Brain Research最新文献_第4页

Electroacupuncture extends the time window of thrombolytic therapy in rats by reducing disruptions of blood–brain barrier and inhibiting GSDMD-mediated pyroptosis 电针通过减少对血脑屏障的破坏和抑制 GSDMD 介导的热蛋白沉积，延长大鼠溶栓治疗的时间窗

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-28 DOI: 10.1016/j.brainres.2024.149296

Huanhuan Liu , Yiting Shen , Zheng Huang , Tao Jiang , Peiyan Huang , Mengning Yang , Xinchang Zhang , Wentao Xu , Guangxia Ni

Objective

Thrombolytic therapy is the primary treatment for acute ischemic stroke. Extending the therapeutic time window can effectively reduce the harmful side effects associated with thrombolytic therapy. Although electroacupuncture (EA) has been shown to extend this time window, the specific mechanisms remain unclear.

Methods

We developed an embolic stroke model in rats and administered EA during thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) either 4.5 or 6 h after stroke onset. Neurological deficits were evaluated at 2 and 24 h post-stroke. Brain tissue was collected for analysis using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, water content measurement, blood–brain barrier (BBB) permeability assessment, electron microscopy, and TUNEL assay. Immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assays were employed to quantify the expression of proteins related to BBB integrity and pyroptosis.

Results

Neuronal damage and BBB disruption along with increased expression of pyroptosis-related proteins were observed following thrombolytic therapy at the 6-hour mark. EA treatment improved neurological outcomes, reduced infarct volume, and alleviated BBB disruption. EA also inhibited the expression of matrix metalloproteinase 9 (MMP9) and enhanced the expression of tissue inhibitor of metalloproteinases 1 (TIMP1), helping to maintain BBB integrity. Furthermore, EA reduced the expression of pyroptosis-related proteins, including gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). EA also reduced the co-expression of GSDMD and MMP9 in brain tissues.

Conclusions

EA may be a promising therapeutic approach for extending the thrombolytic therapy window by protecting the BBB and inhibiting GSDMD-mediated pyroptosis.

目的溶栓疗法是治疗急性缺血性中风的主要方法。延长治疗时间窗可以有效减少溶栓治疗的副作用。方法我们在大鼠中建立了栓塞性中风模型，并在中风发作后 4.5 或 6 h 使用重组组织纤溶酶原激活剂（rt-PA）溶栓治疗期间给予电针治疗。中风后 2 小时和 24 小时对神经功能缺损进行评估。采集的脑组织通过 2,3,5-三苯基氯化四氮唑（TTC）染色、含水量测量、血脑屏障（BBB）通透性评估、电子显微镜和 TUNEL 检测进行分析。免疫荧光染色、Western 印迹和酶联免疫吸附试验被用来定量检测与血脑屏障完整性和热蛋白沉积有关的蛋白质的表达。EA 治疗改善了神经功能预后，缩小了梗死体积，缓解了 BBB 破坏。EA 还抑制了基质金属蛋白酶 9（MMP9）的表达，增强了组织金属蛋白酶抑制剂 1（TIMP1）的表达，有助于维持 BBB 的完整性。此外，EA 还能减少热蛋白沉积相关蛋白的表达，包括气蛋白 D（GSDMD）、白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）。结论EA可保护BBB并抑制GSDMD介导的热蛋白沉积，可能是延长溶栓治疗窗口期的一种有前途的治疗方法。

{"title":"Electroacupuncture extends the time window of thrombolytic therapy in rats by reducing disruptions of blood–brain barrier and inhibiting GSDMD-mediated pyroptosis","authors":"Huanhuan Liu , Yiting Shen , Zheng Huang , Tao Jiang , Peiyan Huang , Mengning Yang , Xinchang Zhang , Wentao Xu , Guangxia Ni","doi":"10.1016/j.brainres.2024.149296","DOIUrl":"10.1016/j.brainres.2024.149296","url":null,"abstract":"<div><h3>Objective</h3><div>Thrombolytic therapy is the primary treatment for acute ischemic stroke. Extending the therapeutic time window can effectively reduce the harmful side effects associated with thrombolytic therapy. Although electroacupuncture (EA) has been shown to extend this time window, the specific mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>We developed an embolic stroke model in rats and administered EA during thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) either 4.5 or 6 h after stroke onset. Neurological deficits were evaluated at 2 and 24 h post-stroke. Brain tissue was collected for analysis using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, water content measurement, blood–brain barrier (BBB) permeability assessment, electron microscopy, and TUNEL assay. Immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assays were employed to quantify the expression of proteins related to BBB integrity and pyroptosis.</div></div><div><h3>Results</h3><div>Neuronal damage and BBB disruption along with increased expression of pyroptosis-related proteins were observed following thrombolytic therapy at the 6-hour mark. EA treatment improved neurological outcomes, reduced infarct volume, and alleviated BBB disruption. EA also inhibited the expression of matrix metalloproteinase 9 (MMP9) and enhanced the expression of tissue inhibitor of metalloproteinases 1 (TIMP1), helping to maintain BBB integrity. Furthermore, EA reduced the expression of pyroptosis-related proteins, including gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). EA also reduced the co-expression of GSDMD and MMP9 in brain tissues.</div></div><div><h3>Conclusions</h3><div>EA may be a promising therapeutic approach for extending the thrombolytic therapy window by protecting the BBB and inhibiting GSDMD-mediated pyroptosis.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149296"},"PeriodicalIF":2.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cortical calretinin-positive neurons: Functional and ontogenetic characteristics and their relationship to brain pathologies 皮质钙蛋白阳性神经元：功能和本体特征及其与脑病理学的关系

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-28 DOI: 10.1016/j.brainres.2024.149285

Lina Vanessa Becerra-Hernández , Manuel F. Casanova , Efraín Buriticá

Cortical GABAergic interneurons can be classified according to electrophysiological, biochemical, and/or morphological criteria. In humans, the use of calcium-binding proteins allows us to differentiate three subpopulations of GABAergic interneurons with minimal overlap. Cortical calretinin-positive neurons mainly include bipolar and double-bouquet morphologies, with a largely non-rapid and adaptive firing pattern, originating from the ganglionic eminence and the ventricular and subventricular regions of the developing brain. These cells are distributed from layer I to VI of the neocortex, with predominance in layers II and III. Given their morphology, distribution of processes, and elucidated synaptic contacts, these neurons are considered important in the control of intraminicolumnar processing through vertical inhibition. They have been extensively studied in the context of pathologies characterized by excitation/inhibition imbalance, such as Alzheimer’s disease, epilepsy, traumatic brain injury, and autism. In light of the current evidence, this review considers these aspects in depth and discusses the pathophysiological role and selective vulnerability (pathoclisis) vs. the resistance that these interneurons can present against different types of injury.

