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Neuroprotection of Human Umbilical Cord-Derived Mesenchymal Stem Cells (hUC-MSCs) in Alleviating Ischemic Stroke-Induced Brain Injury by Regulating Inflammation and Oxidative Stress 人脐带间充质干细胞(hUC-MSCs)通过调节炎症和氧化应激在缓解缺血性脑卒中诱发的脑损伤中的神经保护作用
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1007/s11064-024-04212-x
Guangyang Liu, Daohui Wang, Jianru Jia, Chunhua Hao, Qinggang Ge, Liqiang Xu, Chenliang Zhang, Xin Li, Yi Mi, Herui Wang, Li Miao, Yaoyao Chen, Jingwen Zhou, Xiaodan Xu, Yongjun Liu

Brain injury caused by stroke has a high rate of mortality and remains a major medical challenge worldwide. In recent years, there has been significant attention given to the use of human Umbilical cord-derived Mesenchymal Stem Cells (hUC-MSCs) for the treatment of stroke in different adult and neonate animal models of stroke. However, using hUC-MSCs by systemic administration to treat ischemic stroke has not been investigated sufficiently. In this study, we conducted various experiments to explore the neuroprotection of hUC-MSCs in rats. Our findings demonstrate that an intravenous injection of a high dose of hUC-MSCs at 2 × 10^7 cells/kg markedly ameliorated brain injury resulting from ischemic stroke. This improvement was observed one day after inducing transient middle cerebral artery occlusion (MCAO) and subsequent reperfusion in rats. Notably, the efficacy of this single administration of hUC-MSCs surpassed that of edaravone, even when the latter was used continuously over three days. Mechanistically, secretory factors derived from hUC-MSCs, such as HGF, BDNF, and TNFR1, ameliorated the levels of MDA and T-SOD to regulate oxidative stress. In particular, TNFR1 also improved the expression of NQO-1 and HO-1, important proteins associated with oxidative stress. More importantly, TNFR1 played a significant role in reducing inflammation by modulating IL-6 levels in the blood. Furthermore, TNFR1 was observed to influence the permeability of the blood–brain barrier (BBB) as demonstrated in the evan’s blue experiment and protein expression of ZO-1. This study represented a breakthrough in traditional methods and provided a novel strategy for clinical medication and trials.

中风导致的脑损伤死亡率很高,仍然是全球面临的一项重大医学挑战。近年来,利用人体脐带间充质干细胞(hUC-MSCs)在不同的成人和新生儿中风动物模型中治疗中风的研究备受关注。然而,利用脐带间充质干细胞全身给药治疗缺血性中风的研究还不够深入。在本研究中,我们进行了各种实验来探索 hUC 间充质干细胞对大鼠神经的保护作用。我们的研究结果表明,静脉注射 2 × 10^7 cells/kg 的高剂量 hUC-间充质干细胞可明显改善缺血性中风导致的脑损伤。这种改善是在诱导大鼠一过性大脑中动脉闭塞(MCAO)和随后的再灌注一天后观察到的。值得注意的是,单次给药 hUC 间充质干细胞的疗效超过了依达拉奉,即使后者连续使用三天也是如此。从机理上讲,来自 hUC-间充质干细胞的分泌因子(如 HGF、BDNF 和 TNFR1)可改善 MDA 和 T-SOD 的水平,从而调节氧化应激。特别是,TNFR1 还能改善与氧化应激相关的重要蛋白质 NQO-1 和 HO-1 的表达。更重要的是,TNFR1 通过调节血液中 IL-6 的水平,在减少炎症方面发挥了重要作用。此外,TNFR1 还能影响血脑屏障(BBB)的通透性,这一点在伊凡蓝实验和 ZO-1 蛋白表达中均有体现。这项研究突破了传统方法,为临床用药和试验提供了一种新策略。
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引用次数: 0
Scavenger Receptor Class B Type I Modulates Epileptic Seizures and Receptor α2δ-1 Expression 清道夫受体 B 类 I 型调节癫痫发作和受体 α2δ-1 的表达
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-17 DOI: 10.1007/s11064-024-04209-6
Yunyi Huang, Yuan Gao, Zhongwen Huang, Minxue Liang, Yangmei Chen

