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The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: Implications for deep space missions, female crews, and potential antioxidant countermeasures. 雌性 C57BL/6J 小鼠急性暴露于银河宇宙辐射的纵向行为影响:对深空任务、女性乘员和潜在抗氧化对策的影响。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1111/jnc.16225
Sanghee Yun, Frederico C Kiffer, Grace L Bancroft, Caterina S Guzman, Ivan Soler, Harley A Haas, Raymon Shi, Riya Patel, Jaysen Lara-Jiménez, Priya L Kumar, Fionya H Tran, Kyung Jin Ahn, Yuying Rong, Krishna Luitel, Jerry W Shay, Amelia J Eisch

Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment are lacking. We asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound (CDDO-EA) mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received CDDO-EA (400 μg/g of food) or a control diet (vehicle, Veh) for 5 days and Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: (1) location discrimination reversal (tests behavior pattern separation and cognitive flexibility, abilities reliant on the dentate gyrus) and (2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment's end (14.25-month post-IRR), an index relevant to neurogenesis was quantified (doublecortin-immunoreactive [DCX+] dentate gyrus immature neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. One radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had slower stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice showed normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change relevant to neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew's longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks.

银河宇宙辐射(GCR)是宇航员不可避免的风险,可能会影响任务的成功。雄性啮齿动物暴露于 33 射束-GCR(33-GCR)后会出现短期认知障碍,但缺乏关于雌性啮齿动物和长期评估的报告。我们想知道33-GCR 对雌性小鼠的纵向行为影响是什么?此外,抗氧化/抗炎化合物(CDDO-EA)能否减轻 33-GCR 的影响?成熟(6 个月大)的 C57BL/6J 雌性小鼠连续 5 天接受 CDDO-EA(400 μg/g 食物)或对照饮食(载体,Veh),第 4 天接受 Sham-irradiation (IRR) 或全身 33-GCR (0.75Gy)。IRR后三个月,小鼠接受了两项触摸屏平台测试:(1)位置辨别逆转(测试行为模式分离和认知灵活性,这些能力依赖于齿状回)和(2)刺激-反应学习/消退。然后,小鼠接受基于竞技场的行为测试(如开放场地、3 室社会互动)。实验结束时(IRR 后 14.25 个月),对与神经发生相关的指标(双皮质素免疫反应性 [DCX+] 齿状回未成熟神经元)进行量化。暴露于 Veh/Sham 与 Veh/33-GCR 的雌性小鼠具有相似的模式分离能力(第一次逆转的正确率)。饮食有两种影响:与各自的对照组(Veh/Sham、Veh/33-GCR)相比,CDDO-EA/Sham 和 CDDO-EA/33-GCR 小鼠的模式分离能力更强;与 Veh/33-GCR 小鼠相比,CDDO-EA/33-GCR 小鼠的认知灵活性(逆转次数)更强。还出现了一种辐射效应/CDDO-EA 反效应:与包括 CDDO-EA/33-GCR 小鼠在内的所有其他组相比,Veh/33-GCR 小鼠的刺激-反应学习(完成天数)较慢。总体而言,所有小鼠都表现出正常的焦虑样行为、探索和对新环境的适应。神经发生方面也有变化:与 Veh/Sham 小鼠相比,Veh/33-GCR 小鼠的齿状回未成熟神经元 DCX+ 更少。我们的研究表明,太空辐射对女性乘员与飞行任务相关的纵向认知过程构成风险,而CDDO-EA是应对太空辐射中枢神经系统风险的潜在饮食对策。
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引用次数: 0
DJ-1 regulates astrocyte activation through miR-155/SHP-1 signaling in cerebral ischemia/reperfusion injury. DJ-1通过miR-155/SHP-1信号调节脑缺血再灌注损伤中星形胶质细胞的激活
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1111/jnc.16230
Ying Xue, Yuan Wang, Tianyi Chen, Li Peng, Chenglong Wang, Guijun Xue, Shanshan Yu