皮质 GABA 能中间神经元可根据电生理学、生物化学和/或形态学标准进行分类。在人体中，利用钙结合蛋白，我们可以区分出 GABA 能中间神经元的三个亚群，其重叠程度极低。皮层钙调蛋白阳性神经元主要包括双极和双束形态，其发射模式大多是非快速和适应性的，起源于发育中大脑的神经节突起、脑室和脑室下区域。这些细胞分布在新皮层的第一层到第六层，主要集中在第二层和第三层。鉴于其形态、突触分布和已阐明的突触接触，这些神经元被认为在通过垂直抑制控制柱内处理方面起着重要作用。在阿尔茨海默病、癫痫、脑外伤和自闭症等以兴奋/抑制失衡为特征的病理情况下，对这些神经元进行了广泛的研究。鉴于目前的证据，本综述深入探讨了这些方面，并讨论了这些中间神经元的病理生理作用和选择性易损性（pathoclisis），以及它们对不同类型损伤的抵抗力。

{"title":"Cortical calretinin-positive neurons: Functional and ontogenetic characteristics and their relationship to brain pathologies","authors":"Lina Vanessa Becerra-Hernández , Manuel F. Casanova , Efraín Buriticá","doi":"10.1016/j.brainres.2024.149285","DOIUrl":"10.1016/j.brainres.2024.149285","url":null,"abstract":"<div><div>Cortical GABAergic interneurons can be classified according to electrophysiological, biochemical, and/or morphological criteria. In humans, the use of calcium-binding proteins allows us to differentiate three subpopulations of GABAergic interneurons with minimal overlap. Cortical calretinin-positive neurons mainly include bipolar and double-bouquet morphologies, with a largely non-rapid and adaptive firing pattern, originating from the ganglionic eminence and the ventricular and subventricular regions of the developing brain. These cells are distributed from layer I to VI of the neocortex, with predominance in layers II and III. Given their morphology, distribution of processes, and elucidated synaptic contacts, these neurons are considered important in the control of intraminicolumnar processing through vertical inhibition. They have been extensively studied in the context of pathologies characterized by excitation/inhibition imbalance, such as Alzheimer’s disease, epilepsy, traumatic brain injury, and autism. In light of the current evidence, this review considers these aspects in depth and discusses the pathophysiological role and selective vulnerability (pathoclisis) vs. the resistance that these interneurons can present against different types of injury.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149285"},"PeriodicalIF":2.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quantitative synthetic MRI for evaluation of hippocampus in patients with multiple sclerosis 用于评估多发性硬化症患者海马体的定量合成磁共振成像。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-25 DOI: 10.1016/j.brainres.2024.149298

Jing Huang , Yan Liang , Jiyuan Wang , Yi Shan , Cheng Zhao , Qiongge Li , Huiqing Dong , Jie Lu

Objective

To identify early changes in hippocampal quantitative parameters in multiple sclerosis (MS) patients using synthetic MRI, and to correlate these changes with clinical variables.

Methods

45 MS patients and 26 healthy controls (HCs) underwent synthetic MRI and 3D-T1 MRI. The hippocampus volumes were assessed by using voxel-based morphometry. Synthetic MRI parameters (T1, T2, and proton density (PD)) from hippocampus and its subfield were measured and compared, and their associations with the Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT) scores were further investigated.

Results

There was no significant difference in hippocampal volume between MS patients and HCs. Compared with HCs, the T1, T2 and PD values of hippocampus and its subfield increased in MS patients. T2 values showed positive correlation with EDSS and negative correlation with SDMT.

Conclusions

Synthetic MRI can detect subtle quantitative changes of the hippocampus in MS patients with normal hippocampal volume. Specifically, Synthetic MRI parameters may apply as potentially effective imaging biomarker for hippocampus evaluation.

目的方法：45 名多发性硬化症患者和 26 名健康对照者（HCs）接受了合成 MRI 和 3D-T1 MRI 检查。方法：45 名多发性硬化症患者和 26 名健康对照者（HC）接受了合成 MRI 和三维-T1 MRI 检查，并使用基于体素的形态测量法评估了海马体积。对海马及其子野的合成 MRI 参数（T1、T2 和质子密度 (PD)）进行了测量和比较，并进一步研究了它们与残疾状况扩展量表 (EDSS)、符号数字模型测试 (SDMT) 评分之间的关系：结果：多发性硬化症患者的海马体积与普通人无明显差异。与普通人相比，多发性硬化症患者海马及其亚区的 T1、T2 和 PD 值均有所增加。T2值与EDSS呈正相关，与SDMT呈负相关：结论：合成 MRI 可以检测海马体积正常的多发性硬化症患者海马的细微定量变化。具体而言，合成 MRI 参数可作为评估海马的潜在有效成像生物标志物。