Scavenger receptor class B type I (SR-BI) is abundant in adult mouse and human brains, but its function in the central nervous system (CNS) remains unclear. This study explored the role of SR-BI in epilepsy and its possible underlying mechanism. Expression patterns of SR-BI in the brains of mice with kainic acid (KA)-induced epilepsy were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting(WB). Behavioral analysis was performed by 24-hour video monitoring and hippocampal local field potential (LFP) recordings were employed to verify the role of SR-BI in epileptogenesis. RNA sequencing (RNA-seq) was used to obtain biological information on SR-BI in the CNS. WB, qPCR, and co-immunoprecipitation (Co-IP) were performed to identify the relationship between SR-BI and the gabapentin receptor α2δ-1.The results showed that SR-BI was primarily co-localized with astrocytes and its expression was down-regulated in the hippocampus of KA mice. Notably, overexpressing SR-BI alleviated the epileptic behavioral phenotype in KA mice. Hippocampal transcriptomic analysis revealed 1043 differentially expressed genes (DEGs) in the SR-BI-overexpressing group. Most DEGs confirmed by RNA-seq analysis were associated with synapses, neuronal projections, neuron development, and ion binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the DEGs were enriched in the glutamatergic synapse pathway. Furthermore, the gabapentin receptor α2δ-1 decreased with SR-BI overexpression in epileptic mice. Overall, these findings highlight the important role of SR-BI in regulating epileptogenesis and that the gabapentin receptor α2δ-1 is a potential downstream target of SR-BI.

清道夫受体 B 类 I 型(SR-BI)在成年小鼠和人类大脑中含量丰富,但其在中枢神经系统(CNS)中的功能仍不清楚。本研究探讨了SR-BI在癫痫中的作用及其可能的内在机制。研究采用免疫荧光染色、实时定量聚合酶链反应(qPCR)和免疫印迹(WB)技术检测了SR-BI在凯尼酸(KA)诱导的癫痫小鼠大脑中的表达模式。通过24小时视频监测和海马局域电位(LFP)记录进行行为分析,以验证SR-BI在癫痫发生中的作用。RNA测序(RNA-seq)用于获取中枢神经系统中SR-BI的生物学信息。结果显示,SR-BI主要与星形胶质细胞共定位,其在KA小鼠海马中的表达下调。值得注意的是,过表达SR-BI可减轻KA小鼠的癫痫行为表型。海马转录组分析显示,SR-BI过表达组有1043个差异表达基因(DEGs)。通过RNA-seq分析确认的大多数DEGs与突触、神经元投射、神经元发育和离子结合有关。京都基因组百科全书(KEGG)分析表明,DEGs富集于谷氨酸能突触通路。此外,在癫痫小鼠中,加巴喷丁受体α2δ-1随着SR-BI的过表达而减少。总之,这些发现强调了SR-BI在调节癫痫发生中的重要作用,以及加巴喷丁受体α2δ-1是SR-BI的潜在下游靶点。
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引用次数: 0
Single-cell RNA Sequencing Identifies a Novel Subtype of Microglia with High Cd74 Expression that Facilitates White Matter Inflammation During Chronic Cerebral Hypoperfusion 单细胞 RNA 测序鉴定出一种 Cd74 高表达的新型小胶质细胞亚型,它在慢性脑灌注不足过程中促进了白质炎症。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.1007/s11064-024-04206-9
Wenchao Cheng, Yuhan Wang, Chang Cheng, Xiuying Chen, Lan Zhang, Wen Huang