Reactive astrocyte activation in the context of cerebral ischemia/reperfusion (I/R) injury gives rise to two distinct subtypes: the neurotoxic A1 type and the neuroprotective A2 type. DJ-1 (Parkinson disease protein 7, PARK7), originally identified as a Parkinson's disease-associated protein, is a multifunctional anti-oxidative stress protein with molecular chaperone and signaling functions. SHP-1 (Src homology 2 domain-containing phosphatase-1) is a protein tyrosine phosphatase closely associated with cellular signal transduction. miR-155 is a microRNA that participates in cellular functions by regulating gene expression. Recent studies have uncovered the relationship between DJ-1 and astrocyte-mediated neuroprotection, which may be related to its antioxidant properties and regulation of signaling molecules such as SHP-1. Furthermore, miR-155 may exert its effects by influencing SHP-1, providing a potential perspective for understanding the molecular mechanisms of stroke. A middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen-glucose deprivation/reperfusion (OGD/R) model were established to simulate focal cerebral I/R injury in vivo and in vitro, respectively. The in vivo interaction between DJ-1 and SHP-1 has been experimentally validated through immunoprecipitation. Overexpression of DJ-1 attenuates I/R injury and suppresses miR-155 expression. In addition, inhibition of miR-155 upregulates SHP-1 expression and modulates astrocyte activation phenotype. These findings suggest that DJ-1 mediates astrocyte activation via the miR-155/SHP-1 pathway, playing a pivotal role in the pathogenesis of cerebral ischemia-reperfusion injury. Our results provide a potential way for exploring the pathogenesis of ischemic stroke and present promising targets for pharmacological intervention.

脑缺血/再灌注(I/R)损伤背景下的反应性星形胶质细胞活化产生了两种不同的亚型:神经毒性 A1 型和神经保护性 A2 型。DJ-1(帕金森病蛋白 7,PARK7)最初被鉴定为帕金森病相关蛋白,是一种多功能抗氧化应激蛋白,具有分子伴侣和信号传导功能。SHP-1(Src homology 2 domain-containing phosphatase-1)是一种与细胞信号传导密切相关的蛋白酪氨酸磷酸酶。最近的研究发现了 DJ-1 与星形胶质细胞介导的神经保护之间的关系,这可能与 DJ-1 的抗氧化特性和对 SHP-1 等信号分子的调控有关。此外,miR-155 可能通过影响 SHP-1 发挥作用,这为了解中风的分子机制提供了一个潜在的视角。研究人员建立了大脑中动脉闭塞/再灌注(MCAO/R)模型和氧-葡萄糖剥夺/再灌注(OGD/R)模型,分别在体内和体外模拟局灶性大脑I/R损伤。通过免疫沉淀实验验证了DJ-1和SHP-1在体内的相互作用。过表达 DJ-1 可减轻 I/R 损伤并抑制 miR-155 的表达。此外,抑制 miR-155 会上调 SHP-1 的表达并调节星形胶质细胞的活化表型。这些发现表明,DJ-1通过miR-155/SHP-1途径介导星形胶质细胞活化,在脑缺血再灌注损伤的发病机制中起着关键作用。我们的研究结果为探索缺血性中风的发病机制提供了一条潜在的途径,并为药物干预提供了有前景的靶点。
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引用次数: 0
Chronic in vivo sequelae of repetitive acute mfb-DBS on accumbal dopamine and midbrain neuronal activity. 重复性急性 mfb-DBS 对累积多巴胺和中脑神经元活动的慢性体内后遗症。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-22 DOI: 10.1111/jnc.16223
Lidia Miguel Telega, Danesh Ashouri Vajari, Chockalingam Ramanathan, Volker A Coenen, Máté D Döbrössy

Medial Forebrain Bundle Deep Brain Stimulation (MFB-DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute-repetitive DBS are lacking. Long-Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb-DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non-behaving animals. DBS-induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long-term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)-mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration-dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS.