{"title":"Quantitative synthetic MRI for evaluation of hippocampus in patients with multiple sclerosis","authors":"Jing Huang , Yan Liang , Jiyuan Wang , Yi Shan , Cheng Zhao , Qiongge Li , Huiqing Dong , Jie Lu","doi":"10.1016/j.brainres.2024.149298","DOIUrl":"10.1016/j.brainres.2024.149298","url":null,"abstract":"<div><h3>Objective</h3><div>To identify early changes in hippocampal quantitative parameters in multiple sclerosis (MS) patients using synthetic MRI, and to correlate these changes with clinical variables.</div></div><div><h3>Methods</h3><div>45 MS patients and 26 healthy controls (HCs) underwent synthetic MRI and 3D-T1 MRI. The hippocampus volumes were assessed by using voxel-based morphometry. Synthetic MRI parameters (T1, T2, and proton density (PD)) from hippocampus and its subfield were measured and compared, and their associations with the Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT) scores were further investigated.</div></div><div><h3>Results</h3><div>There was no significant difference in hippocampal volume between MS patients and HCs. Compared with HCs, the T1, T2 and PD values of hippocampus and its subfield increased in MS patients. T2 values showed positive correlation with EDSS and negative correlation with SDMT.</div></div><div><h3>Conclusions</h3><div>Synthetic MRI can detect subtle quantitative changes of the hippocampus in MS patients with normal hippocampal volume. Specifically, Synthetic MRI parameters may apply as potentially effective imaging biomarker for hippocampus evaluation.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1847 ","pages":"Article 149298"},"PeriodicalIF":2.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A coloaded liposome in situ gel as a novel therapeutic strategy to treat cerebral ischemia reperfusion injury 将胶体脂质体原位凝胶作为治疗脑缺血再灌注损伤的一种新型治疗策略。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-24 DOI: 10.1016/j.brainres.2024.149292

Qiang Tian , Jin Li , Rongbin Lv , Guangan Zhou , Xinyun Liu , Yanfen Wang , Baoliang Sun , Zhangyong Xia

Background

Ischemic stroke has become one of the leading causes of death and disability worldwide in individuals aged 60 and above. However, currently available drugs show limited efficacy. Therefore, research to find more effective and safer therapeutic strategies is an urgent requirement for the treatment of cerebral ischemia reperfusion injury (CIRI).

Methods

First, the free radical scavenger Edaravone and a Ginseng active ingredient were coloaded into liposomes (aER@Lip), followed by optimization and characterization. Pluronic F127 and F68 at different concentrations were mixed and stored at 4 °C for more than 24 h to obtain gel solutions. Then, aER@Lip was added to the gel solutions to prepare the drug-loaded in situ gel, termed aER@Lip-TSG.

Results

In vitro experiments showed that aER@Lip-TSG was taken up by cells and had a good protective effect on oxygen-glucose deprivation/reoxygenation in pheochromocytoma 12 cells. In a rat CIRI model, aER@Lip-TSG delivered by intranasal administration not only decreased the apoptosis in brain tissue induced by CIRI, but also decreased the resultant inflammatory response. Moreover, the results suggested that aER@Lip-TSG had good biosafety.

Conclusion

This delivery system provides a promising multi-factor combination, synergistic effects, sustained-release capabilities, and is a non-invasive treatment strategy for CIRI. It thus meets the urgent need for effective treatments of central nervous system diseases.

背景：缺血性中风已成为全球 60 岁及以上人群死亡和残疾的主要原因之一。然而，现有药物的疗效有限。因此，研究更有效、更安全的治疗策略是治疗脑缺血再灌注损伤（CIRI）的迫切要求：首先，将自由基清除剂依达拉奉和人参有效成分加入脂质体（aER@Lip）中，然后进行优化和表征。将不同浓度的 Pluronic F127 和 F68 混合并在 4 °C 下储存 24 小时以上，得到凝胶溶液。然后将 aER@Lip 添加到凝胶溶液中，制备药物负载原位凝胶，称为 aER@Lip-TSG.Results：体外实验表明，aER@Lip-TSG能被细胞吸收，并对嗜铬细胞瘤12细胞的氧-葡萄糖剥夺/缺氧有良好的保护作用。在大鼠 CIRI 模型中，aER@Lip-TSG 通过鼻内给药不仅减少了 CIRI 诱导的脑组织凋亡，还降低了由此引起的炎症反应。此外，研究结果表明，aER@Lip-TSG 具有良好的生物安全性：该递送系统具有多因素组合、协同效应、持续释放能力等优点，是一种非侵入性的 CIRI 治疗策略。因此，它满足了有效治疗中枢神经系统疾病的迫切需要。

{"title":"A coloaded liposome in situ gel as a novel therapeutic strategy to treat cerebral ischemia reperfusion injury","authors":"Qiang Tian , Jin Li , Rongbin Lv , Guangan Zhou , Xinyun Liu , Yanfen Wang , Baoliang Sun , Zhangyong Xia","doi":"10.1016/j.brainres.2024.149292","DOIUrl":"10.1016/j.brainres.2024.149292","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic stroke has become one of the leading causes of death and disability worldwide in individuals aged 60 and above. However, currently available drugs show limited efficacy. Therefore, research to find more effective and safer therapeutic strategies is an urgent requirement for the treatment of cerebral ischemia reperfusion injury (CIRI).</div></div><div><h3>Methods</h3><div>First, the free radical scavenger Edaravone and a Ginseng active ingredient were coloaded into liposomes (aER@Lip), followed by optimization and characterization. Pluronic F127 and F68 at different concentrations were mixed and stored at 4 °C for more than 24 h to obtain gel solutions. Then, aER@Lip was added to the gel solutions to prepare the drug-loaded <em>in situ</em> gel, termed aER@Lip-TSG.</div></div><div><h3>Results</h3><div><em>In vitro</em> experiments showed that aER@Lip-TSG was taken up by cells and had a good protective effect on oxygen-glucose deprivation/reoxygenation in pheochromocytoma 12 cells. In a rat CIRI model, aER@Lip-TSG delivered by intranasal administration not only decreased the apoptosis in brain tissue induced by CIRI, but also decreased the resultant inflammatory response. Moreover, the results suggested that aER@Lip-TSG had good biosafety.</div></div><div><h3>Conclusion</h3><div>This delivery system provides a promising multi-factor combination, synergistic effects, sustained-release capabilities, and is a non-invasive treatment strategy for CIRI. It thus meets the urgent need for effective treatments of central nervous system diseases.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1847 ","pages":"Article 149292"},"PeriodicalIF":2.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3,5-Dihydroxy-4-methoxybenzyl alcohol, a novel antioxidant isolated from oyster meat, inhibits the hypothalamus–pituitary–adrenal axis to regulate the stress response 3,5-二羟基-4-甲氧基苄醇是从牡蛎肉中分离出来的一种新型抗氧化剂，它能抑制下丘脑-垂体-肾上腺轴，从而调节应激反应。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-24 DOI: 10.1016/j.brainres.2024.149290

Mitsugu Watanabe , Kenji Yoshiike , Emiko Miki , Katsuya Kuroki

Background

Antioxidants that can scavenge reactive oxygen in the brain and inhibit hyperactivity of the HPA axis are desirable.