Vascular dementia (VaD) causes progressive cognitive decline in the elderly population, but there is short of available therapeutic measures. Microglia-mediated neuroinflammation is vigorously involved in the pathogenesis of VaD, but the traditional classification of microglial M1/M2 phenotypes remains restrictive and controversial. This study aims to investigate whether microglia transform into novel subtypes in VaD. Chronic cerebral hypoperfusion (CCH) rat model was constructed to mimic VaD. Microglia were isolated via magnetic-activated cell sorting and analyzed by single-cell RNA sequencing (scRNA-seq) and bioinformatics. The findings inferred from scRNA-seq and bioinformatics were further validated through in vivo experiments. In this study, microglia were divided into eight clusters. The proportion of MG5 cluster was significantly increased in the white matter of the CCH group compared with the Sham group and was named chronic ischemia-associated microglia (CIAM). Immunity- and inflammation-related genes, including RT1-Db1, RT1-Da, RT1-Ba, Cd74, Spp1, C3, and Cd68, were markedly upregulated in CIAM. Enrichment analysis illustrated that CIAM possessed the function of evoking neuroinflammation. Further studies unveiled that Cd74 is associated with the most abundant GO terms involved in inflammation as well as cell proliferation and differentiation. In addition, microglia-specific Cd74 knockdown mediated by adeno-associated virus decreased the abundance of CIAM in the white matter, thereby mitigating inflammatory cytokine levels, alleviating white matter lesions, and improving cognitive impairment for CCH rats. These findings indicate that Cd74 is the core molecule of CIAM to trigger neuroinflammation and induce microglial differentiation to CIAM, suggesting that Cd74 may be a potential therapeutic target for VaD.

血管性痴呆(VaD)导致老年人群认知能力逐渐下降,但却缺乏可用的治疗措施。小胶质细胞介导的神经炎症与血管性痴呆的发病机制密切相关,但传统的小胶质细胞 M1/M2 表型分类仍具有局限性和争议性。本研究旨在探讨小胶质细胞是否会在 VaD 中转变为新的亚型。研究人员构建了慢性脑灌注不足(CCH)大鼠模型来模拟 VaD。通过磁激活细胞分拣技术分离小胶质细胞,并通过单细胞 RNA 测序(scRNA-seq)和生物信息学进行分析。通过体内实验进一步验证了 scRNA-seq 和生物信息学推断的结果。在这项研究中,小胶质细胞被分为八个集群。与Sham组相比,MG5群在CCH组白质中的比例明显增加,被命名为慢性缺血相关小胶质细胞(CIAM)。免疫和炎症相关基因,包括 RT1-Db1、RT1-Da、RT1-Ba、Cd74、Spp1、C3 和 Cd68 在 CIAM 中明显上调。富集分析表明,CIAM 具有诱发神经炎症的功能。进一步的研究发现,Cd74 与涉及炎症、细胞增殖和分化的最丰富的 GO 术语相关。此外,腺相关病毒介导的小胶质细胞特异性Cd74敲除降低了白质中CIAM的丰度,从而缓解了炎症细胞因子水平,减轻了白质病变,改善了CCH大鼠的认知障碍。这些研究结果表明,Cd74是CIAM引发神经炎症和诱导小胶质细胞分化为CIAM的核心分子,提示Cd74可能是VaD的潜在治疗靶点。
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引用次数: 0
Correction: HDAC1 Promotes Mitochondrial Pathway Apoptosis and Inhibits the Endoplasmic Reticulum Stress Response in High Glucose-Treated Schwann Cells via Decreased U4 Spliceosomal RNA 更正:HDAC1 通过减少 U4 拼接体 RNA 促进线粒体通路凋亡并抑制高血糖处理的许旺细胞的内质网应激反应
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1007/s11064-024-04208-7
Tingting Jin, Ziming Wang, Fan Fan, Wandi Wei, Chenming Zhou, Ziyu Zhang, Yue Gao, Wenhui Li, Lin Zhu, Jun Hao
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引用次数: 0
MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer’s Disease MAMs 和线粒体质量控制:概述及其在阿尔茨海默病中的作用。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-13 DOI: 10.1007/s11064-024-04205-w
Jian-Sheng Luo, Wen-Hu Zhai, Ling-Ling Ding, Xian-Jie Zhang, Jia Han, Jia-Qi Ning, Xue-Meng Chen, Wen-Cai Jiang, Ru-Yu Yan, Meng-Jie Chen

Alzheimer’s disease (AD) represents the most widespread neurodegenerative disorder, distinguished by a gradual onset and slow progression, presenting a substantial challenge to global public health. The mitochondrial-associated membrane (MAMs) functions as a crucial center for signal transduction and material transport between mitochondria and the endoplasmic reticulum, playing a pivotal role in various pathological mechanisms of AD. The dysregulation of mitochondrial quality control systems is considered a fundamental factor in the development of AD, leading to mitochondrial dysfunction and subsequent neurodegenerative events. Recent studies have emphasized the role of MAMs in regulating mitochondrial quality control. This review will delve into the molecular mechanisms underlying the imbalance in mitochondrial quality control in AD and provide a comprehensive overview of the role of MAMs in regulating mitochondrial quality control.