内侧前脑束深部脑刺激(MFB-DBS)可对治疗耐受性抑郁症(TRD)患者产生快速而持久的抗抑郁效果。其机制尚不十分清楚,但有一种假设认为,多巴胺能(DAergic)纤维的调节有助于治疗效果。已经研究了急性 DBS 对 DA 释放的影响,但还缺乏急性重复性 DBS 的纵向研究。在对行为动物和非行为动物进行急性和重复性刺激后的 8 周内,我们使用纤维光度计测量了 Long-Evans accumbal DA 释放和腹侧被盖区(VTA)钙离子对不同 mfb-DBS 参数的强直性和相位性信号传导。随着频率和 DBS 持续时间的增加,在两个目标中都观察到了 DBS 诱导的释放。随着时间的推移,130 Hz 刺激会增加相性和强直性 DA 反应,后者是其长期临床有效性的潜在机制。VTA钙离子瞬时降低,而相性活动随频率增加而增加。脉宽(PW)介导的峰值释放时间差异也表明,它可能会平行激活不同的纤维类型。此外,在高架迷宫(EPM)过程中,DA瞬时率的降低表明DA的释放与环境和刺激持续时间有关。这些数据证实了慢性反向/正向 DAergic 反应与刺激参数相关的可变性,为 mfb DBS 的时间适应性、连接性和纤维招募提供了新的见解。
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引用次数: 0
Mass spectrometry identifies tau C-terminal phosphorylation cluster during neuronal hyperexcitation. 质谱法确定神经元过度兴奋时 tau C 端磷酸化群。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-22 DOI: 10.1111/jnc.16221
Amanda Schneeweis, Dawson Hillyer, Tsering Lama, Daeun Kim, Charles Palka, Sarra Djemil, Mai Abdel-Ghani, Kelly Mandella, William Zhu, Nicole Alvarez, Lara Stefansson, Robert Yasuda, Junfeng Ma, Daniel T S Pak

Tau is a microtubule-associated protein implicated in Alzheimer's disease (AD) and other neurodegenerative disorders termed tauopathies. Pathological, aggregated forms of tau form neurofibrillary tangles (NFTs), impairing its ability to stabilize microtubules and promoting neurotoxicity. Indeed, NFTs correlate with neuronal loss and cognitive impairment. Hyperphosphorylation of tau is seen in all tauopathies and mirrors disease progression, suggesting an essential role in pathogenesis. However, hyperphosphorylation remains a generic and ill-defined term, obscuring the functional importance of specific sites in different physiological or pathological settings. Here, we focused on global mapping of tau phosphorylation specifically during conditions of neuronal hyperexcitation. Hyperexcitation is a property of AD and other tauopathies linked to human cognitive deficits and increased risk of developing seizures and epilepsy. Moreover, hyperexcitation promotes extracellular secretion and trans-synaptic propagation of tau. Using unbiased mass spectrometry, we identified a novel phosphorylation signature in the C-terminal domain of tau detectable only during neuronal hyperactivity in primary cultured rat hippocampal neurons. These sites influenced tau localization to dendrites as well as the size of excitatory postsynaptic sites. These results demonstrate novel physiological tau functions at synapses and the utility of comprehensive analysis of tau phosphorylation during specific signaling contexts.