Aims

We investigated the cerebral translocation of the antioxidant 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) and the effects of DHMBA administration on the hypothalamus–pituitary–adrenal (HPA) axis in stress-loaded rats.

Methods

Experiment 1: Plasma and brain DHMBA concentrations were measured over time after oral DHMBA administration to male B6 mice. Experiment 2: Female Wistar Imamichi rats were used. The normal group was not subjected to stress. The stress, DHMBA, and vitamin E groups were subjected to individual and overcrowding stress. Brain and hippocampal 8-hydroxy-2′-deoxyguanosine levels, hippocampal glucocorticoid receptor-α levels, plasma corticosterone levels and RNA levels of glutathione peroxidase 4, catalase, and glutathione reductase in the hippocampus were measured.

Results

In Experiment 1, DHMBA was not detected in the plasma or brain before DHMBA administration but was detected in both after administration. In Experiment 2, brain and hippocampal 8-hydroxy-2′-deoxyguanosine levels and plasma corticosterone levels were significantly lower in the DHMBA than in the stress group. Glucocorticoid receptor-α levels were higher in the DHMBA than in the stress group. DHMBA increased RNA levels of antioxidant enzymes in the hippocampus. Conclusion: DHMBA was translocated to the brain after administration. DHMBA administration decreased 8-hydroxy-2′-deoxyguanosine levels in the brain and hippocampus, increased hippocampal glucocorticoid receptor-α levels, and decreased the plasma corticosterone concentration, suggesting that DHMBA inhibits hyperactivity of the HPA axis. Nrf2 pathway activity induced by DHMBA resulted in increased antioxidant enzyme levels in the hippocampus.

背景：目的：我们研究了抗氧化剂3,5-二羟基-4-甲氧基苯甲醇（DHMBA）在大脑中的转运以及给药对应激负荷大鼠下丘脑-垂体-肾上腺（HPA）轴的影响：实验 1：给雌性 B6 小鼠口服 DHMBA 后，随时间推移测量血浆和大脑中 DHMBA 的浓度。实验 2：使用雌性 Wistar Imamichi 大鼠。正常组不承受压力。应激组、DHMBA 组和维生素 E 组受到单独和过度拥挤的应激。测定大鼠大脑和海马的 8-羟基-2'-脱氧鸟苷水平、海马糖皮质激素受体-α水平、血浆皮质酮水平以及海马中谷胱甘肽过氧化物酶 4、过氧化氢酶和谷胱甘肽还原酶的 RNA 水平：实验 1：在服用 DHMBA 之前，血浆和大脑中均未检测到 DHMBA，但在服用后，血浆和大脑中均检测到了 DHMBA。在实验 2 中，DHMBA 组的脑和海马 8-羟基-2'-脱氧鸟苷水平以及血浆皮质酮水平显著低于应激组。DHMBA 组的糖皮质激素受体-α 水平高于应激组。DHMBA增加了海马中抗氧化酶的RNA水平：结论：DHMBA在给药后被转运到大脑。结论：服用DHMBA后，DHMBA被转运到大脑，降低了大脑和海马中8-羟基-2'-脱氧鸟苷的水平，增加了海马糖皮质激素受体-α的水平，降低了血浆皮质酮的浓度，表明DHMBA抑制了HPA轴的过度活跃。DHMBA诱导的Nrf2通路活性增加了海马中抗氧化酶的水平。

{"title":"3,5-Dihydroxy-4-methoxybenzyl alcohol, a novel antioxidant isolated from oyster meat, inhibits the hypothalamus–pituitary–adrenal axis to regulate the stress response","authors":"Mitsugu Watanabe , Kenji Yoshiike , Emiko Miki , Katsuya Kuroki","doi":"10.1016/j.brainres.2024.149290","DOIUrl":"10.1016/j.brainres.2024.149290","url":null,"abstract":"<div><h3>Background</h3><div>Antioxidants that can scavenge reactive oxygen in the brain and inhibit hyperactivity of the HPA axis are desirable.</div></div><div><h3>Aims</h3><div>We investigated the cerebral translocation of the antioxidant 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) and the effects of DHMBA administration on the hypothalamus–pituitary–adrenal (HPA) axis in stress-loaded rats.</div></div><div><h3>Methods</h3><div>Experiment 1: Plasma and brain DHMBA concentrations were measured over time after oral DHMBA administration to male B6 mice. Experiment 2: Female Wistar Imamichi rats were used. The normal group was not subjected to stress. The stress, DHMBA, and vitamin E groups were subjected to individual and overcrowding stress. Brain and hippocampal 8-hydroxy-2′-deoxyguanosine levels, hippocampal glucocorticoid receptor-α levels, plasma corticosterone levels and RNA levels of glutathione peroxidase 4, catalase, and glutathione reductase in the hippocampus were measured.</div></div><div><h3>Results</h3><div>In Experiment 1, DHMBA was not detected in the plasma or brain before DHMBA administration but was detected in both after administration. In Experiment 2, brain and hippocampal 8-hydroxy-2′-deoxyguanosine levels and plasma corticosterone levels were significantly lower in the DHMBA than in the stress group. Glucocorticoid receptor-α levels were higher in the DHMBA than in the stress group. DHMBA increased RNA levels of antioxidant enzymes in the hippocampus. <em>Conclusion</em>: DHMBA was translocated to the brain after administration. DHMBA administration decreased 8-hydroxy-2′-deoxyguanosine levels in the brain and hippocampus, increased hippocampal glucocorticoid receptor-α levels, and decreased the plasma corticosterone concentration, suggesting that DHMBA inhibits hyperactivity of the HPA axis. Nrf2 pathway activity induced by DHMBA resulted in increased antioxidant enzyme levels in the hippocampus.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149290"},"PeriodicalIF":2.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aging of Krushinsky-Molodkina audiogenic rats is accompanied with pronounced neurodegeneration and dysfunction of the glutamatergic system in the hippocampus 克鲁辛斯基-莫洛金娜致听大鼠的衰老伴随着明显的神经变性和海马中谷氨酸能系统的功能障碍。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-24 DOI: 10.1016/j.brainres.2024.149294