阿尔茨海默病(AD)是最普遍的神经退行性疾病,以逐渐发病和缓慢进展为特征,给全球公共卫生带来了巨大挑战。线粒体相关膜(MAMs)是线粒体和内质网之间信号转导和物质运输的重要中心,在阿尔茨海默病的各种病理机制中发挥着关键作用。线粒体质量控制系统失调被认为是导致线粒体功能障碍和随后的神经退行性病变的一个基本因素。最近的研究强调了 MAMs 在调节线粒体质量控制中的作用。本综述将深入探讨AD线粒体质量控制失衡的分子机制,并全面概述MAMs在调节线粒体质量控制中的作用。
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引用次数: 0
Luteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection 木犀草素能缓解D-半乳糖诱导的大鼠脑衰老:SIRT1 介导的神经保护。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1007/s11064-024-04203-y
Reham L Younis, Rehab M El-Gohary, Asmaa A Ghalwash, Islam Ibrahim Hegab, Maram M Ghabrial, Azza M Aboshanady, Raghad A Mostafa, Alaa H. Abd El-Azeem, Eman E. Farghal, Asmaa A.E. Belal, Haidy Khattab

Luteolin is an essential natural polyphenol found in a variety of plants. Numerous studies have supported its protective role in neurodegenerative diseases, yet the research for its therapeutic utility in D-galactose (D-gal)-induced brain ageing is still lacking. In this study, the potential neuroprotective impact of luteolin against D-gal-induced brain ageing was explored. Forty rats were randomly divided into four groups: control, luteolin, D-gal, and luteolin-administered D-gal groups. All groups were subjected to behavioural, cholinergic function, and hippocampal mitochondrial respiration assessments. Hippocampal oxidative, neuro-inflammatory, senescence and apoptotic indicators were detected. Gene expressions of SIRT1, BDNF, and RAGE were assessed. Hippocampal histopathological studies, along with GFAP and Ki67 immunoreactivity, were performed. Our results demonstrated that luteolin effectively alleviated D-gal-induced cognitive impairment and reversed cholinergic abnormalities. Furthermore, luteolin administration substantially mitigated hippocampus oxidative stress, mitochondrial dysfunction, neuro-inflammation, and senescence triggered by D-gal. Additionally, luteolin treatment considerably attenuated neuronal apoptosis and upregulated hippocampal SIRT1 mRNA expression. In conclusion, our findings revealed that luteolin administration attenuated D-gal-evoked brain senescence, improving mitochondrial function and enhancing hippocampal neuroregeneration in an ageing rat model through its antioxidant, senolytic, anti-inflammatory, and anti-apoptotic impacts, possibly due to upregulation of SIRT1. Luteolin could be a promising therapeutic modality for brain aging-associated abnormalities.

叶黄素是一种存在于多种植物中的重要天然多酚。大量研究证实了叶黄素在神经退行性疾病中的保护作用,但对其在 D-半乳糖(D-gal)诱导的脑衰老中的治疗作用的研究仍然缺乏。本研究探讨了叶黄素对 D-gal 诱导的脑老化的潜在神经保护作用。研究人员将 40 只大鼠随机分为四组:对照组、木犀草素组、D-gal 组和木犀草素注射 D-gal 组。所有组均接受行为、胆碱能功能和海马线粒体呼吸评估。检测海马氧化、神经炎症、衰老和凋亡指标。评估了 SIRT1、BDNF 和 RAGE 的基因表达。还进行了海马组织病理学研究,以及 GFAP 和 Ki67 免疫反应。我们的研究结果表明,叶黄素能有效缓解 D-gal 诱导的认知障碍,并逆转胆碱能异常。此外,叶黄素还能显著减轻D-gal诱导的海马氧化应激、线粒体功能障碍、神经炎症和衰老,并能显著减少神经元凋亡和上调海马SIRT1 mRNA的表达。总之,我们的研究结果表明,叶黄素通过抗氧化、抗衰老、抗炎症和抗凋亡作用,可减轻D-gal诱发的脑衰老,改善线粒体功能,促进老龄大鼠海马神经再生,这可能是由于SIRT1的上调所致。木犀草素可能是治疗脑衰老相关异常的一种很有前景的方法。
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引用次数: 0
Investigating the Impact of Intracerebroventricular Streptozotocin on Female Rats with and without Ovaries: Implications for Alzheimer’s Disease 研究脑室内注射链脲佐菌素对有卵巢和无卵巢雌性大鼠的影响:对阿尔茨海默病的影响
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1007/s11064-024-04204-x
Juliette López Hanotte, Facundo Peralta, Paula Cecilia Reggiani, María Florencia Zappa Villar