Tau 是一种微管相关蛋白,与阿尔茨海默病(AD)和其他神经退行性疾病(称为 tauopathies)有关。病理上,tau的聚集形式会形成神经纤维缠结(NFT),损害其稳定微管的能力并促进神经毒性。事实上,神经纤维缠结与神经元丧失和认知障碍有关。tau的高磷酸化可见于所有tau病,并反映了疾病的进展,这表明它在发病机制中起着至关重要的作用。然而,高磷酸化仍然是一个定义不清的通用术语,模糊了特定位点在不同生理或病理环境中的功能重要性。在这里,我们重点研究了神经元过度兴奋条件下 tau 磷酸化的全局图谱。过度兴奋是注意力缺失症和其他与人类认知缺陷以及癫痫发作和癫痫风险增加有关的 tau 病的一种特性。此外,过度兴奋还会促进细胞外分泌和 tau 的跨突触传播。通过无偏质谱分析,我们在原代培养的大鼠海马神经元中发现了一种仅在神经元过度兴奋时才能检测到的新型磷酸化特征。这些位点影响了 tau 在树突上的定位以及兴奋性突触后位点的大小。这些结果证明了tau在突触处的新生理功能,以及在特定信号背景下对tau磷酸化进行全面分析的实用性。
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引用次数: 0
RETRACTION: Extensive degradation of myelin basic protein isoforms by calpain following traumatic brain injury. 回归:脑外伤后,钙蛋白酶对髓鞘碱性蛋白异构体的广泛降解。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-20 DOI: 10.1111/jnc.16229

Retraction: M. C. Liu, V. Akle, W. Zheng, J. Kitlen, B. O'Steen, S. F. Larner, J. R. Dave, F. C. Tortella, R. L. Hayes, and K. K. W. Wang, "Extensive Degradation of Myelin Basic Protein Isoforms by Calpain Following Traumatic Brain Injury," Journal of Neurochemistry 98, no. 3 (2006): 700-712. https://doi.org/10.1111/j.1471-4159.2006.03882.x. The above article, published online on 19 June 2006, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley and Sons Ltd. A third party reported that they had detected evidence of image manipulation and duplication throughout the published article. An investigation by the publisher and the editors concluded that there was evidence of splicing in Figures 2a, 2b, 3a, 5a, 6a, and 8a. The investigation also found duplications of lanes in Figures 3a, 3d, and 4a. Lastly, the investigation found that the same actin blots in Figure 3 have been used in two other articles by many of the same authors, despite representing different experimental conditions. The authors did not respond to an inquiry by the publisher. The retraction has been agreed to because the results presented in the article can no longer be considered reliable. The authors did not respond to the notice of retraction.

撤回:M. C. Liu, V. Akle, W. Zheng, J. Kitlen, B. O'Steen, S. F. Larner, J. R. Dave, F. C. Tortella, R. L. Hayes, and K. K. W. Wang, "Extensive Degradation of Myelin Basic Protein Isoforms by Calpain Following Traumatic Brain Injury," Journal of Neurochemistry 98, no.3 (2006):700-712。https://doi.org/10.1111/j.1471-4159.2006.03882.x。上述文章于 2006 年 6 月 19 日在线发表于 Wiley Online Library (wileyonlinelibrary.com),经期刊主编 Andrew Lawrence、国际神经化学学会和 John Wiley and Sons Ltd.协商,该文章已被撤回。第三方报告称,他们在已发表的文章中发现了篡改和复制图片的证据。出版商和编辑调查后认为,图 2a、2b、3a、5a、6a 和 8a 中存在拼接的证据。调查还发现图 3a、图 3d 和图 4a 中的泳道存在重复。最后,调查发现图 3 中相同的肌动蛋白印迹被许多相同的作者用在了另外两篇文章中,尽管代表了不同的实验条件。作者没有回复出版商的询问。由于文章中的结果不再可靠,因此同意撤稿。作者未对撤稿通知做出回应。
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引用次数: 0
Sex‐dependent differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice 尼古丁调节小鼠辨别学习和认知灵活性能力的性别差异
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1111/jnc.16227
Yoshiatsu Aomine, Yuto Shimo, Koki Sakurai, Mayuka Abe, Tom Macpherson, Takaaki Ozawa, Takatoshi Hikida
Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex‐dependent differences in the effect of daily nicotine intraperitoneal (i.p.) administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, 0.5 mg/kg nicotine significantly improved performance in the VDR, but not the VD, task, while 0.5 mg/kg nicotine significantly worsened performance in the VD, but not VDR task in female mice. Furthermore, 0.25 mg/kg nicotine significantly worsened performance in the VD and VDR task only in female mice. Next, to investigate the cellular mechanisms that underlie the sex difference in the effects of nicotine on cognition, transcriptomic analyses were performed focusing on the medial prefrontal cortex tissue samples from male and female mice that had received continuous administration of nicotine for 3 or 18 days. As a result of pathway enrichment analysis and protein–protein interaction analysis using gene sets of differentially expressed genes, decreased expression of postsynaptic‐related genes in males and increased expression of innate immunity‐related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility. Our result suggests that nicotine modulates cognitive function in a sex‐dependent manner by alternating the expression of specific gene sets in the medial prefrontal cortex.image
尼古丁是一种存在于烟草中的成瘾性化合物,它是大脑中烟碱乙酰胆碱受体(nAChRs)的激动剂。有趣的是,据报道尼古丁对人类和实验动物都有增强认知能力的作用。然而,尼古丁在动物实验中的效果并不总是一致的,而且尼古丁对几种行为的影响也存在性别差异。具体来说,性别在调节尼古丁对啮齿动物辨别学习和认知灵活性的影响方面所起的作用仍不清楚。在此,我们评估了不同剂量(0.125、0.25 和 0.5 mg/kg)尼古丁腹腔注射对小鼠视觉辨别(VD)学习和逆转(VDR)学习影响的性别差异。在雄性小鼠中,0.5 毫克/千克尼古丁能显著提高视觉分辨学习(VDR)任务的成绩,但不能提高视觉反转学习(VD)任务的成绩;在雌性小鼠中,0.5 毫克/千克尼古丁能显著降低视觉反转学习(VDR)任务的成绩,但不能降低视觉分辨学习(VD)任务的成绩。此外,0.25 毫克/千克尼古丁只会明显降低雌性小鼠在 VD 和 VDR 任务中的表现。接下来,为了研究尼古丁对认知影响的性别差异的细胞机制,研究人员对连续服用尼古丁3天或18天的雌雄小鼠的内侧前额叶皮层组织样本进行了转录组分析。通过对差异表达基因集进行通路富集分析和蛋白-蛋白相互作用分析,发现尼古丁对小鼠辨别学习和认知灵活性认知影响的性别差异可能与雄性突触后相关基因表达减少和雌性先天免疫相关基因表达增加的分子机制有关。我们的研究结果表明,尼古丁通过交替表达内侧前额叶皮层的特定基因组,以性别依赖的方式调节认知功能。
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引用次数: 0
Exosomal miR‐142‐3p from M1‐polarized macrophages suppresses cell growth and immune escape in glioblastoma through regulating HMGB1‐mediated PD‐1/PD‐L1 checkpoint 来自 M1 极化巨噬细胞的外泌体 miR-142-3p 通过调节 HMGB1 介导的 PD-1/PD-L1 检查点抑制胶质母细胞瘤的细胞生长和免疫逃逸
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1111/jnc.16224
Yigong Wei, Kun Zhou, Cheng Wang, Xiaolin Du, Zhengdi Wang, Guangtang Chen, Huan Zhang, Xuhui Hui
Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1‐polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA‐142‐3p (miR‐142‐3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit‐8 (CCK‐8), colony formation assay and 5‐ethynyl‐2′‐deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR‐142‐3p and M1 exosomes affect GBM progression. Upregulation of miR‐142‐3p expression was detected in M1‐polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR‐142‐3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR‐142‐3p inhibits GBM cell growth via targeting high‐mobility group box 1 (HMGB1). In addition, miR‐142‐3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death‐1/programmed death ligand‐1 (PD‐1/PD‐L1) checkpoint. Our study demonstrated that exosomal miR‐142‐3p from M1‐polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1‐mediated PD‐1/PD‐L1 checkpoint.image