Ekaterina P. Aleksandrova , Andrey P. Ivlev , Alexey A. Kulikov , Alexandra A. Naumova , Margarita V. Glazova , Elena V. Chernigovskaya

Advancing age strongly correlates with an increased risk of epilepsy development. On the other hand, epilepsy may exacerbate the negative effects of aging making it pathological. In turn, the possible link between aging and epileptogenesis is dysregulation of glutamatergic transmission. In the present study, we analyzed the functional state of the glutamatergic system in the hippocampus of aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats to disclose alterations associated with aging on the background of inherited predisposition to audiogenic seizures (AGS). Naïve KM rats with no AGS experience were recruited in the experiments. Wistar rats of the corresponding age were used as a control. First of all, aging KM rats demonstrated a significant decrease in cell population and synaptopodin expression in the hippocampus indicating enhanced loss of cells and synapses. Meanwhile, elevated phosphorylation of ERK1/2 and CREB and increased glutamate in the neuronal perikarya were revealed indicating increased activity of the rest hippocampal cells and increased glutamate production. However, glutamate in the fibers and synapses was mainly unchanged, and the proteins regulating glutamate exocytosis showed variable changes which could compensate each other and maintain glutamate release at the unchanged level. In addition, we revealed downregulation of NMDA-receptor subunit GluN2B and upregulation of AMPA-receptor GluA2 subunit, which could also prevent overexcitation and support cell survival in the hippocampus of aging KM rats. Nevertheless, abnormally high glutamate production, observed in aging KM rats, may provide the basis for hyperexcitability of the hippocampus and increased seizure susceptibility in old age.

年龄的增长与癫痫发病风险的增加密切相关。另一方面，癫痫可能会加剧衰老的负面影响，使其成为病态。反过来，衰老与癫痫发生之间的可能联系是谷氨酸能传导失调。在本研究中，我们分析了老龄（18 个月大）克鲁欣斯基-莫洛金娜（KM）致听性大鼠海马中谷氨酸能系统的功能状态，以揭示在遗传性致听性癫痫发作（AGS）易感性背景下与老龄相关的改变。实验招募了未经历过 AGS 的纯种 KM 大鼠。相应年龄的 Wistar 大鼠作为对照。首先，衰老的 KM 大鼠表现出海马细胞数量和突触素表达的显著减少，这表明细胞和突触的丢失加剧。同时，ERK1/2 和 CREB 磷酸化升高，神经元周围谷氨酸增加，这表明海马休止期细胞活动增加，谷氨酸分泌增加。然而，神经纤维和突触中的谷氨酸主要没有变化，调节谷氨酸外泌的蛋白质也出现了不同的变化，这些变化可以相互补偿，并将谷氨酸的释放维持在不变的水平。此外，我们还发现了 NMDA 受体亚基 GluN2B 的下调和 AMPA 受体亚基 GluA2 的上调，这也可以防止老化 KM 大鼠海马的过度兴奋并支持细胞存活。然而，在衰老的 KM 大鼠身上观察到的谷氨酸异常高分泌可能是老年海马过度兴奋和癫痫易感性增加的基础。

{"title":"Aging of Krushinsky-Molodkina audiogenic rats is accompanied with pronounced neurodegeneration and dysfunction of the glutamatergic system in the hippocampus","authors":"Ekaterina P. Aleksandrova , Andrey P. Ivlev , Alexey A. Kulikov , Alexandra A. Naumova , Margarita V. Glazova , Elena V. Chernigovskaya","doi":"10.1016/j.brainres.2024.149294","DOIUrl":"10.1016/j.brainres.2024.149294","url":null,"abstract":"<div><div>Advancing age strongly correlates with an increased risk of epilepsy development. On the other hand, epilepsy may exacerbate the negative effects of aging making it pathological. In turn, the possible link between aging and epileptogenesis is dysregulation of glutamatergic transmission. In the present study, we analyzed the functional state of the glutamatergic system in the hippocampus of aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats to disclose alterations associated with aging on the background of inherited predisposition to audiogenic seizures (AGS). Naïve KM rats with no AGS experience were recruited in the experiments. Wistar rats of the corresponding age were used as a control. First of all, aging KM rats demonstrated a significant decrease in cell population and synaptopodin expression in the hippocampus indicating enhanced loss of cells and synapses. Meanwhile, elevated phosphorylation of ERK1/2 and CREB and increased glutamate in the neuronal perikarya were revealed indicating increased activity of the rest hippocampal cells and increased glutamate production. However, glutamate in the fibers and synapses was mainly unchanged, and the proteins regulating glutamate exocytosis showed variable changes which could compensate each other and maintain glutamate release at the unchanged level. In addition, we revealed downregulation of NMDA-receptor subunit GluN2B and upregulation of AMPA-receptor GluA2 subunit, which could also prevent overexcitation and support cell survival in the hippocampus of aging KM rats. Nevertheless, abnormally high glutamate production, observed in aging KM rats, may provide the basis for hyperexcitability of the hippocampus and increased seizure susceptibility in old age.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149294"},"PeriodicalIF":2.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuritin attenuates neuroinflammation and apoptosis in early brain injury after subarachnoid hemorrhage via endoplasmic reticulum stress-related inflammatory pathways 神经营养素通过内质网应激相关炎症途径减轻蛛网膜下腔出血后早期脑损伤中的神经炎症和细胞凋亡。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-23 DOI: 10.1016/j.brainres.2024.149293

Kunhao Ren , Linzhi Dai , Hao Zhang , Yaowen He , Bin Liu , Youjie Hu , Ketao Ma , Weidong Tian , Dong Zhao