To contribute to research on female models of Alzheimer’s disease (AD), our aim was to study the effect of intracerebroventricular (ICV) injection of streptozotocin (STZ) in female rats, and to evaluate a potential neuroprotective action of ovarian steroids against STZ. Female rats were either ovariectomized (OVX) or kept with ovaries (Sham) two weeks before ICV injections. Animals were injected with either vehicle (artificial cerebrospinal fluid, aCSF) or STZ (3 mg/kg) and separated into four experimental groups: Sham + aCSF, Sham + STZ, OVX + aCSF and OVX + STZ. Nineteen days post-injection, we assessed different behavioral aspects: burying, anxiety and exploration, object recognition memory, spatial memory, and depressive-like behavior. Immunohistochemistry and Immunoblot analyses were performed in the hippocampus to examine changes in AD-related proteins and neuronal and microglial populations. STZ affected burying and exploratory behavior depending on ovarian status, and impaired recognition but not spatial memory. STZ and ovariectomy increased depressive-like behavior. Interestingly, STZ did not alter the expression of β-amyloid peptide or Tau phosphorylated forms. STZ affected the neuronal population from the Dentate Gyrus, where immature neurons were more vulnerable to STZ in OVX rats. Regarding microglia, STZ increased reactive cells, and the OVX + STZ group showed an increase in the total cell number. In sum, STZ partially affected female rats, compared to what was previously reported for males. Although AD is more frequent in women, reports about the effect of ICV-STZ in female rats are scarce. Our work highlights the need to deepen into the effects of STZ in the female brain and study possible sex differences.

为了促进阿尔茨海默病(AD)雌性模型的研究,我们的目的是研究雌性大鼠脑室内注射链脲佐菌素(STZ)的影响,并评估卵巢类固醇对 STZ 的潜在神经保护作用。雌性大鼠在接受 ICV 注射前两周被切除卵巢(OVX)或保留卵巢(Sham)。给大鼠注射载体(人工脑脊液)或 STZ(3 毫克/千克),并将其分为四个实验组:Sham + aCSF、Sham + STZ、OVX + aCSF 和 OVX + STZ。注射后19天,我们对不同的行为进行了评估:埋葬、焦虑和探索、物体识别记忆、空间记忆和抑郁样行为。我们对海马进行了免疫组化和免疫印迹分析,以检测与AD相关的蛋白质以及神经元和小胶质细胞群的变化。STZ会影响埋藏和探索行为,这取决于卵巢状态,并且会损害识别能力,但不会损害空间记忆。STZ和卵巢切除术增加了抑郁样行为。有趣的是,STZ并未改变β-淀粉样肽或Tau磷酸化形式的表达。STZ影响了齿状回的神经元群,在OVX大鼠中,未成熟的神经元更容易受到STZ的影响。在小胶质细胞方面,STZ 增加了反应性细胞,OVX + STZ 组显示细胞总数增加。总之,STZ 对雌性大鼠产生了部分影响,而之前的报告显示对雄性大鼠产生了影响。虽然注意力缺失症在女性中更为常见,但有关 ICV-STZ 对雌性大鼠影响的报道却很少。我们的研究突出表明,有必要深入研究 STZ 对雌性大鼠大脑的影响,并研究可能存在的性别差异。
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引用次数: 0
Ribosomal Protein Dynamics and Its Association with Actin Filaments and Local Translation in Axonal Growth Cones of Dorsal Root Ganglia Neurons 背根神经节神经元轴突生长锥中核糖体蛋白的动态及其与肌动蛋白丝和局部翻译的关联
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-08 DOI: 10.1007/s11064-024-04195-9
Osamu Hoshi, Nobuyuki Takei