胶质母细胞瘤(GBM)是最常见的脑肿瘤之一。以前的研究报告称,来自 M1 极化巨噬细胞的外泌体(M1 外泌体)通过传递肿瘤抑制基因抑制肿瘤的发生和发展。此外,microRNA-142-3p(miR-142-3p)也被证实具有抑癌基因的功能。通过细胞计数试剂盒-8(CCK-8)、菌落形成检测和 5-乙炔基-2′-脱氧尿苷(EdU)检测评估了 GBM 细胞的增殖情况;通过流式细胞仪分析和末端脱氧核苷酸转移酶 dUTP 缺口标记(TUNEL)检测确定了细胞凋亡情况。研究人员进行了机制研究,以分析 miR-142-3p 和 M1 外泌体影响 GBM 进展的分子机制。在M1极化巨噬细胞和M1外泌体中检测到了miR-142-3p的上调表达。M1 外泌体抑制 GBM 细胞增殖并引发细胞凋亡。在功能上,沉默miR-142-3p可促进经M1外泌体处理的GBM细胞增殖并抑制其凋亡。在分子机制方面,miR-142-3p通过靶向高迁移率基团框1(HMGB1)抑制GBM细胞的生长。此外,miR-142-3p/HMGB1轴通过调节程序性死亡-1/程序性死亡配体-1(PD-1/PD-L1)检查点影响GBM细胞的免疫逃逸。我们的研究表明,来自M1极化巨噬细胞的外泌体miR-142-3p通过调节HMGB1介导的PD-1/PD-L1检查点,抑制了GBM的细胞生长和免疫逃逸。
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引用次数: 0
Deciphering the role of sphingosine 1‐phosphate in central nervous system myelination and repair 解密 1-磷酸鞘氨醇在中枢神经系统髓鞘化和修复中的作用
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1111/jnc.16228
Fatima Binish, Junhua Xiao
Sphingosine 1‐phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1‐phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein‐coupled S1P receptors 1–5 (S1PR1–5). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P‐S1PR signalling protects myelin‐forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P–S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation.image
1-phosphate 神经鞘氨醇(S1P)是鞘脂家族的一种生物活性脂质,在哺乳动物神经系统中发挥着关键作用。事实上,S1P 是治疗多发性硬化症等脱髓鞘疾病的靶点。作为相互关联的鞘磷脂代谢网络的一部分,可用于信号传递的 S1P 量在其合成酶(鞘磷脂激酶 1 和 2)和降解酶(1-磷酸鞘磷脂裂解酶)之间保持平衡。S1P 一旦产生,就会通过向五个 G 蛋白偶联 S1P 受体 1-5 (S1PR1-5)家族传递信号来发挥其生物学作用。尽管取得了重大进展,但 S1P 代谢和下游信号在调节髓鞘形成和修复过程中的确切作用在很大程度上仍不明确,并存在一定争议。采用各种模型系统进行的遗传学或药理学研究发现,刺激 S1P-S1PR 信号可在中枢神经系统(CNS)损伤后保护髓鞘形成的少突胶质细胞,并减轻体内脱髓鞘现象。然而,尽管阻断 S1P 的合成能揭示内源性 S1P 在促进中枢神经系统再髓鞘化中的作用,但支持其在哺乳动物中枢神经系统再髓鞘化中发挥作用的证据却很有限。本综述重点总结了目前对 S1P 在中枢神经系统髓鞘形成和修复中作用的认识,讨论了 S1P-S1PR 相互作用的复杂性以及 S1P 生物合成和信号调节健康和受伤哺乳动物中枢神经系统少突胶质细胞髓鞘化的潜在机制,并提出了未来研究的新问题。
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引用次数: 0
The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases GFAP 蛋白形态之谜:如何推动 GFAP 成为神经系统疾病的体液生物标记物
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1111/jnc.16226
Dea Gogishvili, Madison I. J. Honey, Inge M. W. Verberk, Lisa Vermunt, Elly M. Hol, Charlotte E. Teunissen, Sanne Abeln
Glial fibrillary acidic protein (GFAP) is a well‐established biomarker of reactive astrogliosis in the central nervous system because of its elevated levels following brain injury and various neurological disorders. The advent of ultra‐sensitive methods for measuring low‐abundant proteins has significantly enhanced our understanding of GFAP levels in the serum or plasma of patients with diverse neurological diseases. Clinical studies have demonstrated that GFAP holds promise both as a diagnostic and prognostic biomarker, including but not limited to individuals with Alzheimer's disease. GFAP exhibits diverse forms and structures, herein referred to as its