Neuroinflammation is a key destructive pathophysiological process in early brain injury (EBI) following subarachnoid hemorrhage (SAH). Recent studies have discovered that endoplasmic reticulum stress-related inflammatory pathways include the IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT −NF-κB pathway leading to neuroinflammatory response. Neuritin is a neurotrophin that is involved in neuronal plasticity and regeneration. Studies have suggested that Neuritin has a vital role in reducing neuroinflammation, and can also decrease the expression of proteins related to endoplasmic reticulum stress following SAH. This suggests that Neuritin could be a potential therapeutic target for SAH and other neurological conditions. However, the regulatory mechanisms of Neuritin in ER stress-related inflammatory pathways after SAH are not yet fully understood. In this work, we discovered that the activation of ER stress-related inflammatory pathways leads to neuroinflammation, which further aggravates neuronal apoptosis after SAH. Our findings indicate that Neuritin overexpression play a neuroprotective role by inhibiting IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT-NF-κB pathway associated with endoplasmic reticulum stress. These inhibitory effects on neuroinflammation ultimately reduce nerve cell apoptosis.

神经炎症是蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的一个关键破坏性病理生理过程。最新研究发现，内质网应激相关炎症通路包括 IRE1α-TRAF2-NF-κB 通路、PERK-eIF2α-NF-κB 通路和 ATF6-AKT -NF-κB 通路，这些通路导致神经炎症反应。Neuritin 是一种神经营养素，参与神经元的可塑性和再生。研究表明，Neuritin 在减少神经炎症方面发挥着重要作用，还能减少 SAH 后内质网应激相关蛋白的表达。这表明，Neuritin 可能是治疗 SAH 和其他神经疾病的潜在靶点。然而，Neuritin 在 SAH 后与 ER 应激相关的炎症通路中的调控机制尚未完全明了。在这项研究中，我们发现 ER 应激相关炎症通路的激活会导致神经炎症，而神经炎症会进一步加重 SAH 后神经元的凋亡。我们的研究结果表明，Neuritin过表达可抑制与内质网应激相关的IRE1α-TRAF2-NF-κB通路、PERK-eIF2α-NF-κB通路和ATF6-AKT-NF-κB通路，从而发挥神经保护作用。这些对神经炎症的抑制作用最终会减少神经细胞的凋亡。

{"title":"Neuritin attenuates neuroinflammation and apoptosis in early brain injury after subarachnoid hemorrhage via endoplasmic reticulum stress-related inflammatory pathways","authors":"Kunhao Ren , Linzhi Dai , Hao Zhang , Yaowen He , Bin Liu , Youjie Hu , Ketao Ma , Weidong Tian , Dong Zhao","doi":"10.1016/j.brainres.2024.149293","DOIUrl":"10.1016/j.brainres.2024.149293","url":null,"abstract":"<div><div>Neuroinflammation is a key destructive pathophysiological process in early brain injury (EBI) following subarachnoid hemorrhage (SAH). Recent studies have discovered that endoplasmic reticulum stress-related inflammatory pathways include the IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT −NF-κB pathway leading to neuroinflammatory response. Neuritin is a neurotrophin that is involved in neuronal plasticity and regeneration. Studies have suggested that Neuritin has a vital role in reducing neuroinflammation, and can also decrease the expression of proteins related to endoplasmic reticulum stress following SAH. This suggests that Neuritin could be a potential therapeutic target for SAH and other neurological conditions. However, the regulatory mechanisms of Neuritin in ER stress-related inflammatory pathways after SAH are not yet fully understood. In this work, we discovered that the activation of ER stress-related inflammatory pathways leads to neuroinflammation, which further aggravates neuronal apoptosis after SAH. Our findings indicate that Neuritin overexpression play a neuroprotective role by inhibiting IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT-NF-κB pathway associated with endoplasmic reticulum stress. These inhibitory effects on neuroinflammation ultimately reduce nerve cell apoptosis.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149293"},"PeriodicalIF":2.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quinic acid contributes to neurogenesis: Targeting Notch pathway a key player in hippocampus 奎宁酸有助于神经发生：以海马中的关键角色 Notch 通路为目标

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-22 DOI: 10.1016/j.brainres.2024.149291

Maryam Niaz , Kanwal Iftikhar , Maha Shahid , Shaheen Faizi , Shabana Usman Simjee

Coordinated proliferation and differentiation of neural stem cells (NSCs) results in continuous neurogenesis. The present study provides novel insights into the Notch intracellular signaling in neuronal cell proliferation, maintenance, migration, and differentiation regulated by naturally based Quinic acid (QA) in primary hippocampal cell culture. Further, this study might help in the discovery and development of lead molecules that can overcome the challenges in the treatment of neurodegenerative diseases. The growth supporting effect of QA was studied using Alamar Blue assay. The migratory potential of QA was evaluated using scratch assay. The in vitro H₂O₂-induced oxidative stress model was used to upregulate neuronal survival after QA treatment. The RT-qPCR and immunocytochemical analysis were performed for selected markers of Notch signaling to determine the proliferation, differentiation, and maintenance of NSCs at gene and molecular levels. The Mash1 and Ngn2 are the upstream proneural genes of the Notch pathway which were included to evaluate the differentiation of NSCs into mature neurons after treatment with QA.

Furthermore, regarding the role of QA in maintaining the pool of NPCs, we used Notch1 and Hes1 markers for proliferation analysis. Also, secondary neuronal markers i.e. Pax6, PCNA, and Mcm2 were included in this study and their gene expression analysis was analyzed following treatment with QA. Based on the study’s results, we suggest that naturally based QA can promote the growth and differentiation of neonatal NSCs residing in hippocampal regions into neuronal lineage. Therefore, we propose that the neurogenic potential of QA can be employed to prevent and treat neurodegenerative diseases.