Local translation in growth cones plays a critical role in responses to extracellular stimuli, such as axon guidance cues. We previously showed that brain-derived neurotrophic factor activates translation and enhances novel protein synthesis through the activation of mammalian target of rapamycin complex 1 signaling in growth cones of dorsal root ganglion neurons. In this study, we focused on 40S ribosomal protein S6 (RPS6), 60S ribosomal protein P0/1/2 (RPP0/1/2), and actin filaments to determine how localization of ribosomal proteins changes with overall protein synthesis induced by neurotrophins. Our quantitative analysis using immunocytochemistry and super-resolution microscopy indicated that RPS6, RPP0/1/2, and actin tend to colocalize in the absence of stimulation, and that these ribosomal proteins tend to dissociate from actin and associate with each other when local protein synthesis is enhanced. We propose that this is because stimulation causes ribosomal subunits to associate with each other to form actively translating ribosomes (polysomes). This study further clarifies the role of cytoskeletal components in local translation in growth cones.

Graphical Abstract

Schematic representation of ribosomal protein localization in the the growth cone. a Ribosomal proteins RPS6 and RP0/1/2 are associated with actin in the absence of stimulation. b Upon stimulation by neurotrophins, these two subunit proteins dissociate from actin and bind to each other to form the 80S ribosome initiation complex

生长锥中的局部翻译在对轴突导向线索等细胞外刺激的反应中起着至关重要的作用。我们以前的研究表明,脑源性神经营养因子通过激活背根神经节神经元生长锥中的哺乳动物雷帕霉素复合体 1 信号靶激活翻译并增强新蛋白合成。在这项研究中,我们重点研究了 40S 核糖体蛋白 S6 (RPS6)、60S 核糖体蛋白 P0/1/2 (RPP0/1/2) 和肌动蛋白丝,以确定核糖体蛋白的定位如何随着神经营养素诱导的整体蛋白质合成而发生变化。我们利用免疫细胞化学和超分辨率显微镜进行的定量分析表明,在没有刺激的情况下,RPS6、RPP0/1/2 和肌动蛋白倾向于共定位,而当局部蛋白质合成增强时,这些核糖体蛋白倾向于与肌动蛋白分离并相互结合。我们认为这是因为刺激会导致核糖体亚基相互结合,形成活跃翻译的核糖体(多聚体)。这项研究进一步阐明了细胞骨架成分在生长锥局部翻译中的作用。
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引用次数: 0
Omega-3 Attenuates Disrupted Neurotransmission and Partially Protects Metabolic Dysfunction Caused by Obesity in Wistar Rats 欧米茄-3 可减轻肥胖对 Wistar 大鼠神经传递的干扰,并部分保护肥胖引起的代谢功能障碍。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-03 DOI: 10.1007/s11064-024-04201-0
Gabriel de Farias Fraga, Fernanda da Silva Rodrigues, Jeferson Jantsch, Victor Silva Dias, Vitória Milczarski, Fernanda Wickert, Camila Pereira Medeiros, Sarah Eller, Alethéa Gatto Barschak, Marcia Giovenardi, Renata Padilha Guedes

Omega-3 (n3) is a polyunsaturated fatty acid well known for its anti-inflammatory and neuroprotective properties. Obesity is linked to chronic inflammation that disrupts metabolism, the intestine physiology and the central nervous system functioning. This study aims to determine if n3 supplementation can interfere with the effects of obesity on the mitochondrial activity, intestinal barrier, and neurotransmitter levels in the brain of Wistar rats that received cafeteria diet (CAF). We examined adipose tissue, skeletal muscle, plasma, intestine, and the cerebral cortex of four groups: CT (control diet), CTn3 (control diet with n3 supplementation), CAF, and CAFn3 (CAF and n3). Diets were offered for 13 weeks, with n3 supplementation in the final 5 weeks. Adipose tissue Electron Transport Chain complexes I, II, and III showed higher activity in CAF groups, as did complexes III and IV in skeletal muscle. Acetate levels in plasma were reduced in CAF groups, and Lipopolysaccharide (LPS) was higher in the CAF group but reduced in CAFn3 group. Claudin-5 in the intestine was lower in CAF groups, with no n3 supplementation effect. In the cerebral cortex, dopamine levels were decreased with CAF, which was reversed by n3. DOPAC, a dopamine metabolite, also showed a supplementation effect, and HVA, a diet effect. Serotonin levels increased in the CAF group that received supplementation. Therefore, we demonstrate disturbances in mitochondria, plasma, intestine and brain of rats submitted to CAF and the potential benefit of n3 supplementation in endotoxemia and neurotransmitter levels.