proteoform complexity, encompassing conformational dynamics, isoforms and post‐translational modifications (PTMs). In this review, we explore how the proteoform complexity of GFAP influences its detection, which may affect the differential diagnostic performance of GFAP in different biological fluids and can provide valuable insights into underlying biological processes. Additionally, proteoforms are often disease‐specific, and our review provides suggestions and highlights areas to focus on for the development of new assays for measuring GFAP, including isoforms, PTMs, discharge mechanisms, breakdown products, higher‐order species and interacting partners. By addressing the knowledge gaps highlighted in this review, we aim to support the clinical translation and interpretation of GFAP in both CSF and blood and the development of reliable, reproducible and specific prognostic and diagnostic tests. To enhance disease pathology comprehension and optimise GFAP as a biomarker, a thorough understanding of detected proteoforms in biofluids is essential.image
胶质纤维酸性蛋白(GFAP)是中枢神经系统中反应性星形胶质细胞增生的一种公认的生物标志物,因为它在脑损伤和各种神经系统疾病后水平升高。超灵敏低富集蛋白测量方法的出现大大提高了我们对各种神经系统疾病患者血清或血浆中 GFAP 水平的了解。临床研究表明,GFAP 有望成为诊断和预后的生物标志物,包括但不限于阿尔茨海默氏症患者。GFAP 表现出多种形式和结构,这里称为其蛋白形式的复杂性,包括构象动态、同工酶和翻译后修饰 (PTM)。在这篇综述中,我们探讨了 GFAP 蛋白形态的复杂性如何影响其检测,这可能会影响 GFAP 在不同生物液体中的不同诊断性能,并能为潜在的生物过程提供有价值的见解。此外,蛋白形态通常具有疾病特异性,我们的综述为开发新的 GFAP 检测方法提供了建议,并强调了应重点关注的领域,包括同工酶、PTM、排出机制、分解产物、高阶物种和相互作用伙伴。通过解决本综述中强调的知识差距,我们旨在支持 CSF 和血液中 GFAP 的临床转化和解释,以及可靠、可重复和特异性预后和诊断测试的开发。为了提高对疾病病理的理解并优化作为生物标志物的 GFAP,透彻了解生物流体中检测到的蛋白形式至关重要。
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引用次数: 0
Compensatory changes after spinal cord injury in a remyelination deficient mouse model 再髓鞘化缺陷小鼠模型脊髓损伤后的补偿性变化
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-13 DOI: 10.1111/jnc.16220
S. B. Manesh, B. R. Kondiles, S. Wheeler, J. Liu, L. Zhang, C. Chernoff, G. J. Duncan, M. S. Ramer, W. Tetzlaff
The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury‐induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3‐month‐old mice. The present analysis investigated two potential mechanisms by which animals can re‐establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage‐gated sodium channel, a sub‐type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.image
由于目前还没有有效的疗法,因此开发治疗策略以减少脊髓损伤(SCI)后的损伤成为一个活跃的研究领域。其中一种策略是通过促进内源性或外源性再髓鞘化来解决损伤引起的幸免轴突脱髓鞘问题。然而,我们之前的研究表明,3 个月大的小鼠在中度胸脊髓挫伤后恢复后肢步态并不需要新的髓鞘。本分析研究了动物在没有髓鞘再形成的情况下重建运动的两种潜在机制:通过完整的白质进行补偿和通过幸免的轴突进行传导。我们诱导了严重的挫伤,以减少再髓鞘化缺陷模型中幸免的白质边缘,再髓鞘化缺陷动物与受伤的同窝对照组在恢复方面没有差异。我们研究了病变处轴突的结节特性,发现在再髓鞘化缺陷模型中,轴突表达Nav1.2电压门控钠通道,这种亚型通常不在成熟的Ranvier结节中表达。在中度挫伤中,通过髓鞘再形成缺陷动物病变部位的传导速度与受伤后具有髓鞘再形成能力的动物相似。详细的步态分析和运动学研究显示,再髓鞘化缺陷动物与有再髓鞘化能力的对照组之间存在细微差别,但没有更严重的缺陷。Nav1.2通道的上调可能有助于通过病变建立传导。这种传导可能有助于脊髓损伤小鼠模型的代偿和运动功能的恢复。这种代偿机制可能对解释小鼠再髓鞘化干预的疗效结果和开发改善 SCI 后恢复的疗法有影响。
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引用次数: 0
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Journal of Neurochemistry
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