神经干细胞（NSCs）的协调增殖和分化可导致持续的神经发生。本研究提供了关于天然奎尼酸（QA）在原代海马细胞培养中调控神经细胞增殖、维持、迁移和分化的细胞内Notch信号的新见解。此外，这项研究可能有助于发现和开发先导分子，从而克服治疗神经退行性疾病的难题。使用阿拉玛蓝检测法研究了 QA 的生长支持效应。划痕试验评估了 QA 的迁移潜力。体外 H2O2 诱导的氧化应激模型用于上调 QA 处理后神经元的存活率。对选定的 Notch 信号转导标记物进行 RT-qPCR 和免疫细胞化学分析，以确定 NSCs 在基因和分子水平上的增殖、分化和维持。其中，Mash1和Ngn2是Notch通路的上游朊病毒基因，它们被用于评估经QA处理后NSCs向成熟神经元的分化。此外，关于 QA 在维持 NPCs 池中的作用，我们使用 Notch1 和 Hes1 标记进行增殖分析。本研究还纳入了次要神经元标记，即 Pax6、PCNA 和 Mcm2，并分析了它们在 QA 处理后的基因表达分析。根据研究结果，我们认为天然 QA 可促进海马区新生儿神经干细胞的生长和分化，使其向神经元系分化。因此，我们建议利用 QA 的神经源潜力来预防和治疗神经退行性疾病。

{"title":"Quinic acid contributes to neurogenesis: Targeting Notch pathway a key player in hippocampus","authors":"Maryam Niaz , Kanwal Iftikhar , Maha Shahid , Shaheen Faizi , Shabana Usman Simjee","doi":"10.1016/j.brainres.2024.149291","DOIUrl":"10.1016/j.brainres.2024.149291","url":null,"abstract":"<div><div>Coordinated proliferation and differentiation of neural stem cells (NSCs) results in continuous neurogenesis. The present study provides novel insights into the Notch intracellular signaling in neuronal cell proliferation, maintenance, migration, and differentiation regulated by naturally based Quinic acid (QA) in primary hippocampal cell culture. Further, this study might help in the discovery and development of lead molecules that can overcome the challenges in the treatment of neurodegenerative diseases. The growth supporting effect of QA was studied using Alamar Blue assay. The migratory potential of QA was evaluated using scratch assay. The <em>in vitro</em> H<sub>2</sub>O<sub>2</sub>-induced oxidative stress model was used to upregulate neuronal survival after QA treatment. The RT-qPCR and immunocytochemical analysis were performed for selected markers of Notch signaling to determine the proliferation, differentiation, and maintenance of NSCs at gene and molecular levels. The Mash1 and Ngn2 are the upstream proneural genes of the Notch pathway which were included to evaluate the differentiation of NSCs into mature neurons after treatment with QA.</div><div>Furthermore, regarding the role of QA in maintaining the pool of NPCs, we used Notch1 and Hes1 markers for proliferation analysis. Also, secondary neuronal markers i.e. Pax6, PCNA<strong>,</strong> and Mcm2 were included in this study and their gene expression analysis was analyzed following treatment with QA. Based on the study’s results, we suggest that naturally based QA can promote the growth and differentiation of neonatal NSCs residing in hippocampal regions into neuronal lineage. Therefore, we propose that the neurogenic potential of QA can be employed to prevent and treat neurodegenerative diseases.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149291"},"PeriodicalIF":2.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In-depth investigation of the complex pathophysiological mechanisms between diabetes and ischemic stroke through gene expression and regulatory network analysis 通过基因表达和调控网络分析，深入研究糖尿病与缺血性中风之间复杂的病理生理机制。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-22 DOI: 10.1016/j.brainres.2024.149276

Ling Lin , Yuanxin Zhang , Fengshan Zeng , Chanyan Zhu , Chunmao Guo , Haixiong Huang , Hanna Jin , Huahua He , Shaolan Chen , Jinyan Zhou , Yao Chen , Yuqian Xu , Dongqi Li , Wenlin Yu

This study explores the intricate relationship between diabetes and ischemic stroke (IS) through gene expression analysis and regulatory network investigation to identify potential biomarkers and therapeutic targets. Using datasets from the Gene Expression Omnibus (GEO) database, differential gene analysis was conducted on GSE43950 (diabetes) and GSE16561 (IS), revealing overlapping differentially expressed genes (DEGs). Functional enrichment analysis, Protein-Protein Interaction (PPI) network construction, and hub gene identification were performed, followed by validation in independent datasets (GSE156035 and GSE58294). The analysis identified 307 upregulated and 156 downregulated overlapping DEGs with significant enrichment in GO and KEGG pathways. Key hub genes (TLR2, TLR4, HDAC1, ITGAM) were identified through a PPI network (257 nodes, 456 interactions), with their roles in immune and inflammatory responses highlighted through GeneMANIA analysis. TRRUST-based transcription factor enrichment analysis revealed regulatory links involving RELA, SPI1, STAT3, and SP1. Differential expression analysis confirmed that RELA and SPI1 were upregulated in diabetes, while SPI1, STAT3, and SP1 were linked to IS. These transcription factors are involved in regulating immunity and inflammation, providing insights into the molecular mechanisms underlying diabetes-IS comorbidity. This bioinformatics-driven approach offers new understanding of the gene interactions and pathways involved, paving the way for potential therapeutic targets.

本研究通过基因表达分析和调控网络调查探讨糖尿病与缺血性中风（IS）之间错综复杂的关系，以确定潜在的生物标记物和治疗靶点。利用基因表达总库（GEO）数据库中的数据集，对GSE43950（糖尿病）和GSE16561（IS）进行了差异基因分析，发现了重叠的差异表达基因（DEGs）。研究人员进行了功能富集分析、蛋白质-蛋白质相互作用（PPI）网络构建和中心基因鉴定，并在独立数据集（GSE156035 和 GSE58294）中进行了验证。分析发现了 307 个上调和 156 个下调的重叠 DEGs，这些 DEGs 在 GO 和 KEGG 通路中具有显著的富集性。通过 PPI 网络（257 个节点，456 个相互作用）确定了关键枢纽基因（TLR2、TLR4、HDAC1、ITGAM），并通过 GeneMANIA 分析强调了它们在免疫和炎症反应中的作用。基于 TRRUST 的转录因子富集分析揭示了涉及 RELA、SPI1、STAT3 和 SP1 的调控联系。差异表达分析证实，RELA 和 SPI1 在糖尿病中上调，而 SPI1、STAT3 和 SP1 则与 IS 有关。这些转录因子参与了免疫和炎症的调控，有助于深入了解糖尿病-IS并发症的分子机制。这种以生物信息学为驱动的方法使人们对相关基因的相互作用和通路有了新的认识，为潜在的治疗目标铺平了道路。

