显下调(P < 0.05)。脂肪组织特异性过表达 Adipsin 能明显改善 DCM 的心功能并缓解心脏重构(P < 0.05)。过表达 Adipsin 还能缓解糖尿病应激中的线粒体氧化磷酸化功能(P < 0.05)。LC-MS/MS分析、GST牵引技术和Co-IP研究显示,白细胞介素-1受体相关激酶样2(Irak2)是Adipsin的下游调节因子。免疫荧光分析也显示,Adipsin 与 Irak2 共同定位在心肌细胞中。免疫胶体金电镜和 Western 印迹分析表明,Adipsin 可抑制 Irak2 在 DCM 中的线粒体转位,从而抑制 Irak2 与线粒体上的禁用素(Phib)-视神经萎缩蛋白 1(Opa1)之间的相互作用,改善线粒体的结构完整性和功能(P < 0.05)。有趣的是,在 Irak2 被敲除的情况下,Adipsin 的过表达并没有进一步缓解心肌线粒体破坏和心功能障碍,这表明 Irak2 在 Adipsin 诱导的反应中起下游作用(P < 0.05)。与这些发现一致的是,在敲除 Irak2 后,过量表达 Adipsin 并没有进一步减少心肌中脂类及其代谢物的积累,也没有增强暴露于棕榈酸酯(PA)的心肌细胞的氧化能力(P < 0.05)。这些结果表明,Irak2 可能是 Adipsin 的下游调节因子。Adipsin能改善DCM的脂肪酸β氧化,减轻线粒体损伤。其机制与Irak2相互作用和抑制Irak2线粒体转位有关。
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引用次数: 0
Targeting the epigenome to reinvigorate T cells for cancer immunotherapy. 靶向表观基因组激活T细胞用于癌症免疫治疗。
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-04 DOI: 10.1186/s40779-023-00496-2
Dian Xiong, Lu Zhang, Zhi-Jun Sun

Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.

使用免疫检查点抑制剂(ICIs)的癌症免疫治疗已经彻底改变了癌症治疗领域;然而,ICI的疗效受到CD8+肿瘤浸润淋巴细胞(TILs)进行性功能障碍的限制,这被称为T细胞衰竭。这一过程是由异质性肿瘤免疫微环境(TIME)的多种外在因素驱动的。同时,肿瘤发生需要对表观遗传景观进行强大的重塑,可能会引发T细胞衰竭。在这篇综述中,我们总结了控制肿瘤微环境信号导致T细胞衰竭的表观遗传机制,并讨论了靶向表观遗传调节因子用于免疫治疗的治疗潜力。最后,我们概述了涉及免疫刺激剂和表观遗传疗法的潜在治疗范例的概念和技术进展。
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引用次数: 0
BET inhibitors potentiate melanoma ferroptosis and immunotherapy through AKR1C2 inhibition. BET抑制剂通过抑制AKR1C2增强黑色素瘤铁下垂和免疫治疗。
IF 21.1 2区 医学 Q1 Medicine Pub Date : 2023-12-04 DOI: 10.1186/s40779-023-00497-1
Yu Meng, Hui-Yan Sun, Yi He, Qian Zhou, Yi-Huang Liu, Hui Su, Ming-Zhu Yin, Fu-Rong Zeng, Xiang Chen, Guang-Tong Deng
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引用次数: 0
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Military Medical Research
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