Graphical Abstract

奥米加-3(n3)是一种多不饱和脂肪酸,以其抗炎和保护神经的特性而闻名。肥胖与慢性炎症有关,慢性炎症会破坏新陈代谢、肠道生理机能和中枢神经系统功能。本研究旨在确定补充 n3 是否能干扰肥胖对接受食堂饮食(CAF)的 Wistar 大鼠脑内线粒体活性、肠道屏障和神经递质水平的影响。我们检测了四组大鼠的脂肪组织、骨骼肌、血浆、肠道和大脑皮层:CT组(控制饮食)、CTn3组(控制饮食并补充n3)、CAF组和CAFn3组(CAF和n3)。饮食提供 13 周,最后 5 周补充 n3。在 CAF 组中,脂肪组织电子传递链复合物 I、II 和 III 的活性较高,骨骼肌中复合物 III 和 IV 的活性也较高。CAF组血浆中的醋酸盐水平降低,CAF组的脂多糖(LPS)水平升高,而CAFn3组则降低。CAF组肠道中的Claudin-5含量较低,补充n3无影响。在大脑皮层中,CAF组的多巴胺水平降低,而n3则可逆转。多巴胺代谢物 DOPAC 也显示出补充效应,而 HVA 则显示出饮食效应。接受补充剂的 CAF 组血清素水平升高。因此,我们证明了接受 CAF 的大鼠线粒体、血浆、肠道和大脑的紊乱,以及补充 n3 对内毒素血症和神经递质水平的潜在益处。
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引用次数: 0
Propofol Protects the Blood-Brain Barrier After Traumatic Brain Injury by Stabilizing the Extracellular Matrix via Prrx1: From Neuroglioma to Neurotrauma 丙泊酚通过 Prrx1 稳定细胞外基质保护创伤性脑损伤后的血脑屏障:从神经胶质瘤到神经创伤。
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1007/s11064-024-04202-z
Lan Zhang, Chenrui Wu, Tao Liu, Yu Tian, Dong Wang, Bo Wang, Yiqing Yin

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs.

本研究旨在探索创伤性脑损伤(TBI)和高级别胶质瘤的共同分子发病机制,并研究丙泊酚(PF)作为一种潜在保护剂的机制。通过分析中国胶质瘤基因组图谱(CGGA)和癌症基因组图谱(TCGA)数据库,我们比较了高级别胶质瘤和创伤性脑损伤患者的转录组数据,以确定共同的病理机制。通过生物信息学分析、体外实验和体内 TBI 模型,我们研究了 PF 在氧化应激下通过 Prrx1 对细胞外基质(ECM)相关基因的调控作用。我们利用双层 BBB 模型研究了 PF 在氧化应激下对 BBB 完整性的影响,并探讨了 PF 对小鼠 TBI 后紧密连接蛋白和 ECM 相关基因的保护作用。研究发现,高级别胶质瘤和创伤性脑损伤共同的重要分子病理机制是 ECM 不稳定。PF 可直接与 Prrx1 结合或通过 miRNA 间接调节 Prrx1,从而稳定 ECM 并保护 BBB。此外,PF 还能降低氧化应激下的细胞内钙离子和 ROS 水平,从而保护 BBB 的完整性。在创伤性脑损伤小鼠模型中,PF 通过上调紧密连接蛋白和稳定 ECM 相关基因的表达来保护 BBB 的完整性。我们的研究揭示了创伤性脑损伤和胶质母细胞瘤之间共同的分子发病机制,并证明了 PF 作为 BBB 保护剂的潜力。这为开发新型神经创伤治疗药物提供了新的靶点和方法。
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Neurochemical Research
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