{"title":"In-depth investigation of the complex pathophysiological mechanisms between diabetes and ischemic stroke through gene expression and regulatory network analysis","authors":"Ling Lin , Yuanxin Zhang , Fengshan Zeng , Chanyan Zhu , Chunmao Guo , Haixiong Huang , Hanna Jin , Huahua He , Shaolan Chen , Jinyan Zhou , Yao Chen , Yuqian Xu , Dongqi Li , Wenlin Yu","doi":"10.1016/j.brainres.2024.149276","DOIUrl":"10.1016/j.brainres.2024.149276","url":null,"abstract":"<div><div>This study explores the intricate relationship between diabetes and ischemic stroke (IS) through gene expression analysis and regulatory network investigation to identify potential biomarkers and therapeutic targets. Using datasets from the Gene Expression Omnibus (GEO) database, differential gene analysis was conducted on GSE43950 (diabetes) and GSE16561 (IS), revealing overlapping differentially expressed genes (DEGs). Functional enrichment analysis, Protein-Protein Interaction (PPI) network construction, and hub gene identification were performed, followed by validation in independent datasets (GSE156035 and GSE58294). The analysis identified 307 upregulated and 156 downregulated overlapping DEGs with significant enrichment in GO and KEGG pathways. Key hub genes (TLR2, TLR4, HDAC1, ITGAM) were identified through a PPI network (257 nodes, 456 interactions), with their roles in immune and inflammatory responses highlighted through GeneMANIA analysis. TRRUST-based transcription factor enrichment analysis revealed regulatory links involving RELA, SPI1, STAT3, and SP1. Differential expression analysis confirmed that RELA and SPI1 were upregulated in diabetes, while SPI1, STAT3, and SP1 were linked to IS. These transcription factors are involved in regulating immunity and inflammation, providing insights into the molecular mechanisms underlying diabetes-IS comorbidity. This bioinformatics-driven approach offers new understanding of the gene interactions and pathways involved, paving the way for potential therapeutic targets.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149276"},"PeriodicalIF":2.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Variations of neuronal properties in the region of locus coeruleus of mice 小鼠脑区神经元特性的变化

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2024-10-22 DOI: 10.1016/j.brainres.2024.149289

Lucas Silva Tortorelli , Machhindra Garad , Marine Megemont , Sachiko Haga-Yamanaka , Anubhuti Goel , Hongdian Yang

Neurons in the locus coeruleus (LC) have been traditionally viewed as a homogenous population. Recent studies begin to reveal their heterogeneity at multiple levels, ranging from molecular compositions to projection targets. To further uncover variations of neuronal properties in the LC, we took a genetic-based tagging approach to identify these neurons. Our data revealed diverse spike waveforms among neurons in the LC region, including a considerable fraction of narrow-spiking units. While all wide-spiking units possessed the regular waveform polarity (negative-positive deflection), the narrow units can be further divided based on opposing waveform polarities. Under anesthesia, wide units emitted action potential at a higher rate than the narrow units. Under wakefulness, only one subtype of narrow units exhibited fast-spiking phenotype. These neurons also had long latencies to optogenetic stimulation. In-situ hybridization further supported the existence of a small population of putative GABAergic neurons in the LC core. Together, our data reveal characteristic differences among neurons in the LC region, and suggest that a fraction of electrophysiologically-identified narrow-spiking neurons can be fast-spiking interneurons, and their fast-spiking feature is masked by anesthesia.

传统上，人们一直将神经元视作同质群体。最近的研究开始从分子组成到投射目标等多个层面揭示其异质性。为了进一步揭示 LC 神经元特性的变化，我们采用了一种基于基因的标记方法来识别这些神经元。我们的数据揭示了 LC 区域神经元的不同尖峰波形，包括相当一部分窄尖峰单元。虽然所有的宽尖峰单元都具有规则的波形极性（负偏转-正偏转），但窄尖峰单元可根据相反的波形极性进一步划分。在麻醉状态下，宽单位比窄单位以更高的速率发出动作电位。在清醒状态下，只有一种亚型的窄单元表现出快速尖峰表型。这些神经元对光遗传刺激的潜伏期也较长。原位杂交进一步证实了LC核心存在一小部分假定的GABA能神经元。总之，我们的数据揭示了LC区域神经元之间的特征性差异，并表明一部分电生理鉴定的窄尖峰神经元可能是快速尖峰中间神经元，它们的快速尖峰特征会被麻醉所掩盖。

{"title":"Variations of neuronal properties in the region of locus coeruleus of mice","authors":"Lucas Silva Tortorelli , Machhindra Garad , Marine Megemont , Sachiko Haga-Yamanaka , Anubhuti Goel , Hongdian Yang","doi":"10.1016/j.brainres.2024.149289","DOIUrl":"10.1016/j.brainres.2024.149289","url":null,"abstract":"<div><div>Neurons in the locus coeruleus (LC) have been traditionally viewed as a homogenous population. Recent studies begin to reveal their heterogeneity at multiple levels, ranging from molecular compositions to projection targets. To further uncover variations of neuronal properties in the LC, we took a genetic-based tagging approach to identify these neurons. Our data revealed diverse spike waveforms among neurons in the LC region, including a considerable fraction of narrow-spiking units. While all wide-spiking units possessed the regular waveform polarity (negative-positive deflection), the narrow units can be further divided based on opposing waveform polarities. Under anesthesia, wide units emitted action potential at a higher rate than the narrow units. Under wakefulness, only one subtype of narrow units exhibited fast-spiking phenotype. These neurons also had long latencies to optogenetic stimulation. <em>In-situ</em> hybridization further supported the existence of a small population of putative GABAergic neurons in the LC core. Together, our data reveal characteristic differences among neurons in the LC region, and suggest that a fraction of electrophysiologically-identified narrow-spiking neurons can be fast-spiking interneurons, and their fast-spiking feature is masked by anesthesia.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149289"},"PeriodicalIF":2.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0